Photochemistry 2024

PHOTO CHEMISTRY

Version: IB8_3

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II

Empowering Peptide Innovation With this guiding theme in mind, Iris Biotech’s mission is to support researchers by supplying • innovative technologies, • rare compounds, • as well as a broad portfolio on standard consumables, available in flexible quantities from small scale to bulk quantities. To fulfill our dedication “Empowering Peptide Innovation”, we are attending various conferences, symposia, and exhibitions each year. This allows us to remain in direct contact with scientists all over the world, both from academia and industry, to exchange knowledge, and to gather new ideas to tackle your current challenges.

Guided by our dedication to provide • competent service, • as well as novel substances and • latest technologies, Iris Biotech is your trusted partner for the world of peptides, while having strong expertise in associated disciplines. Thus, our portfolio comprises reagents and tools for the synthesis and modification of peptides, e.g. amino acids, resins and solvents but also for related technologies such as Drug Delivery, Linkerology® and Life Sciences.

Amino Acids

Building Blocks

Life Sciences

Drug Delivery

Reagents

Resins

Linkerology®

Click Chemistry

Owed to the growing demand for tailor-made compounds, our portfolio is fine-tuned by our Custom Synthesis Service at Iris Biotech Laboratories. Our skilled scientists offer profound expertise in • de novo route development, • upscaling towards larger scale production, • as well as synthesis optimization for increased efficiency.

Examples are the synthesis of rare chiral building blocks, unnatural amino acid derivatives, sophisticated orthogonal protecting groups, heterocycles, building blocks for nucleotides, PEGs and PEG-analogues as well as specific linkers for controlled drug delivery and release.

Iris Biotech GmbH • Email: info@iris-biotech.de • www.iris-biotech.de • Empowering Peptide Innovation

III

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Portfolio Overview Peptide Synthesis and Modification

Linkerology® and Drug Delivery

(Protected) Amino Acids

Linkers for Solid Phase Peptide Synthesis

Standards such as Fmoc-D/L-AAA and Boc-D/L-AAA, Smoc amino acids for peptide synthesis in water, variety of protecting groups (e.g. Pbf, Trt, tBu, Bzl, Acm,

Cleavable Linkers Val-Ala based, Val-Cit based, disulfide-based, Dde-helping

Life Sciences

Biotinylation Reagents Carbohydrates Galactose, Glucose, Maltose, Mannose, Xylose and others

hands

Drug Metabolites

Photo-Activatable Linkers

Peptides

Functionalized Linkers

Substrates & Inhibitors

Building Blocks

Clickable linkers, trifunctional

E.g. protein kinase inhibitors,

Amino alcohols, amino aldehy-

linkers, linkers with maleimide

Mob, SIT, Phacm, Allocam, Mmt), unusual amino acids, fluorinated derivatives, substituted prolines, arginine analogues

des, diamines and hydrazines, (pseudoproline) dipeptides, polyamines and spermines, fatty acid derivatives Reagents Coupling reagents, solvents and scavengers, protecting groups Resins Preloaded resins (e.g. based on Trityl, TCP, TentaGel, Methoxybenzhydryl, Merrifield, PAM, Rink, Wang), scavenger resins, hydrazone resins

function, cross-linkers, selective N-term acylation and biotiny-

substrates for fusion (Halo/ Snap/Clip)-tagged proteins

lation

Natural Products

PROTACs

Dyes and Fluorescent Labels

Ligands, linkers & modules

E.g. ICG, AMC, DAPI

Fullerenes, Poly(2-oxazolines) & Dextrans

Maillard & Amadori Reaction Products

Poly-Amino Acids Poly-Arg, Poly-Glu, Poly-Lys, Poly-Orn, Poly-Sar PEGylation Branched PEGylating reagents, (amino-)PEG-acids, PEG-amines & hydrazides & guanidines, reagents for Click-conjugation, Biotin-PEG-reagents, PEG-thiols, PEG-maleimides, other PEGylating reagents

Large portfolio of derivatives useful as standards for food, pharma and cosmetics industry Vitamins

Custom Synthesis Your project requires a compound not listed in our portfolio?

Get in contact and inquire about our custom synthesis capabilities.

Our experienced scientists are excited to accept your synthetic challenge!

In such cases, your request undergoes the following stages:

search Step-by-Step Analysis

Process Evaluation

Strategy Development

Quality Consistency

• Customer’s demands

• Detailed literature review • Synthetic possibilities

• Protocol development • Method development and validation • Customized synthesis

• Identity confirmation • Purity verification

Our Service Promise All our services are based on high standards, transparency & documentation, trust, honesty & confidentiality, as well as the required know-how.

High Standards

Transparency & Documentation

• Values: sustainability & responsibility

• Talk to our specialists – customer care

• State-of-the-art equipment & latest

• Certificates of analysis & impurity profiling

technologies

• Analytical and process reports

• High quality standards • Qualified suppliers & regular audits

Trust, Honesty & Confidentiality

Our Know-How

• Intergenerational business valuing

• One-step reactions & complex

partnerships

multi-step synthesis

• Meeting the customer‘s expectations

• Scalability from mg to kg quantities

• Integrity towards our customers

• Route scouting

Iris Biotech GmbH • Email: info@iris-biotech.de • www.iris-biotech.de • Empowering Peptide Innovation

V

Table of contents

Photochemistry 1.

Photochemistry in Peptide Synthesis and Bioconjugation

1

2. Diazirine Amino Acids for Photo-Crosslinkage in Living Cells

2

3. Photo-Crosslinkers for Various Applications

6

3.1.

Photo-Crosslinkers

6

3.2.

Tetrafluorophenyl-Azide-based Photo-Crosslinkers

10

4. Photoactivated Self-Cleaving Linkers and Protecting Groups via Trimethyl Lock

12

5. Furfuryl-Alanine for Side Chain Modification and Bioconjugation

14

6. Photocaged Amino Acid Building Blocks

16

7.

21

Photoswitches

8. Photocleavable Auxiliary Reagent for Native Chemical Ligation

23

9.

25

Photo-Linker for Solid Phase Synthesis of Peptide Amides and Acids

10. Related Products 10.1.

10.2.

27

Fmoc-Phe-Aca – a Cell Internalization Reporter, and further Fluorescent Amino Acid Derivatives

27

Building Blocks for the SPPS of FRET-based fluorogenic protease substrates

33

Code of Conduct

35

Terms and Conditions of Sales

37

Index

41

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VII

Photochemistry

1. Photochemistry . in Peptide Synthesis and Bioconjugation The term photochemistry describes a group of chemical transformations initiated by irradiation with light. Photochemical reactions usually occur at room temperature and normal pressure, and mostly do not require additional reagents or catalysts, with the notable exception of some cases where the presence of a photosensitizer is necessary. Therefore, photochemical transformations are usually orthogonal to classical chemical transformations, a characteristic that renders them a valuable tool for chemists.

Consequently, the applications of photochemistry are numerous. Orthogonality is a trait often sought for in protecting groups and linkers, as it allows for their selective cleavage. Furthermore, photocleavage is a convenient method for selective removal of auxiliaries after their function has been served. The typical moiety that is incorporated into protecting groups, linkers and auxiliaries to facilitate light-induced cleavage is an o-nitrobenzyl group, which undergoes a Norrish-type II reaction upon UV-irradiation.

Another common application of photochemistry is the labeling or crosslinking of biomolecules in vitro and in vivo. The latter is of particular interest as a photochemical reaction is one of the few chemical transformations that can be selectively initiated in living cells.

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1

.

Do you require different photoactivated compounds?

Inquire with our Custom Synthesis service and download our booklet.

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2. Diazirine .

Amino Acids for Photo-Crosslinkage in Living Cells Iris Biotech introduces a comprehensive set of photo-crosslinking amino acids bearing the diazirine moiety. Irradiation of diazirines with UV light (ca. 350 nm – 360 nm) yields a

CO2H H2N

Leu

Photo-Leu

N N

highly reactive carbene species that can undergo insertions into C-C, CH, O-H and X-H (X = heteroatom) bonds of neigh-

CO2H H2N

boring molecules to irreversibly form a covalent bond. The diazirine moiety is the smallest of all photophores, so intro-

CO2H H 2N

CO2H H 2N

Photo-Met

Met

duction of a diazirine-bearing amino acid into a peptide or

N

S

N

protein usually does not impair its biological activity. Further CO2H

advantages of diazirine crosslinkers are their stability at

H2N

room temperature, as well as their relative stability to

CO2H H 2N

Photo-Lys

Lys

nucleophiles, and to both acidic and basic conditions.

O NH2

Applications:

HN O

• Probing protein–protein and protein- peptide interac-

CO2H

Pro

CO2H

HN

tions by photo-crosslinking (e.g. site-specific incorpora-

protein in E. coli) • Probing protein- peptide interactions in order to identify

N CO2H

Phe

H 2N

N

Photo-Pro

HN

tion of Photo-Lys into glutathione S-transferase allowing covalent crosslinking of the two subunits of the dimeric

N

N

CO2H

Photo-Phe

H 2N

cellular targets of peptides of interest • Studying protein−drug interactions and identifying new drug targets By comparing results obtained from different proteomic setups (e.g. live cells and cell lysates), more putative targets can be identified.

CF3

N N

Fig. 1: Diazirine amino acids and their natural counterparts.

These amino acids are available in Fmoc- as well as Boc-protected versions for their incorporation into synthetic peptides via standard coupling methods. Furthermore, the unprotected diazirine amino acids are also available for incorporation into expressed peptides and proteins by utilizing the appropriate aminoacyl-tRNA synthetase/tRNA pair. A combination of synthetic and recombinant approaches utilizing NCL has been demonstrated as well. Unnatural amino acids are frequently toxic to cells; however, these photo-amino acids are functional and nontoxic, which allows them to be a premium tool for studying mechanisms and interactions in living cells.

N N

N

R

N

Sar-R-V-Y-V-H-P-F

Sar-R-V-Y-V-H-P-F

125

125I

I

Internalization

R

R

Sar-R-V-Y-V-H-P-F UV irradiation

125

I

noncovalent binding

covalent bound

Live Cell

Live Cell

Fig. 2: Use of photo-phenylalanine for the identification of angiotensin-II-receptor binding sites; 125 I is used as a radiotracer.

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2

Photochemistry Product details

HAA3100

H-L-Photo-Leucine*HCl

(S)-2-amino-3-(3-methyl-3H-diazirin-3-yl)propanoic acid hydrochloride CAS-No. Formula Mol. weight

851960-91-3 C 5H9N3 O 2*HCl 143,14*36,45 g/mol

BAA3070

Boc-L-Photo-Leucine*DCHA

(S)-2-(tert-butoxycarbonylamino)-3-(3-methyl-3H-diazirin-3-yl)propanoic acid dicyclohexylamine CAS-No. Formula Mol. weight

1000770-97-7 net C10 H17N3 O4*C12H23N 243,26*181,34 g/mol

FAA4590

Fmoc-L-Photo-Leucine

O H2N

(S)

OH

N

N

O

H N

O

(S)

OH

O N

N

(S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(3-methyl-3H-diazirin-3-yl)propanoic acid CAS-No. Formula Mol. weight

1360651-24-6 C 20 H19N3 O4 365,38 g/mol

HAA3110

H-L-Photo-Lysine*HCl

(S)-2-amino-6-((2-(3-methyl-3H-diazirin-3-yl)ethoxy) carbonylamino)hexanoic acid hydrochloride CAS-No. Formula Mol. weight

1253643-88-7 C11H20 N4O4*HCl 272,30*36,45 g/mol

N

O H2N

HN

OH

(S)

O N

N

Fmoc-L-Photo-Lysine

CAS-No. Formula Mol. weight

2250437-42-2 C 26H30 N4O 6 494,54 g/mol

BAA3080

Boc-L-Photo-Lysine

(S)-2-(tert-butoxycarbonylamino)-6-((2-(3-methyl-3Hdiazirin-3-yl)ethoxy)carbonylamino)hexanoic acid 1330088-06-6 C16H28N4O 6 372,42 g/mol

O

H N

O

OH

(S)

O

HN

O N

O

H N

O

N

O (S)

OH

O

HN

O O

3

OH

N

(S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-6((2-(3-methyl-3H-diazirin-3-yl)ethoxy)carbonylamino) hexanoic acid

CAS-No. Formula Mol. weight

(S)

O

O

FAA4600

O

H N

O

N

N

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Product details

HAA3120

H-L-Photo-Methionine*HCl

(S)-2-amino-4-(3-methyl-3H-diazirin-3-yl)butanoic acid hydrochloride CAS-No. Formula Mol. weight

851960-68-4 net C 6H11N3 O 2*HCl 157,17*36,45 g/mol

BAA3090

Boc-L-Photo-Methionine*DCHA

O H2N

1002754-75-7 net C11H19N3 O4*C12H23N 257,29*181,34 g/mol

FAA4610

Fmoc-L-Photo-Methionine

N

945859-89-2 C 21H21N3 O4 379,41 g/mol

HAA3490

H-L-Photo-Phe-OH

4-(trifluoromethyldiazirin)-L-phenylalanine CAS-No. Formula Mol. weight

92367-16-3 C11H10 F3N3 O 2 273,21 g/mol

O

H N

O

(S)

N N

FAA5690

OH

O N N

O (S)

H2N

OH

N N F

F

92367-17-4 C16H18F3N3 O4 373,33 g/mol

O H N

O

(S)

OH

O N N F

F

F

Fmoc-L-Photo-Phe-OH

N-alpha-(9-Fluorenylmethyloxycarbonyl)-4-(trifluoromethyldiazirin)-L-phenylalanine CAS-No. Formula Mol. weight

(S)

Boc-L-Photo-Phe-OH

N-alpha-(t-Butyloxycarbonyl)-4-(trifluoromethyldiazirin)-L-phenylalanine CAS-No. Formula Mol. weight

O

H N

O

F

BAA1530

OH

O

(S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-(3-methyl-3H-diazirin-3-yl)butanoic acid CAS-No. Formula Mol. weight

OH

N

(S)-2-(tert-butoxycarbonylamino)-4-(3-methyl-3H-diazirin-3-yl)butanoic acid dicyclohexylamine CAS-No. Formula Mol. weight

(S)

133342-64-0 C 26H20 F3N3 O4 495,45 g/mol

O H N

O

(S)

OH

O N N F

F

F

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4

Photochemistry Product details

HAA3130

H-L-Photo-Proline*HCl

(S)-1,2,5-triazaspiro[2.4]hept-1-ene-6-carboxylic acid CAS-No. Formula Mol. weight

1675206-55-9 C 5H7N3 O 2*HCl 141,13*36,45 g/mol

N

HN

N

(S)

OH

O

BAA3100

Boc-L-Photo-Proline

(S)-5-(tert-butoxycarbonyl)-1,2,5-triazaspiro[2.4]hept-1ene-6-carboxylic acid CAS-No. Formula Mol. weight

1266778-55-5 C10 H15N3 O4 241,24 g/mol

FAA4620

Fmoc-L-Photo-Proline

N

O

N O

(S)

OH

O

(S)-5-(((9H-fluoren-9-yl)methoxy)carbonyl)-1,2,5-triazaspiro[2.4]hept-1-ene-6-carboxylic acid CAS-No. Formula Mol. weight

1266778-58-8 C 20 H17N3 O4 363,37 g/mol

N

N

O

N O

O

N

(S)

OH

References: → Protein-polymer conjugation via ligand affinity and photoactivation of glutathione S-transferase; E. W. Lin, N. Boehnke, H. D. Maynard; Bioconjug Chem 2014; 25: 1902-9. https://doi.org/10.1021/bc500380r → Cell-based proteome profiling of potential dasatinib targets by use of affinity-based probes; H. Shi, C. J. Zhang, G. Y. Chen, S. Q. Yao; J Am Chem Soc 2012; 134: 3001-14. https://doi.org/10.1021/ja208518u → Probing protein-protein interactions with a genetically encoded photo-crosslinking amino acid; H. W. Ai, W. Shen, A. Sagi, P. R. Chen, P. G. Schultz; Chembiochem 2011; 12: 1854-7. https://doi.org/10.1002/cbic.201100194 → Proteome profiling reveals potential cellular targets of staurosporine using a clickable cell-permeable probe; H. Shi, X. Cheng, S. K. Sze, S. Q. Yao; Chem Commun (Camb) 2011; 47: 11306-8. https://doi.org/10.1039/c1cc14824a → Aliphatic diazirines as photoaffinity probes for proteins: recent developments; J. Das; Chem Rev 2011; 111: 4405-17. https://doi.org/10.1021/cr1002722 → Photo-crosslinking of proteins in intact cells reveals a dimeric structure of cyclooxygenase-2 and an inhibitor-sensitive oligomeric structure of microsomal prostaglandin E2 synthase-1; P. O. Hetu, M. Ouellet, J. P. Falgueyret, C. Ramachandran, J. Robichaud, R. Zamboni, D. Riendeau; Arch. Biochem. Biophys. 2008; 477: 155-62. https://doi.org/10.1016/j.abb.2008.04.038 → Covalent capture of phospho-dependent protein oligomerization by site-specific incorporation of a diazirine photo-cross-linker; M. Vila-Perello, M. R. Pratt, F. Tulin, T. W. Muir; J Am Chem Soc 2007; 129: 8068-9. https://doi.org/10.1021/ja072013j → Photo-leucine incorporation reveals the target of a cyclodepsipeptide inhibitor of cotranslational translocation; A. L. MacKinnon, J. L. Garrison, R. S. Hegde, J. Taunton; J Am Chem Soc 2007; 129: 14560-1. https://doi.org/10.1021/ja076250y → Synthesis of photoactive analogues of a cystine knot trypsin inhibitor protein; T. Durek, J. Zhang, C. He, S. B. Kent; Org Lett 2007; 9: 5497-500. https://doi.org/10.1021/ol702461z → Photo-leucine and photo-methionine allow identification of protein-protein interactions in living cells; M. Suchanek, A. Radzikowska, C. Thiele; Nat Methods 2005; 2: 261-7. https://doi.org/10.1038/nmeth752

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3. Photo-Crosslinkers . for Various Applications Many photo-crosslinkers for photoaffinity labeling rely on benzophenone as the crosslinking agent.

However, these types of crosslinkers usually show low crosslinking yields and require relatively long irradiation times due to slow reaction rates, which may lead to non-specific labeling. Moreover, the irradiation conditions for benzophenones have been shown to lead to cell damage and cell death.

Conversely, diazirine- and perfluorophenyl-based crosslinkers generate a reactive species (carbene and nitrene, respectively) upon relatively short irradiation with UV light. Consequently, diazirine- and perfluorophenyl-crosslinkers are commonly used in molecular biology and biochemistry.

N3 F

F

F

R1

O

N C

N

R2

F R

hν 260 nm - N2 N F

hν 350 - 360 nm - N2 R1

F

hν 350 nm

O C R2

F

F R

Fig. 3: Three types of photophores: Perfluorophenyl azides, diazirines and benzophenones.

3.1. Photo-Crosslinkers Diazirine-bearing crosslinkers are activated at wavelengths that cause little to no damage to cells. In addition to this, trifluoromethylaryl diazirines show a fast initial reaction rate and rapid termination of reaction. Consequently, they exhibit a highly ligand-dependent reactivity, which renders them ideal probes for ligand binding to low-affinity targets, e.g. for probing carbohydrate-lectin interactions.

Moreover, the small size of the diazirine group minimizes the risk of impairing or altering the biological activity of a ligand. Our diazirine crosslinkers are functionalized to react with either carboxyl- or aminereactive ligands, respectively.

Another application of diazirine photo crosslinkers is the surface immobilization of molecules of interest. The linker is bound to a surface through its carboxyl or amino functionality, leaving the diazirine group free to react with any type of molecule. Since this reaction takes place irrespective of available functional groups, it is not necessary to chemically modify molecules of interest prior to immobilization.

This virtually ensures that molecules are immobilized without altering their binding properties. By using this approach, it is possible to easily create microarrays of whole libraries of small molecules for rapid screening.

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6

Photochemistry

N

R

N

R = H or Tfm

potential binder

R

Aryl- / alkyl-spacer

Aryl- / alkyl-spacer

potential binder UV irradiation

N2

Surface

Surface

Fig. 4: Immobilization of molecules of interest on a surface (e.g. a glass slide) using a diazirine crosslinker.

N

N

Aryl- / alkyl-spacer R2

R1

coupling to amine- or carboxy-reactive probe N

N

Aryl- / alkyl-spacer R

Probe

2

N2

UV irradiation

R2

Aryl- / alkyl-spacer Target

Probe

R1 = COOH or CH2NH2 R2 = H or Tfm

Fig. 5: Photoaffinity labeling of a target molecule by a diazirine-functionalized binding probe.

Product details

RL-2890

Photo-Pentanoic acid

3-(3-methyl-3H-diazirin-3-yl)propanoic acid CAS-No. Formula Mol. weight

O

25055-86-1 C 5H8N2O 2 128,13 g/mol

OH N

RL-2900

Photo-Hexanoic acid

4-(3-methyl-3H-diazirin-3-yl)butanoic acid CAS-No. Formula Mol. weight

7

N

16297-97-5 C 6H10 N2O 2 142,16 g/mol

N

N

O OH

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Product details

RL-3410

Photo-Click-Heptanoic acid

2-(3-(but-3-ynyl)-3H-diazirin-3-yl)acetic acid CAS-No. Formula Mol. weight

2049109-24-0 C 7H 8 N2 O 2 152,15 g/mol

RL-3740

Photo-Palmitic acid

N

2100292-41-7 C16H30 N2O 2 282,43 g/mol

RL-3720

Photo-Click-Palmitic acid

O OH N

N

11-(3-(but-3-yn-1-yl)-3H-diazirin-3-yl)undecanoic acid Formula Mol. weight

C16H26N2O 2 278,40 g/mol

RL-3750

Photo-Stearic acid

O OH N

N

11-(3-hexyl-3H-diazirin-3-yl)undecanoic acid CAS-No. Formula Mol. weight

1704120-02-4 C18H34N2O 2 310,48 g/mol

RL-3760

Photo-Click-Stearic acid

O OH N

13-(3-(but-3-yn-1-yl)-3H-diazirin-3-yl)tridecanoic acid Formula Mol. weight

C18H30 N2O 2 306,45 g/mol

RL-2920

Photo-Benzoic acid

4-[3-(Trifluoromethyl)-3H-diazirin-3-yl]benzoic acid CAS-No. Formula Mol. weight

85559-46-2 C9H5F3N2O 2 230,14 g/mol

O OH

9-(3-hexyl-3H-diazirin-3-yl)nonanoic acid CAS-No. Formula Mol. weight

N

N

O OH N

N F3C

N

N

O

OH

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8

Photochemistry Product details

RL-2910

Photo-Butylamine

NH2

2-(3-methyl-3H-diazirin-3-yl)ethan-1-amine hydrochloride CAS-No. Formula Mol. weight

25055-95-2 C 4H9N3*HCl 99,13*36,45 g/mol

RL-2930

Photo-Benzylamine*HCl

4-[3-(Trifluoromethyl)-3H-diazirin-3-yl]benzylamine hydrochloride CAS-No. Formula Mol. weight

1258874-29-1 C9H 8N3F3*HCl 215,18*36,45 g/mol

N

N

N

N

NH2

F3C

References: Reviews: → Hide and seek: Identification and confirmation of small molecule protein targets; A. Ursu, H. Waldmann; Bioorg Med Chem Lett 2015; 25: 3079-86. https://doi.org/10.1016/j.bmcl.2015.06.023 → Development and leading-edge application of innovative photoaffinity labeling; Y. Hatanaka; Chem Pharm Bull (Tokyo) 2015; 63: 1-12. https://doi.org/10.1248/cpb.c14-00645 → Diazirine based photoaffinity labeling; L. Dubinsky, B. P. Krom, M. M. Meijler; Bioorg Med Chem 2012; 20: 554-70. https://doi.org/10.1016/j.bmc.2011.06.066 → Aliphatic diazirines as photoaffinity probes for proteins: recent developments; J. Das; Chem Rev 2011; 111: 4405-17. https://doi.org/10.1021/cr1002722 → Recent Progress in Diazirine-Based Photoaffinity Labeling; M. Hashimoto, Y. Hatanaka; Eur. J. Org. Chem.

2008; 2008: 2513-2523. https://doi.org/10.1002/ejoc.200701069 → Endeavors to make the photophore, diazirine easy to use; Y. Sadakane; Yakugaku Zasshi 2007; 127: 1693-9. https://doi.org/10.1248/yakushi.127.1693 Photoaffinity labeling: → Comparison of the reactivity of carbohydrate photoaffinity probes with different photoreactive groups; K. Sakurai, S. Ozawa, R. Yamada, T. Yasui, S. Mizuno; Chembiochem 2014; 15: 1399-403. https://doi.org/10.1002/cbic.201402051 → Identification of a substrate-binding site in a peroxisomal beta-oxidation enzyme by photoaffinity labeling with a novel palmitoyl derivative; Y. Kashiwayama, T. Tomohiro, K. Narita, M. Suzumura, T. Glumoff, J. K. Hiltunen, P. P. Van Veldhoven, Y. Hatanaka, T. Imanaka; J Biol Chem 2010; 285: 26315-25. https://doi.org/10.1074/jbc.M110.104547 → Developing photoactive affinity probes for proteomic profiling: hydroxamate-based probes for metalloproteases; E. W. Chan, S. Chattopadhaya, R. C. Panicker, X. Huang, S. Q. Yao; J Am Chem Soc 2004; 126: 14435-46. https://doi.org/10.1021/ja047044i → Insecticidal and neural activities of candidate photoaffinity probes for neonicotinoid binding sites; K. Matsuda, M. Ihara, K. Nishimura, D. B. Sattelle, K. Komai; Biosci Biotechnol Biochem 2001; 65: 1534-41. https://doi.org/10.1271/bbb.65.1534 → Synthesis of Photoactive α-Mannosides and Mannosyl Peptides and Their Evaluation for Lectin Labeling; M. Wiegand, T. K. Lindhorst; Eur. J. Org. Chem. 2006; 2006: 4841-4851. https://doi.org/10.1002/ejoc.200600449

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Photoaffinity microarray: → A study on photolinkers used for biomolecule attachment to polymer surfaces; D. M. Dankbar, G. Gauglitz; Anal Bioanal Chem 2006; 386: 1967-74. https://doi.org/10.1007/s00216-006-0871-x → SPR imaging of photo-cross-linked small-molecule arrays on gold; N. Kanoh, M. Kyo, K. Inamori, A. Ando, A. Asami, A. Nakao, H. Osada; Anal Chem 2006; 78: 2226-30. https://doi.org/10.1021/ac051777j → Grafting Organic and Biomolecules on H-Terminated Porous Silicon from a Diazirine; S. Wei, J. Wang, D.-J. Guo, Y.-Q. Chen, S.-J. Xiao; Chem. Lett. 2006; 35: 1172-1173. https://doi.org/10.1246/cl.2006.1172 → Immobilization of natural products on glass slides by using a photoaffinity reaction and the detection of protein-small-molecule interactions; N. Kanoh, S. Kumashiro, S. Simizu, Y. Kondoh, S. Hatakeyama, H. Tashiro, H. Osada; Angew. Chem. Int. Ed. 2003; 42: 5584-7. https://doi.org/10.1002/anie.200352164

3.2. Tetrafluorophenyl-Azide-based Photo-Crosslinkers Tetrafluorophenyl-azides follow a principle similar to diazirines. Upon irradiation with UV light (ca. 260 nm), a highly stabilized nitrene is formed. Nitrenes are the nitrogen analogs of carbenes (isoelectronic) and react in a comparable fashion. In terms of crosslinking yield and duration of irradiation, they compare favorably to benzophenones. Moreover, the azido group can also undergo classical copper-catalyzed azide-alkyne cycloadditions. Tetrafluorophenyl-azido crosslinkers are also available with a short PEG-spacer for increased solubility (PEG5000), and as Biotin-TEG-ATFBA (PEG2065) for applications such as surface functionalization with biotin, or the biotinylation of biomacromolecules.

Fig. 6: Applications of Tetrafluorophenyl-azides.

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Photochemistry Product details

RL-2035

ATFB -N

4-Azido-2,3,5,6-tetrafluorobenzoic acid CAS-No. Formula Mol. weight

F

F

N+

122590-77-6 C 7HF4N3 O 2 235,1 g/mol

O

N OH F

RL-2045

ATFB-NHS

N-Succinimidyl 4-azido-2,3,5,6-tetrafluorobenzoate CAS-No. Formula Mol. weight

F

-

N

F

F

N+

126695-58-7 C11H4F4N4O4 332,17 g/mol

O

O

O

N

N F

F O

PEG2065

Biotin-TEG-ATFBA

Biotin-triethylenglycol-(p-azido-tetrafluorobenzamide) CAS-No. Formula Mol. weight

1264662-85-2 C 27H37F4N7 O 6 S 663,68 g/mol

PEG5000

N3 -TFBA-O2Oc

{2-[2-(4-Azido-2,3,5,6-tetrafluorobenzoyl-amino)ethoxy] ethoxy}acetic acid CAS-No. Formula Mol. weight

1993119-45-1 C13H12F4N4O 5 380,25 g/mol

O

O

O

NH

HN

N H

S

O

O

O

F F

N H F

N3 F

-N

F

F

N+

O

N

O

O

HN F

F

OH O

References: → Tri- and Tetravalent Photoactivable Cross-Linking Agents; A. Welle, F. Billard, J. Marchand-Brynaert; Synthesis 2012; 44: 2249-2254. https://doi.org/doi:10.1055/s-0031-1290444 → Perfluorophenyl azides: new applications in surface functionalization and nanomaterial synthesis; L. H. Liu, M. Yan; Acc Chem Res 2010; 43: 1434-43. https://doi.org/10.1021/ar100066t → Photo-click immobilization of carbohydrates on polymeric surfaces--a quick method to functionalize surfaces for biomolecular recognition studies; O. Norberg, L. Deng, M. Yan, O. Ramstrom; Bioconjug Chem 2009; 20: 2364-70. https://doi.org/10.1021/bc9003519 → Photoreactive insulin derivatives for the detection of the doubly labeled insulin receptor; J. Kleinjung, M. Fabry; Peptides 2000; 21: 401-6. https://doi.org/10.1016/S0196-9781(00)00164-9 → Recent Trends in the Evaluation of Photochemical Insertion Characteristics of Heterobifunctional Perfluoroaryl Azide Chelating Agents: Biochemical Implications in Nuclear Medicine; R. S. Pandurangi, S. R. Karra, R. R. Kuntz, W. A. Volkert; Photochem. Photobiol. 1997; 65: 208-221. https://doi.org/10.1111/j.1751-1097.1997.tb08547.x

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4. Photoactivated .

Self-Cleaving Linkers and Protecting Groups via Trimethyl Lock Iris Biotech introduces a series of self-immolative compounds that find application as protecting groups, linkers, or amino acid derivatives (Spr = stimulus-responsive peptide bond cleaving residue). The selfcleavage is induced by irradiation with UV light (ca. 350 – 365 nm) that leads to the unmasking of a hydroxyl group of a 2-alkyl-3,5-dimethyl phenol moiety. The photocleavable group is either o-nitrobenzyl or o-nitroveratryl, which can be cleaved at wavelengths > 350 nm. Since wavelengths above 350 nm tend to be unproblematic for biomacromolecules, this technique is especially interesting for cell-based systems.

The liberated OH-group serves as a nucleophile that intramolecularly cleaves ester (or amide) bonds at neutral pH and room temperature by cyclization via a six-membered transition state. This reaction is greatly accelerated since the sterically unfavorable interaction between the methyl group at the 3-position of the phenol core and the two geminal CH3 -groups on the alkyl chain (in β-position to the ester or amide carbonyl group) favor conformations that bring the phenolic OH-group and the neighboring carbonyl function into closer vicinity. This phenomenon is termed the gem-dialkyl effect, for which a theory was first proposed by Thorpe and Ingold in 1915 (“Thorpe-Ingold effect”). An alternative explanation for this effect was posited by Bruice and Pandit in 1960 (“reactive rotamer effect”).

O R2

O X O

R1 PG

R2

X

R1

hν

H

OH

X

R1

PG O R2

phenol core

sterically unfavorable interaction

O

Fig. 7: Principle of photoactivated trimethyl lock; PG = o-nitrobenzyl or o-nitroveratryl; X = O or NH; R1–XH = target molecule; R2 = H or NH-alkyl.

The applications for this approach are numerous. Incorporation of a Spr-residue into a peptide sequence enables the photoactivated self-cleavage of the peptide at the position of said residue.

This technique allows for the intracellular removal of e.g. cell penetrating peptides or localization sequences from a bioactive molecule. The Spr-residue can also be used as a photolabile linker in order to reversibly connect a moiety such as biotin to a molecule of interest. Finally, while o-nitroveratryl itself is a valuable protecting group for sulfhydryl groups, the combination of o-Nv with a trimethyl lock moiety also allows for its use as a protecting group for hydroxyl and amino functions.

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Photochemistry Product details

FAA7190

Fmoc-Spr(oNB)-OH

N-alpha-(9-Fluorenylmethyloxycarbonyl)-beta,beta-dimethyl-(2,4-dimethyl-6-(2-nitrobenzyloxy)phenyl) alanine (rac.)

CAS-No. Formula Mol. weight

1032400-98-8 C 35H34N2O 7 594,66 g/mol

FAA7200

Fmoc-Spr(oNv)-OH

1228829-20-6 C 36H36N2O 9 640,68 g/mol

RL-2970

Photo-Trimethyl-Lock

O NO2

2095134-25-9 C 22H27NO 7 417,45 g/mol

O

H N

O

OH

O

MeO

O

MeO NO2

3-(2-Nitroveratryl-4,6-dimethylphenyl)-3-methylbutyric acid CAS-No. Formula Mol. weight

OH

O

N-alpha-(9-Fluorenylmethyloxycarbonyl)-beta,beta-dimethyl-(2-methyl-6-(2-nitroveratryl)phenyl)alanine (rac.)

CAS-No. Formula Mol. weight

O

H N

O

NO2 O

O

MeO

OH OMe

References: → Invention of stimulus-responsive peptide-bond-cleaving residue (Spr) and its application to chemical biology tools; A. Shigenaga, J. Yamamoto, T. Kohiki, T. Inokuma, A. Otaka; J. Pept. Sci. 2017; 23: 505-513. https://doi.org/10.1002/psc.2961 → Syntheses and kinetic studies of cyclisation-based self-immolative spacers; S. Huvelle, A. Alouane, T. Le Saux, L. Jullien, F. Schmidt; Org Biomol Chem 2017; 15: 3435-3443. https://doi.org/10.1039/c7ob00121e → Photo-triggered fluorescent labelling of recombinant proteins in live cells; D. Jung, K. Sato, K. Min, A. Shigenaga, J. Jung, A. Otaka, Y. Kwon; Chem Commun (Camb) 2015; 51: 9670-3. https://doi.org/10.1039/c5cc01067e → Trimethyl lock: A trigger for molecular release in chemistry, biology, and pharmacology; M. N. Levine, R. T. Raines; Chem. Sci. 2012; 3: 2412-2420. https://doi.org/10.1039/C2SC20536J → Design and synthesis of caged ceramide: UV-responsive ceramide releasing system based on UV-induced amide bond cleavage followed by O–N acyl transfer; A. Shigenaga, H. Hirakawa, J. Yamamoto, K. Ogura, M. Denda, K. Yamaguchi, D. Tsuji, K. Itoh, A. Otaka; Tetrahedron 2011; 67: 3984-3990. https://doi.org/10.1016/j.tet.2011.04.048 → Development and photo-responsive peptide bond cleavage reaction of two-photon near-infrared excitationresponsive peptide; A. Shigenaga, J. Yamamoto, Y. Sumikawa, T. Furuta, A. Otaka; Tetrahedron Lett. 2010; 51: 2868-2871. https://doi.org/10.1016/j.tetlet.2010.03.079 → gem-disubstituent effect: theoretical basis and synthetic applications; M. E. Jung, G. Piizzi; Chem Rev 2005; 105: 1735-66. https://doi.org/10.1021/cr940337h → The Effect of Geminal Substitution Ring Size and Rotamer Distribution on the Intramolecular Nucleophilic Catalysis of the Hydrolysis of Monophenyl Esters of Dibasic Acids and the Solvolysis of the Intermediate Anhydrides; T. C. Bruice, U. K. Pandit; J. Am. Chem. Soc. 1960; 82: 5858-5865. https://doi.org/10.1021/ja01507a023 → CXIX.—The formation and stability of spiro-compounds. Part I. spiro-Compounds from cyclohexane; R. M. Beesley, C. K. Ingold, J. F. Thorpe; J. Chem. Soc., Trans. 1915; 107: 1080-1106. https://doi.org/10.1039/ct9150701080

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5. Furfuryl-Alanine . for Side Chain Modification and Bioconjugation 2-Furyl-alanine can be incorporated into peptides via SPPS or by using enzymatic approaches. UV-irradiation in the presence of oxygen and a photosensitizer converts furyl-alanine to an intermediate that selectively reacts with certain nucleophiles. This property can be employed for site-specific labeling of peptides and proteins.

Labeling with different tags and reporter groups is a pivotal technique for the elucidation of peptide and protein function.

A novel and innovative approach is the site-specific labeling using the unnatural amino acid 2-furylalanine. UV-irradiation in the presence of oxygen and a photosensitizer converts furyl-alanine to an unsaturated dicarbonyl compound. This intermediate selectively reacts with certain nucleophiles such as hydrazine derivatives of dyes or fluorescent labels. This reaction can be used for the site-specific labeling of peptides and proteins and can be carried out in aqueous solution.

H2N

Peptide

COOH

hν, O2, H2O photosensitizer

H2N

H2N-NH

Peptide

H2N

COOH

Peptide

COOH

O

O

O

H2N-NH

hν, O2, H2O O

photosensitizer

O

O

Fig. 8: Site-specific labeling of peptides and proteins using 2-Furyl-alanine.

Iris Biotech offers Fmoc-L-Ala(2-Furyl)-OH suitable for SPPS, as well as H-L-Ala(2-Furyl)-OH which can be incorporated into proteins using the amber suppression methodology.

Product details

HAA2930

H-L-Ala(2-Furyl)-OH

3-(2-Furyl)-L-alanine CAS-No. Mol. weight

O

127682-08-0 155,15 g/mol

H2N

OH

(S)

O

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Photochemistry Product details

FAA4250

Fmoc-L-Ala(2-Furyl)-OH

N-alpha-(9-Fluorenylmethyloxycarbonyl)-3-(2-furyl)-L-alanine CAS-No. Formula Mol. weight

159611-02-6 C 22H19NO 5 377,39 g/mol

H N

O

O OH

(S)

O O

References: → Novel furan-oxidation based site-specific conjugation methodology for peptide labeling and antibody drug conjugates; presented at the 6th World ADC meeting October 19 th-22nd 2015, San Diego, CA; An Van Den Bulcke, Eirini Antonatou, Willem Vannecke, Kurt Hoogewijs, Annemieke Madder. → Exploiting furan‘s versatile reactivity in reversible and irreversible orthogonal peptide labeling; K. Hoogewijs, D. Buyst, J. M. Winne, J. C. Martins, A. Madder; Chem Commun (Camb) 2013; 49: 2927-9. https://doi.org/10.1039/c3cc40588e → Sequence specific DNA cross-linking triggered by visible light; M. Op de Beeck, A. Madder; J Am Chem Soc 2012; 134: 10737-40. https://doi.org/10.1021/ja301901p → Unprecedented C-selective interstrand cross-linking through in situ oxidation of furan-modified oligodeoxynucleotides; M. Op de Beeck, A. Madder; J Am Chem Soc 2011; 133: 796-807. https://doi.org/10.1021/ja1048169 → Furan-modified oligonucleotides for fast, high-yielding and site-selective DNA inter-strand cross-linking with non-modified complements; K. Stevens, A. Madder; Nucleic Acids Res 2009; 37: 1555-65. https://doi.org/10.1093/nar/gkn1077 → From DNA cross-linking to peptide labeling: on the versatility of the furan-oxidation-conjugation strategy; A. Deceuninck, A. Madder; Chem Commun (Camb) 2009; 340-2. https://doi.org/10.1039/b817447d → Bioorthogonal chemistry: fishing for selectivity in a sea of functionality; E. M. Sletten,C. R. Bertozzi; Angew. Chem. Int. Ed. 2009; 48: 6974-98. https://doi.org/10.1002/anie.200900942 → Structural basis of furan-amino acid recognition by a polyspecific aminoacyl-tRNA-synthetase and its genetic encoding in human cells; M. J. Schmidt, A. Weber, M. Pott, W. Welte, D. Summerer; Chembiochem 2014; 15: 1755-60. https://doi.org/10.1002/cbic.201402006 → Red-light-controlled protein-RNA crosslinking with a genetically encoded furan; M. J. Schmidt, D. Summerer; Angew. Chem. Int. Ed. 2013; 52: 4690-3. https://doi.org/10.1002/anie.201300754

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6. Photocaged .

Amino Acid Building Blocks Photocaged amino acids offer a mild and selective way to deprotect reactive side-chain functional groups such as amines or thiols, thus adding another level of orthogonality to the peptide chemist’s toolbox. Photolabile protecting groups (PGs) are frequently based on the ortho-nitrobenzyl moiety or variations thereof. Upon irradiation with UV light, such nitrobenzyl-based PGs undergo a Norrish type II reaction, liberating the protected functional group.

A common modification to the ortho-nitrobenzyl motif is the addition of two methoxy groups to the phenyl ring. The resulting ortho-nitroveratryl (oNv) group is compatible with SPPS protocols and can be cleaved by irradiation with UV light (350 nm) under ambient conditions.

One possible application of the oNv PG is the regiospecific formation of disulfide bonds. When combined with S-pyridinesulfenyl activation by employing Fmoc-L-Cys(Npys)-OH (FAA1975), the Fmoc-L-Cys(oNv)-OH (FAA3970) building block allows for a rapid in situ SS-bond formation. The versatility of this approach was demonstrated by applying it in the synthesis of a number of model peptides such as oxytocin, alpha-conotoxin ImI, and human insulin.

O FmocHN

O FmocHN

OH

OH

OMe

S O2N

S

S

OMe

N

O2N SPPS

Peptide AcmS

MeO MeO

S

S

S

NO2

SAcm N

O2N hν

Peptide AcmS

SH

S S

SAcm N

O2N

Peptide AcmS

S

S

SAcm

Fig. 9: Selective deprotection of 2-nitroveratryl in the presence of other cysteine protecting groups, and subsequent disulfide bond formation with an Npys-functionalized cysteine.

The oNv group can also be employed to protect the side chain of lysine if it is used as the corresponding oxycarbonyl derivative, abbreviated Nvoc (o-nitroveratryloxycarbonyl). The corresponding building block Fmoc-L-Lys(Nvoc)-OH (FAA7230) is available at Iris Biotech. Additionally, o-nitroveratryl may be used as a solubilizing tag on the alpha-amino group of glycine for internal solubilization, which can be cleaved by photolysis (350 nm) under ambient conditions.

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Photochemistry Another variation of the o-nitrobenzyl motif is the nitrodibenzofuran (NDBF) group that has an additional benzofuran ring system fused to the existing phenyl ring. NDBF is a one- and two-photon sensitive protecting group for cysteine. Analogous to the oNv group, NDBF can also be used to protect the epsilon amino group of lysine in the form of the corresponding oxycarbonyl derivative NDBFOC. Both Fmoc-LCys(NDBF)-OH (FAA8420) and Fmoc-L-Lys(NDBFOC)-OH (FAA8425) are available at Iris Biotech as readyto-use building blocks for peptide synthesis. Selective deprotection by photolysis is achieved either by irradiation with UV light (365 nm), or by two-photon excitation with near-infrared (800 nm) light.

The latter aspect renders this derivative particularly useful for biological applications in live cells or intact organisms due to the increased penetration depth of NIR light, as well as its biocompatibility. In addition, this cage exhibits a faster UV photolysis rate relative to simple nitroveratryl derivatives. An example showed that NDBF is photolyzed 16–160 times more efficiently than other nitrobenzyl PPGs. Further variations include the dimethoxynitrobenzyl group, as well as the methyl-o-nitropiperonyl group, which are used to protect selenocysteine and cysteine, respectively.

Product details

FAA3970

Fmoc-L-Cys(oNv)-OH

N-alpha-(9-Fluorenylmethyloxycarbonyl)-S-(2-nitroveratryl)-L-cysteine CAS-No. Formula Mol. weight

214633-71-3 C 27H26N2O 8 S 538,57 g/mol

FAA1975

Fmoc-L-Cys(Npys)-OH

N-alpha-(9-Fluorenylmethyloxycarbonyl)-S-(3-nitro-2-pyridylthio)-L-cysteine CAS-No. Formula Mol. weight

159700-51-3 C 23H19N3 O 6 S 2 497,54 g/mol

FAA7230

Fmoc-L-Lys(Nvoc)-OH

N-alpha-(9-Fluorenylmethyloxycarbonyl)-N-epsilon-(o-nitroveratryloxycarbonyl)-L-lysine CAS-No. Formula Mol. weight

150571-28-1 C 31H33N3 O 10 607,61 g/mol

O

H N

O

OH

(R)

O

OMe

S O2N

O

H N

O

S

17

N

S

O2N

H N

O

O (S)

OH

O

OMe OMe O

HN

NO2

Fmoc-L-Cys(NDBF)-OH

N-alpha-(9-Fluorenylmethyloxycarbonyl)-S-(1-(3-nitro-dibenzofuran-2-yl)-ethyl)-L-cysteine CAS-No. Formula Mol. weight

OH

(R)

O

O

FAA8420

OMe

1895883-28-9 C 32H26N2O 7S 582,62 g/mol

O HN

O

O OH S

O

NO2

Iris Biotech GmbH • Email: info@iris-biotech.de • www.iris-biotech.de • Empowering Peptide Innovation

Product details

FAA8425

Fmoc-L-Lys(NDBFOC)-OH

N-alpha-(9-Fluorenylmethyloxycarbonyl)-N-epsilon-(1-(3-nitro-dibenzofuran-2-yl)-ethoxycarbonyl)-L-lysine Formula Mol. weight

O

O

HN

O OH

C 36H33N3 O 9 651,66 g/mol

O HN

O O

HAA9360

H-L-Sec(MDNPE)-OH

Se-(Methyl-o-nitropiperonyl)-selenocysteine CAS-No. Formula Mol. weight

NO2

O2N

2235373-47-2 C12H14N2O 6 Se 361,21 g/mol

O

H3C

O Se (R)

OH

H2N O

HAA9255

H-L-Sec(DMNB)-OH*TFA

Dimethoxynitrobenzyl selenocysteine TFA salt CAS-No. Formula Mol. weight

O2N

1644398-13-9 C12H16N2O 6 Se*CF3 COOH 363,24*114,02 g/mol

O

O Se OH

H2N O

HAA9320

H-L-Cys(DMNB)-OH

S-(4,5-dimethoxy-2-nitrobenzyl)-L-cysteine CAS-No. Formula Mol. weight

O2N

214633-68-8 C12H16N2O 6 S 316,33 g/mol

O

O S OH

H2N O

HAA9270

H-L-Cys(MDNPE)-OH

1-[4‘,5‘-(methylenedioxy)-2‘-nitrophenyl]ethyl]-L-cysteine CAS-No. Formula Mol. weight

1551078-43-3 C12H14N2O 6 S 314,31 g/mol

O N

O

O O

S

H2N

OH

(R)

O

FAA7945

Fmoc-L-Cys(MDNPE)-OH

N-(((9H-fluoren-9-yl)methoxy)carbonyl)-S-(1-(6-nitrobenzo[d][1,3]dioxol-5-yl)ethyl)-L-cysteine Formula Mol. weight

C 27H24N2O 8 S 536,56 g/mol

O2N

O O

S

O O

N H

OH

(R)

O

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18

Photochemistry Product details

FAA8870

Fmoc-L-hCys(oNv)-OH

N-alpha-(9-Fluorenylmethyloxycarbonyl)-S-(2-nitroveratryl)-L-homocysteine Formula Mol. weight

O H N

O

C 28H28N2O 8 S 552,60 g/mol

(S)

OH

O S O2N

OMe OMe

FAA7350

Fmoc-N(oNv)-Gly-OH

N-alpha (9-Fluorenylmethyloxycarbonyl)-N-alpha-(o-nitroveratryl)-glycine CAS-No. Formula Mol. weight

850859-64-2 C 26H24N2O 8 492,48 g/mol

FAA7200

Fmoc-Spr(oNv)-OH

MeO MeO

NO2 O O

1228829-20-6 C 36H36N2O 9 640,68 g/mol

HAA9465

H-L-Sec(oNB)-OH*HCl

O

H N

O

OH

O

MeO

O

MeO NO2

(R)-2-amino-3-((2-nitrobenzyl)selanyl)propanoic acid CAS-No. Formula Mol. weight

OH

O

N-alpha-(9-Fluorenylmethyloxycarbonyl)-beta,beta-dimethyl-(2-methyl-6-(2-nitroveratryl)phenyl)alanine (rac.)

CAS-No. Formula Mol. weight

N

O O

324582-23-2 net C10 H12N2O4 Se*HCl 303,18*36,46 g/mol

N

Se

H2N

OH

(R)

O

HAA9475

H-L-Sec(NPE)-OH*HCl

(2R)-2-amino-3-((1-(2-nitrophenyl)ethyl)selanyl)propanoic acid Formula Mol. weight

O O

C11H14N2O4 Se*HCl 317,02*36,46 g/mol

N

Se

H2N

OH

(R)

O

References: → Total chemical synthesis of photoactivatable proteins for light-controlled manipulation of antigen– antibody interactions; S. Tang, Z. Wan, Y. Gao, J.-S. Zheng, J. Wang, Y.-Y. Si, X. Chen, H. Qi, L. Liu, W. Liu; Chem. Sci. 2016; 7: 1891-1895. https://doi.org/10.1039/C5SC03404C → 2-Nitroveratryl as a Photocleavable Thiol-Protecting Group for Directed Disulfide Bond Formation in the Chemical Synthesis of Insulin; J. A. Karas, D. B. Scanlon, B. E. Forbes, I. Vetter, R. J. Lewis, J. Gardiner, F. Separovic, J. D. Wade, M. A. Hossain; Chemistry 2014; 20: 9549-9552. https://doi.org/10.1002/chem.201403574

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→ Synthesis, stability and optimized photolytic cleavage of 4-methoxy-2-nitrobenzyl backbone-protected peptides; E. C. B. Johnson, S. B. H. Kent; Chem. Commun. 2006; 1557-1559. https://doi.org/10.1039/B600304D → A red shifted two-photon-only caging group for three-dimensional photorelease. Y. Becker, E. Unger, M. A. H. Fichte, D. A. Gacek, A. Dreuw, J. Wachtveitl, P. J. Walla, A. Heckel; Chem. Sci. 2018; 9: 2797-2902. https://doi.org/10.1039/c7sc05182d → Nitrodibenzofuran: A One- and Two-Photon Sensitive Protecting Group That Is Superior to Brominated Hydroxycoumarin for Thiol Caging in Peptides. M. M. Mahmoodi, D. Abate-Pella, T. J. Pundsack, C. C. Palsuledesai, P. C. Goff, D. A. Blank, M. D. Distefano; J. Am. Chem. Soc. 2016; 138: 5848-5859. https://doi.org/10.1021/jacs.5b11759 → The nitrodibenzofuran chromophore: a new caging group for ulta-efficient photolysis in living cells.

A. Momotake, N. Lindegger, E. Niggli, R. J. Barsotti, G. C. R. Ellis-Davies; Nat. Methods 2006; 3: 35-40. https://doi.org/10.1038/NMETH821 → Methoxy-Substituted Nitrodibenzofuran-Based Protecting Group with an Improved Two-Photon Action Cross-Section for Thiol Protection in Solid Phase Peptide Synthesis. T. K. Bader, F. Xu, M. H. Hodny, D. A. Blank, M. D. Distefano; J. Org. Chem. 2020; 85: 1614-1625. https://doi.org/10.1021/acs.joc.9b02751. → Genetic Encoding of Photocaged Cysteine Allows Photoactivation of TEV Protease in Live Mammalian Cells; D. P. Nguyen, M. Mahesh, S. J. Elsässer, S. M. Hancock, C. Uttamapinant, J. W. Chin; J. Am. Chem. Soc. 2014; 136(6): 2240-2243. https://doi.org/10.1021/ja412191m → Biosynthetic selenoproteins with genetically-encoded photocaged selenocysteines; R. Rakauskaité, G. Urbanavičiūtė, A. Rukšėnaitė, Z. Liutkevičiūtė, R. Juškėnas, V. Masevičiusab, S. Klimašauskas; Chem.

Commun. 2015; 51: 8245-8248. https://doi.org/10.1039/C4CC07910H

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Photochemistry

7. Photoswitches .

Photoswitches are a subtype of molecular switch that undergo a reversible structural change upon irradiation with light to adopt a different configuration. Activation of a molecular switch by light offers several advantages. In addition to being traceless, light can be precisely controlled in its intensity (dosage control) and can be focused with sub-micron accuracy with a high temporal and spatial resolution. Consequently, photoswitches ideally lend themselves to the construction of light-responsive pharmaceutical compounds, a field that is described by the term photopharmacology.

The most common motif that is used in this approach is the azobenzene moiety, owing to the large geometrical change that results from adopting a different configuration. Azobenzene-based photoresponsive systems have also been successfully applied in several biological systems. The azobenzene moiety is synthetically accessible via various pathways (Mills reaction, oxidative/reductive coupling, azo coupling), and its photochromic properties can easily be finetuned. The thermodynamically more stable trans isomer adopts an extended planar configuration with a dipole moment close to zero, while the higher energy, metastable cis isomer is more polar and exhibits unfavorable steric interactions.

H N

O (S)

O

H N

N H

UV

O (S)

O

N H

Vis or Δ N

N

N

N

1.0 nm

1.7 nm

Fig. 10: Interconversion between the trans and cis isomers of the diazobenzene motif in a photoswitchable peptide.

An additional benefit of the azobenzene motif is its high degree of reversibility. It can undergo approximately 100 switching cycles without detectable photodegradation or loss of responsiveness. However, although the trans isomer can be regenerated 100% by thermal relaxation, full conversion of one or the other isomer by irradiation with visible light is impossible owing to a substantial overlap of the absorption spectra of both isomers.

Product details

HAA3710

H-L-Phe(4-N=NPh)-OH*HCl

4-Phenylazo-L-phenylalanine hydrochloride CAS-No. Formula Mol. weight

21

2137036-84-9 C15H15N3 O 2*HCl 269,30*36,45 g/mol

O H2N

(S)

OH

N N

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Product details

BAA1660

Boc-L-Phe(4-N=NPh)-OH

N-alpha-t-Butyloxycarbonyl-4-phenylazo-L-phenylalanine CAS-No. Formula Mol. weight

134816-33-4 C 20 H23N3 O4 369,41 g/mol

FAA7010

Fmoc-L-Phe(4-N=NPh)-OH

H N

O

210366-26-0 C 30 H25N3 O4 491,54 g/mol

FAA9180

Fmoc-AMPB-OH

N N

H N

O

159790-79-1 C 29H23N3 O4 477,52 g/mol

O (S)

OH

O

N N

4-(4-(9-Fluorenylmethoxycarbonylaminomethyl)-phenyldiazenyl)benzoic acid CAS-No. Formula Mol. weight

OH

O

N-alpha-(9-Fluorenylmethyloxycarbonyl)-4-phenylazo-L-phenylalanine CAS-No. Formula Mol. weight

O (S)

O OH N

N

H N

O O

References: → Photopharmacology and Photochemical Biology; A. Deiters, S. Kossatz, O. Vázquez; ChemPhotoChem 2021; 5: 1031-1032. https://doi.org/10.1002/cptc.202100216 → Photoswitchable peptides for spatiotemporal control of biological functions; L. Albert, O. Vazquez; Chem Commun (Camb) 2019; 55: 10192-10213. https://doi.org/10.1039/c9cc03346g → In Vivo Photopharmacology; K. Hull, J. Morstein, D. Trauner; Chem Rev 2018; 118: 10710-10747. https://doi.org/10.1021/acs.chemrev.8b00037 → Photopharmacological control of bipolar cells restores visual function in blind mice; L. Laprell, I. Tochitsky, K. Kaur, M. B. Manookin, M. Stein, D. M. Barber, C. Schon, S. Michalakis, M. Biel, R. H. Kramer, M. P. Sumser, D. Trauner, R. N. Van Gelder; J Clin Invest 2017; 127: 2598-2611. https://doi.org/10.1172/JCI92156 → Emerging Targets in Photopharmacology; M. M. Lerch, M. J. Hansen, G. M. van Dam, W. Szymanski, B. L. Feringa; Angew. Chem. Int. Ed. 2016; 55: 10978-99. https://doi.org/10.1002/anie.201601931 → Genetically encoding photoswitchable click amino acids in Escherichia coli and mammalian cells; C. Hoppmann, V. K. Lacey, G. V. Louie, J. Wei, J. P. Noel, L. Wang; Angew. Chem. Int. Ed. 2014; 53: 3932-6. https://doi.org/10.1002/anie.201400001 → Reversible photocontrol of biological systems by the incorporation of molecular photoswitches; W. Szymanski, J. M. Beierle, H. A. Kistemaker, W. A. Velema, B. L. Feringa; Chem Rev 2013; 113: 6114-78. https://doi.org/10.1021/cr300179f → Photoisomerization in different classes of azobenzene; H. M. Bandara, S. C. Burdette; Chem Soc Rev 2012; 41: 1809-25. https://doi.org/10.1039/c1cs15179g → Azobenzene photoswitches for biomolecules; A. A. Beharry, G. A. Woolley; Chem Soc Rev 2011; 40: 4422-37. https://doi.org/10.1039/c1cs15023e → Properties of the pyramidal tract neuron system within the precentral wrist and hand area of primate motor cortex; D. R. Humphrey, W. S. Corrie, R. Rietz; J Physiol (Paris) 1978; 74: 215-26. https://doi.org/10.1016/j.isci.2021.102771

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Photochemistry

8.

Photocleavable .

Auxiliary Reagent for Native Chemical Ligation Native Chemical Ligation is one of the most powerful tools for the preparation of complex peptides and small proteins. However, the classical variant of NCL requires an N-terminal cysteine at the ligation site. Iris Biotech presents an innovative auxiliary reagent for NCL that can be incorporated in place of a glycine residue.

Since glycine usually occurs several times in a peptide sequence, this approach significantly increases variability regarding the choice of possible ligation sites. In Native Chemical Ligation, the auxiliary’s SH-group mimics the action of an N-terminal cysteine’s sulfhydryl group.

Fig. 11: Native Chemical Ligation utilizing the photocleavable NCL-auxiliary glycine building block (PAA2000).

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Following SPPS, the auxiliary is attached to the N-terminus of a peptide sequence in lieu of a glycine residue. The auxiliary’s Fmoc-protected amino functionality can subsequently be deprotected and functionalized, e.g. with a monodisperse PEG. PEGylation is useful for increasing the solubility of peptide fragments, and for facilitating their purification by precipitation with EtOH/Et 2O. These properties are especially valuable if the peptide’s amino acid side chains are supposed to be further derivatized postSPPS, for example by enzymatic glycosylation. Following NCL, the auxiliary can be conveniently removed by irradiation with UV-light (10 min in water or water/acetonitrile). This method is particularly useful for the synthesis of sophisticated peptides such as glycopeptides, where cost- and labor-intensive short sequences can be prepared separately, and subsequently conjugated to long fragments synthesized in a standard manner.

Product details

PAA2000

tBu-SS-Photo(Fmoc)-Gly-OH

Photocleavable-NCL-auxiliary-Gly-OH CAS-No. Formula Mol. weight

1994388-93-0 C 36H44N4O 9 S 2 740,89 g/mol

S

H N

S

O OH NO2

MeO

O O

N H

H N

O O

Reference: → A PEGylated photocleavable auxiliary mediates the sequential enzymatic glycosylation and native chemical ligation of peptides; C. Bello, S. Wang, L. Meng, K. W. Moremen, C. F. Becker; Angew. Chem. Int. Ed. 2015; 54: 7711-5. https://doi.org/10.1002/anie.201501517

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Photochemistry

9. Photo-Linker . for Solid Phase Synthesis of Peptide Amides and Acids Peptide linkers are usually cleaved under acidic conditions or using two-step procedures. Photocleavage proceeds under neutral conditions using UV light and can either be performed in batch or using flow chemistry.

hν

P

E

P

T

P

I

E

D

P

Linker

E

T

I

D

Resin

E

Fig. 12: Cleavage of photolabile linkers.

Furthermore, photolabile linkers are orthogonal to standard peptide chemistry reaction conditions, thus enabling the use of a wide variety of amino acid protecting groups.

Three different photolabile linkers are available for your convenience:

Photo-linker for the synthesis of C-terminal carboxylic acids Product details

RL-2150

Acid-Photo-Linker

4-(4-(1-hydroxyethyl)-2-methoxy-5-nitrophenoxy) butanoic acid CAS-No. Formula Mol. weight

25

175281-76-2 C13H17NO 7 299,28 g/mol

O2N O O HO

OH OMe

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Fmoc-amino photo-linker for the synthesis of peptide amides Product details

RL-1026

Fmoc-Photo-Linker

4-{4-[1-(9-Fluorenylmethyloxycarbonylamino)ethyl]-2methoxy-5-nitrophenoxy}butanoic acid CAS-No. Formula Mol. weight

162827-98-7 C 28H28N2O 8 520,56 g/mol

BR-5205

Fmoc-Photolabile Resin

O2N O O

O NH

OH

O

OMe

4-{4-[1-(Fmoc-amino)-ethyl]-2-methoxy-5-nitrophenoxy}butanamide polystyrene

O Me

O NH

O HN

Me

NO2 O

References: → Continuous photochemical cleavage of linkers for solid-phase synthesis; M. Hurevich, J. Kandasamy, B. M. Ponnappa, M. Collot, D. Kopetzki, D. T. McQuade, P. H. Seeberger; Org Lett 2014; 16: 1794-7. https://doi.org/10.1021/ol500530q → Photolytic Mass Laddering for Fast Characterization of Oligomers on Single Resin Beads; K. Burgess, C. I. Martinez, D. H. Russell, H. Shin, A. J. Zhang; J. Org. Chem. 1997; 62: 5662-5663. https://doi.org/10.1021/jo970866w → Direct Monitoring of Organic Reactions on Polymeric Supports; M. R. Carrasco, M. C. Fitzgerald, Y. Oda, S. B. H. Kent; Tetrahedron Lett. 1997; 38: 6331-6334. https://doi.org/10.1016/s0040-4039(97)01456-1

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26

Photochemistry

10. Related .

Products 10.1. Fmoc-Phe-Aca – a Cell Internalization Reporter, and further Fluorescent Amino Acid Derivatives The Fmoc-L-Phe-Aca pseudo-dipeptide is a useful reporter group for the successful internalization of CPPs. Phe quenches the fluorescence of Aca. Internalization of the peptide containing Phe-Aca leads to proteolytic cleavage of the Phe-Aca bond and thus to fluorescence.

The unnatural amino acid Aca (7-amino-coumarin-4-acetic acid) is a coumarin derivative and thus exhibits fluorescence. When incorporated into a peptide C-terminally of phenylalanine, Aca is a useful reporter group for the successful internalization of CPPs. The phenyl moiety of Phe quenches the fluorescence of Aca. Internalization of the CPP containing Phe-Aca leads to proteolytic cleavage of the Phe-Aca bond and thus to fluorescence.

However, the peptide bond formation between Phe and Aca is considered to be a difficult coupling and often leads to low coupling yields. For your convenience, Iris Biotech offers Fmoc Phe-Aca as building block suitable for SPPS. This pseudodipeptide can be coupled to the resin of your choice and subsequently elongated to prepare your target cell penetrating peptides.

O OH O

H N

O

Solid Support N H

O

O

O

O

Loading

X

H N

O

X = O or N

O N H

O

O

O

O

SPPS

O OH

H 2N

CPP

H N

O N H

O

O

OH

Cell Internalization and Proteolytic Cleavage H 2N

O

O

Quenching

Fig. 13: Loading of a solid support, subsequent elongation to CPPs and function as a reporter group for successful CPP internalization.

27

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In addition to Fmoc-L-Phe-Aca-OH, we offer various 7-amino-4-methylcoumarin (AMC)-functionalized amino acid derivatives. Like Aca, when bound to a peptide, the AMC-amide fluoresces very weakly and excitation/emission wavelengths are shorter (ca. 330/390 nm). When the free AMC-amine is released by proteolytic cleavage, the fluorescence increases by a factor of approx. 700 and excitation and emission wavelengths are red-shifted. Thus, the low fluorescence of the AMC-amide substrate does not interfere with the fluorometric assay. Besides, Iris Biotech offers dipeptide recognition motifs such as Phe-Arg (ZAA1480) or Arg-Arg (ZAA1470) as fluorogenic 7-amido-4-methylcoumarin based protease substrates.

The acetic acid derivative of AMC, 7-amino-4-methyl coumarin-3-acetic acid (AMCA) emits in the blue region (440-460 nm) upon activation with UV light of 350 nm.

Further fluorescent amino acids include those functionalized with acridine derivatives (2-Acd and 2-Bacd).

Coumarin Derivatives Product details

BAA3650

Boc-L-Lys-AMC*AcOH

N-alpha-t-Butyloxycarbonyl-L-lysine 7-amido-4-methylcoumarin acetate CAS-No. Formula Mol. weight

O H N

O

116883-12-6 net C 21H29N3 O 5*CH3 CO 2H 403,47*60,05

(S)

N H

O

O

O

NH2

FDP1240

Fmoc-L-Phe-Aca-OH

7-[N-alpha-(9-Fluorenylmethyloxycarbonyl)-L-phenylalaninyl-amido]-coumarin-4-acetic acid CAS-No. Formula Mol. weight

2250437-40-0 C 35H28N2O 7 588,61 g/mol

HAA1200

H-L-Ala-AMC

O OH

77471-41-1 C13H14N2O 3 246,27 g/mol

HAA7760

H-L-Thr-AMC

H N

O

(S)

O

L-Alanine-7-amido-4-methylcoumarin CAS-No. Formula Mol. weight

O

H N

H2N

N H

O

O

O

O

O

O

O

L-Threonine 7-amido-4-methylcoumarin, 98% CAS-No. Formula Mol. weight

191723-66-7 C14H16N2O4 276,29 g/mol

O H2N

(S)

N H

HO

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Photochemistry Product details

HAA1174

H-L-Ala-AMC*TFA

L-Alanine 7-amido-4-methylcoumarin trifluoroacetate CAS-No. Formula Mol. weight

96594-10-4 C13H14N2O 3*CF3 CO 2H 360,29 g/mol

HAA7630

H-L-Arg-AMC*2HCl

O H2N

O

N H

O

L-Arginine 7-amido-4-methylcoumarin dihydrochloride CAS-No. Formula Mol. weight

O

113712-08-6 C16H21N 5O 3*2HCl 331,37*72,90 g/mol

H2N

N H

(S)

O

N H

HAA7645

O

NH NH2

Glt-Gly-Arg-AMC.HCl

Glutaryl-glycyl-L-arginine 7-amido-4-methylcoumarin hydrochloride CAS-No. Formula Mol. weight

103213-40-7 C 23H30 ClN 6O 7*HCl 502,53*36,46 g/mol

HAA3200

H-L-Leu-AMC

H N

O

H N

HO O

N H

O

NH2

HCl

NH H N

(S)

O

O

O

(Z)

L-Leucine-7-amido-4-methylcoumarine CAS-No. Formula Mol. weight

66447-31-2 C16H20 N2O 3 288,34 g/mol

HAA7740

H-L-Pyr-AMC

O H2N

N H

(S)

O

O

L-Pyroglutamic acid 7-amido-4-methylcoumarin CAS-No. Formula Mol. weight

66642-36-2 C15H14N2O4 286,29 g/mol

HAA2890

H-L-Asp(AMC)-OH

L-Aspartic acid beta-(7-amido-4-methylcoumarin) CAS-No. Formula Mol. weight

29

133628-73-6 C14H14N2O 5 290,27 g/mol

O H N

(S)

N H

O

O

O H2N

(S)

OH O

HN

O

O

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O

Product details

HAA7971

H-Gly-AMC

Glycine 7-amido-4-methylcoumarin CAS-No. Formula Mol. weight

77471-42-2 C12H12N2O 3 232,24 g/mol

RL-1005

AMCA-OSu

O H2N

N H

O

O

7-Amino-4-methyl-3-coumarinylacetyl succinimidyl ester AMCO-NHS CAS-No. Formula Mol. weight

113721-87-2 C16H14N2O 6 330,29 g/mol

RL-1170

Fmoc-ACA-OH

O

O

H2N

O

O

O

N

O

7-(9-Fluorenylmethyloxycarbonylamino)-coumarin-4-acetic acid CAS-No. Formula Mol. weight

378247-75-7 C 26H19NO 6 441,43 g/mol

ZAA1470

Z-L-Arg-L-Arg-AMC*2HCl

O OH O O

N-alpha-benzyloxycarbonyl-L-arginyl-L-arginine-7-amido-4-methylcoumarin-dihydrochloride CAS-No. Formula Mol. weight

140686-23-3 C 30 H39N9 O 6*2HCl 621,69*72,91 g/mol

ZAA1480

Z-L-Phe-L-Arg-AMC*HCl

65147-22-0 C 33H36N 6O 6*HCl 612,69*36,46 g/mol

O

H N

H N

O

O

NH2 NH

O N H

O

H N

O

O

O

NH HN

N-alpha-benzyloxycarbonyl-L-phenylalanyl-L-arginine-7-amido-4-methylcoumarin hydrochlorid CAS-No. Formula Mol. weight

N H

NH2

H N

H N

O O

NH2 NH

O N H

H N

O

O

O

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Photochemistry Acridine Derivatives Product details

BAA1580

Boc-L-Ala(2-Bacd)-OH

N-alpha-t-Butyloxycarbonyl-3-[benzo[b]acridin-12(5H)on-2-yl]-L-alanine CAS-No. Formula Mol. weight

916834-72-5 C 25H24N2O 5 432,47 g/mol

BAA1590

Boc-L-Ala(2-Acd)-OH

O

643018-86-4 C 21H22N2O 5 382,41 g/mol

FAA5830

Fmoc-L-Ala(2-Acd)-OH

(S)

N H

O H N

O

(S)

1013328-63-6 C 31H24N2O 5 504,53 g/mol

FAA5880

Fmoc-L-Ala(2-Bacd)-OH

N H

O

1157859-85-2 C 35H26N2O 5 554,59 g/mol

HAA3570

H-L-Ala(2-Bacd)-OH*HCl

3-[Benzo[b]acridin-12(5H)-on-2-yl]-L-alanine hydrochloride Formula Mol. weight

C 20 H16N2O 3*HCl 332,35*36,45 g/mol

H N

O

(S)

OH

O

O

N H

N-alpha-(9-Fluorenylmethoxycarbonyl)-3-[benzo[b] acridin-12(5H)-on-2-yl]-L-alanine CAS-No. Formula Mol. weight

O

OH

O

N-alpha-(9-Fluorenylmethoxycarbonyl)-3-{2-[9(10H)-acridonyl]}-L-alanine CAS-No. Formula Mol. weight

O

OH

O

N-alpha-t-Butyloxycarbonyl-3-{2-[9(10H)-acridonyl]}-L-alanine CAS-No. Formula Mol. weight

H N

O

O H N

O

(S)

OH

O

O

N H

O H2N

(S)

OH

O

N H

31

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Product details

HAA3580

H-L-Ala(2-Acd)-OH*HCl

3-{2-[9(10H)-acridonyl]}-L-alanine hydrochloride CAS-No. Formula Mol. weight

854503-32-5 net C16H14N2O 3*HCl 282,29*36,45 g/mol

O H2N

(S)

OH

O

N H

References: → Rapid and general profiling of protease specificity by using combinatorial fluorogenic substrate libraries; J. L. Harris, B. J. Backes, F. Leonetti, S. Mahrus, J. A. Ellman, C. S. Craik; PNAS 2000; 97: 7754-7759. https://doi.org/10.1073/pnas.140132697 → Expedient Solid-Phase Synthesis of Fluorogenic Protease Substrates Using the 7-Amino-4-carbamoylmethylcoumarin (ACC) Fluorophore; D. J. Maly, F. Leonetti, B. J. Backes, D. S. Dauber, J. L. Harris, C. S. Craik, J. A. Ellman; J. Org. Chem. 2002; 67: 910-915. https://doi.org/10.1021/jo016140o → Synthesis of a New Fluorogenic Substrate for Cystine Aminopeptidase; Y. Kanaoka, T. Takahashi, H. Nakayama, T. Ueno, T. Sekine; Chem. Pharm. Bull. 1982; 30(40): 1485-1487. https://doi.org/10.1248/cpb.30.1485 → Sensitive assays for trypsin, elastase, and chymotrypsin using new fluorogenic substrates; M. Zimmerman, B. Ashe, E. C. Yurewicz, G. Patel; Anal. Biochem. 1977; 78(1): 47-51. https://doi.org/10.1016/0003-2697(77)90006-9. → Aminomethyl coumarin acetic acid: a new fluorescent labelling agent for proteins; H. Khalfan, R. Abuknesha, M. Rand-Weaver, R. G. Price, D. Robinson; Histochem J. 1986; 18(9): 497-499. https://doi.org/10.1007/BF01675617 → A Simple Fluorescent Labeling Method for Studies of Protein Oxidation, Protein Modification, and Proteolysis; A. M. Pickering, K. J. A. Davies; Free Radic Biol Med. 2012; 52(2): 239-246. https://doi.org/10.1016/j.freeradbiomed.2011.08.018 → Fluorescence imaging of drug target proteins using chemical probes; H. Zhu, I. Hamachi; J. Pharm. Anal.

2020; 10: 426-433. https://doi.org/10.1016/j.jpha.2020.05.013 → A New Fluorogenic Substrate for Chymotrypsin; M. Zimmerman, E. Yurewicz, G. Patel; Anal. Biochem. 1976; 70: 258-262. https://doi.org/10.1016/S0003-2697(76)80066-8 → Determination of Caspase Specificities Using a Peptide Combinatorial Library; N. A. Thornberry, K. T. Chapman, D. W. Nicholson; Method Enzymol 2000; 322: 100-110. https://doi.org/10.1016/S0076-6879(00)22011-9

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Photochemistry 10.2. Building Blocks for the SPPS of FRET-based fluorogenic protease substrates The classic FRET pair EDANS and DABCYL is now available linked to Fmoc amino acid building blocks that can be readily used in SPPS. Conveniently synthesize your own custom protease substrates!

340 nm

FRET EDANS

DABCYL

Peptide

Proteolysis

340 nm

EDANS

490 nm

DABCYL

Fragment 1

Fragment 2

Fig. 14: Screening of protease activity using FRET-based fluorogenic protease substrates Traditionally, fluorogenic protease substrates for the screening of protease activity are prepared by peptide synthesis and subsequent regioselective deprotection and functionalization with a fluorophore/ quencher pair such as EDANS and DABSYL. For your convenience, we now offer a glutamate and a lysine building block functionalized with EDANS and DABSYL, respectively. Those building blocks are suitable for peptide synthesis using the Fmoc strategy and will allow you to prepare custom protease substrates without additional tedious and yield-reducing functionalization steps post-SPPS.

Product details

FAA1498

Fmoc-L-Lys(Dabcyl)-OH

N-alpha-(9-Fluorenylmethyloxycarbonyl)-N-epsilon-4-[4‘-(dimethylamino)phenylazo]benzoyl-L-lysine CAS-No. Formula Mol. weight

146998-27-8 C 36H37N 5O 5 619,73 g/mol

O

H N

O

Me N

OH

(S)

O

Me

N N

HN O

LS-4180

Dabcyl-KTSAVLQSGFRKM-Glu(Edans)-amide

Dabcyl-lysyl-threonyl-seryl-alanyl-valyl-leucyl-glutaminyl-seryl-glycyl-phenylalanyl-arginyl-lysyl-methionyl-glutamyl(Edans)-amide CAS-No. Formula Mol. weight

33

HN

NH2 H2N O

N H3C

N H N

H N O HO

OH

O N H CH3

H N O

O N H

H N O

O

N H

NH2 HN

O

H N O

O N H OH

H N O

H3C

O N H

H N O

N CH3

S

O N H

O

H N

NH2

O O

NH

NH2 HN

2642630-08-6 C95H142N26O 23 S 2 2080,46 g/mol

Iris Biotech GmbH • Email: info@iris-biotech.de • www.iris-biotech.de • Empowering Peptide Innovation

O S OH

O

Product details

FAA4410

Fmoc-L-Glu(EDANS)-OH

N-alpha-(9-Fluorenylmethyloxycarbonyl)-5-(2-(5-sulfonaphthalen-1-ylamino)ethylamido)-L-glutamic acid 193475-66-0 C 32H31N3 O 8 S 617,67 g/mol

CAS-No. Formula Mol. weight

H N

O

O (S)

OH

O

O

N H

H N

S O

O OH

References: → Enzymatic activity characterization of SARS coronavirus 3C-like protease by fluorescence resonance energy transfer technique; S. Chen, L. L. Chen, H. B. Luo, T. Sun, J. Chen, F. Ye, J. H. Cai, J. K. Shen, X. Shen, H. L. Jiang; Acta Pharmacol Sin 2005; 26: 99-106. https://doi.org/10.1111/j.1745-7254.2005.00010.x → Synthesis and evaluation of fluorescent probes for the detection of calpain activity; S. Mittoo, L. E. Sundstrom, M. Bradley; Anal Biochem 2003; 319: 234-8. https://doi.org/10.1016/s0003-2697(03)00324-5 → A general method for the preparation of internally quenched fluorogenic protease substrates using solid-phase peptide synthesis; L. L. Maggiora, C. W. Smith, Z. Y. Zhang; J Med Chem 1992; 35: 3727-30. https://doi.org/10.1021/jm00099a001 → Novel fluorogenic substrates for assaying retroviral proteases by resonance energy transfer; E. D. Matayoshi, G. T. Wang, G. A. Krafft, J. Erickson; Science 1990; 247: 954-8. https://doi.org/10.1126/science.2106161 → Design and synthesis of new fluorogenic HIV protease substrates based on resonance energy transfer; G. T. Wang, E. Matayoshi, H. Jan Huffaker, G. A. Krafft; Tetrahedron Lett. 1990; 31: 6493-6496. https://doi.org/10.1016/s0040-4039(00)97099-0

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34

Photochemistry

Code of Conduct As business activity of Iris Biotech GmbH impacts people’s lives and health, it must be operated in ethical and correct manner and act with integrity and responsibility. To ensure high ethical standards and fair business practices, Iris Biotech GmbH applies an integrated policy known as its Code of Conduct.

In 2001 Iris Biotech GmbH was founded just at the beginning of the Biotech movement and the first remarkable breakthrough of biotech pharma products. Although the biotech field is rather young compared to other industries we believe on long-term business, a good partnership between our business partners and Iris Biotech GmbH and a good reputation. It is our duty as well as our responsibility to maintain and to extend this over the next generations – based on the principles of an honourable and prudent tradesman which based upon the concept of honourable entrepreneurship.

This Code of Conduct has been developed following the “Voluntary Guidelines for Manufacturers of Fine Chemical Intermediates and Active Ingredients” issued by AIME (Agrochemical & Intermediates Manufacturers in Europe) and the requirements of some of our business associates.

Iris Biotech GmbH commits to hold this Code of Conduct and to include and apply its principles in the management system and the company policies.

Ethics Iris Biotech GmbH undertakes business in an ethical manner and acts with integrity. All corruption, extortion and embezzlement are prohibited. We do not pay or accept bribes or participate in other illegal inducements in business or government relationships. We conduct our business in compliance with all applicable anti-trust laws. Employees are encouraged to report concerns or illegal activities in the workplace, without threat of reprisal, intimidation or harassment.

Labour Iris Biotech GmbH is committed to uphold the human rights of workers and to treat them with dignity and respect. Child labour, workplace harassment, discrimination, and harsh and inhumane treatment are prohibited. Iris Biotech GmbH respects the rights of the employees to associate freely, join or not join labour unions, seek representation and join workers’ councils. Employees are paid and their working timetable is established according to applicable wage and labour laws. Employees are able to communicate openly with management regarding working conditions without threat of reprisal, intimidation or harassment.

General Policies Contracts and Secrecy Agreements are binding and the confidential information received is only used for intended purposes. Clear management and organizational structures exist to provide efficient normal working and to address problems quickly. Know-how is protected and intellectual property isrespected.

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Health and Safety Iris Biotech GmbH provides a safe and healthy working environment to the employees and protects them from overexposure to chemical and physical hazards. Products are produced, stored and shipped under the guidelines of the relevant chemical and safety legislation. Risks and emergency scenarios are identified and evaluated, and their possible impact is minimized by implementing emergency plans and written procedures. Safety information regarding hazardous materials is available to educate, train and protect workers from hazards. Preventive equipment and facilities maintenance is performed at suitable periods to reduce potential hazards. Employees are regularly trained in health and safety matters and are informed about product properties and risk classification when it is required.

Environment Iris Biotech GmbH operates in an environmentally responsible and efficient manner, minimizing adverse impacts on the environment. Waste streams are managed to ensure a safe handling, movement, storage, recycling and reuse, before and after being generated. Systems to prevent and mitigate accidental spills and releases to the environment are in place. All required environmental permits and licenses are obtained and their operational and reporting requirements are complied with.

Production and Quality Management A quality management system following the Good Distribution Practices (GDP rules) of Active Pharmaceutical Ingredients is established covering all the aspects of the worldwide distribution of products.

Regular audits are performed to evaluate the efficiency and fulfilling of the quality system. Process controls to provide reproducible product quality are established. There are preventive maintenance procedures to ensure plant reliability and the lowest risk of failure. Staff is trained periodically about GMP and GDP rules. Procedures are established and installations are designed to avoid cross contamination.

Batch and analytical records are kept for inspection and audit purposes for suitable periods according guidelines.

Research and Development Research and development staff education is appropriate to their functional activity and they are trained to develop, optimize and scale-up the processes. Intellectual property is respected and knowhow protected. Development of manufacturing processes reflects the principles of the Green Chemistry according to the American Chemical Society Green Chemistry Institute. Animal testing is not used unless alternatives are not scientifically valid or accepted by regulators. If animal testing is carried out, animals are treated so that pain and stress are minimized.

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36

Photochemistry

Terms and Conditions of Sales All orders placed by a buyer are accepted and all contracts are made subject to the terms which shall prevail and be effective notwithstanding any variations or additions contained in any order or other document submitted by the buyer. No modification of these terms shall be binding upon Iris Biotech GmbH unless made in writing by an authorised representative of Iris Biotech GmbH.

Placing of Orders Every order made by the buyer shall be deemed an offer by the buyer to purchase products from Iris Biotech GmbH and will not be binding on Iris Biotech GmbH until a duly authorised representative of Iris Biotech GmbH has accepted the offer made by the buyer. Iris Biotech GmbH may accept orders from commercial, educational or government organisations, but not from private individuals and Iris Biotech GmbH reserves the right to insist on a written order and/or references from the buyer before proceeding.

There is no minimum order value. At the time of acceptance of an order Iris Biotech GmbH will either arrange prompt despatch from stock or the manufacture/acquisition of material to satisfy the order. In the event of the latter Iris Biotech GmbH will indicate an estimated delivery date. In addition to all its other rights Iris Biotech GmbH reserves the right to refuse the subsequent cancellation of the order if Iris Biotech GmbH expects to deliver theproduct on or prior to the estimated delivery date. Time shall not be of the essence in respect of delivery of the products. If Iris Biotech GmbH is unable to deliver any products by reason of any circumstances beyond its reasonable control („Force Majeure“) then the period for delivery shall be extended by the time lost due to such Force Majeure. Details of Force Majeure will be forwarded by Iris Biotech GmbH to the buyer as soon as reasonably practicable.

Prices, Quotations and Payments Prices are subject to change. For the avoidance of doubt, the price advised by Iris Biotech GmbH at the time of the buyer placing the order shall supersede any previous price indications. The buyer must contact the local office of Iris Biotech GmbH before ordering if further information is required. Unless otherwise agreed by the buyer and Iris Biotech GmbH, the price shall be for delivery ex-works. In the event that the buyer requires delivery of the products otherwise than ex-works the buyer should contact the local office of Iris Biotech GmbH in order to detail its requirements. Iris Biotech GmbH shall, at its discretion, arrange the buyer‘s delivery requirements including, without limitation, transit insurance, the mode of transit (Iris Biotech GmbH reserves the right to vary the mode of transit if any regulations or other relevant considerations so require) and any special packaging requirements (including cylinders).

For the avoidance of doubt all costs of delivery and packaging in accordance with the buyer‘s requests over and above that of delivery in standard packaging ex-works shall be for the buyer‘s account unless otherwise agreed by both parties. Incoterms 2020 shall apply. Any tax, duty or charge imposed by governmental authority or otherwise and any other applicable taxes, duties or charges shall be for the buyer‘s account. Iris Biotech GmbH may, on request and where possible, provide quotations for multiple packs or bulk quantities, and non-listed items. Irrespective of the type of request or means of response all quotations must be accepted by the buyer without condition and in writing before an order will be accepted by Iris Biotech GmbH. Unless agreed in writing on different terms, quotations are valid for 30 days from the date thereof. Payment terms are net 30 days from invoice date unless otherwise agreed in writing. Iris Biotech GmbH reserves the right to request advance payment at its discretion. For overseas transactions the buyer shall pay all the banking charges of Iris Biotech GmbH. The buyer shall not be entitled to withhold or set-off payment for the products for any reason whatsoever. Government/

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Corporate Visa and MasterCard (and other such credit cards) may be accepted on approved accounts for payment of the products. Personal credit cards are not acceptable. Failure to comply with the terms of payment of Iris Biotech GmbH shall constitute default without reminder. In these circumstances Iris Biotech GmbH may (without prejudice to any other of its rights under these terms) charge interest to accrue on a daily basis at the rate of 2% per month from the date upon which payment falls due to the actual date of payment (such interest shall be paid monthly). If the buyer shall fail to fulfil the payment terms in respect of any invoice of Iris Biotech GmbH Iris Biotech GmbH may demand payment of all outstanding balances from the buyer whether due or not and/or cancel all outstanding orders and/or decline to make further deliveries or provision of services except upon receipt of cash or satisfactory securities.

Until payment by the buyer in full of the price and any other monies due to Iris Biotech GmbH in respect of all other products or services supplied or agreed to be supplied by Iris Biotech GmbH to the buyer (including but without limitation any costs of delivery) the property in the products shall remain vested in Iris Biotech GmbH.

Shipping, Packaging and Returns The buyer shall inspect goods immediately on receipt and inform Iris Biotech GmbH of any shortage or damage within five days. Quality problems must be notified within ten days of receipt. Goods must not be returned without prior written authorisation of Iris Biotech GmbH. Iris Biotech GmbH shall at its sole discretion replace the defective products (or parts thereof) free of charge or refund the price (or proportionate price) to buyer. Opened or damaged containers cannot be returned by the buyer without the written prior agreement of Iris Biotech GmbH. In the case of agreed damaged containers which cannot be so returned, the buyer assumes responsibility for the safe disposal of such containers in accordance with all applicable laws.

Product Quality, Specifications and Technical Information Products are analysed in the Quality Control laboratories of Iris Biotech GmbH’s production partners by methods and procedures which Iris Biotech GmbH considers appropriate. In the event of any dispute concerning reported discrepancies arising from the buyer’s analytical results, determined by the buyer’s own analytical procedures, Iris Biotech GmbH reserves the right to rely on the results of own analytical methods of Iris Biotech GmbH. Certificates of Analysis or Certificates of Conformity are available at the discretion of Iris Biotech GmbH for bulk orders but not normally for prepack orders. Iris Biotech GmbH reserves the right to make a charge for such certification. Specifications may change and reasonable variation from any value listed should not form the basis of a dispute. Any supply by Iris Biotech GmbH of bespoke or custom product for a buyer shall be to a specification agreed by both parties in writing.

Technical information, provided orally, in writing, or by electronic means by or on behalf of Iris Biotech GmbH, including any descriptions, references, illustrations or diagrams in any catalogue or brochure, is provided for guidance purposes only and is subject to change.

Safety All chemicals should be handled only by competent, suitably trained persons, familiar with laboratory procedures and potential chemical hazards. The burden of safe use of the products of Iris Biotech GmbH vests in the buyer. The buyer assumes all responsibility for warning his employees, and any persons who might reasonably be expected to come into contact with the products, of all risks to person and property in any way connected with the products and for instructing them in their safe handling and use.

The buyer also assumes the responsibility for the safe disposal of all products in accordance with all applicable laws.

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Photochemistry Uses, Warranties and Liabilities All products of Iris Biotech GmbH are intended for laboratory research purposes and unless otherwise stated on product labels, in the catalogue and product information sheet of Iris Biotech GmbH or in other literature furnished to the buyer, are not to be used for any other purposes, including but not limited to use as or as components in drugs for human or animal use, medical devices, cosmetics, food additives, household chemicals, agricultural or horticultural products or pesticides. Iris Biotech GmbH offers no warranty regarding the fitness of any product for a particular purpose and shall not be responsible for any loss or damage whatsoever arising there from. No warranty or representation is given by Iris Biotech GmbH that the products do not infringe any letters patent, trademarks, registered designs or other industrial rights. The buyer further warrants to Iris Biotech GmbH that any use of the products in the United States of America shall not result in the products becoming adulterated or misbranded within the meaning of the Federal Food, Drug and Cosmetic Act (or such equivalent legislation in force in the buyer‘s jurisdiction) and shall not be materials which may not, under sections 404, 505 or 512 of the Act, be introduced into interstate commerce. The buyer acknowledges that, since the products of Iris Biotech GmbH are intended for research purposes, they may not be on the Toxic Substances Control Act 1976 („TSCA“) inventory. The buyer warrants that it shall ensure that the products are approved for use under the TSCA (or such other equivalent legislation in force in the buyer‘s jurisdiction), if applicable. The buyer shall be responsible for complying with any legislation or regulations governing the use of the products and their importation into the country of destination (for the avoidance of doubt to include, without limitation, the TSCA and all its amendments, all EINECS, ELINCS and NONS regulations). If any licence or consent of any government or other authority shall be required for the acquisition, carriage or use of the products by the buyer the buyer shall obtain the same at its own expense and if necessary produce evidence of the same to Iris Biotech GmbH on demand. Failure to do so shall not entitle the buyer to withhold or delay payment. Any additional expenses or charges incurred by Iris Biotech GmbH resulting from such failure shall be for the buyer‘s account. Save for death or personal injury caused by negligence of Iris Biotech GmbH, sole obligation of Iris Biotech GmbH and buyer‘s exclusive remedy with respect to the products proved to the satisfaction of Iris Biotech GmbH to be defective or products incorrectly supplied shall be to accept the return of said products to Iris Biotech GmbH for refund of the actual purchase price paid by the buyer (or proportionate part thereof), or replacement of the defective product (or part thereof) with alternative product. Iris Biotech GmbH shall have no liability to the buyer under or arising directly or indirectly out of or otherwise in connection with the supply of products by Iris Biotech GmbH to the buyer and/or their re-sale or use by the buyer or for any product, process or services of the buyer which in any way comprises the product in contract tort (including negligence or breach of statutory duty) or otherwise for pure economic loss, loss of profit, business, reputation, depletion of brand, contracts, revenues or anticipated savings or for any special indirect or consequential damage or loss of any nature except as may otherwise be expressly provided for in these terms. All implied warranties, terms and representations in respect of the products (whether implied by statute or otherwise) are excluded to the fullest extent permitted by law. The buyer shall indemnify Iris Biotech GmbH for and against any and all losses, damages and expenses, including legal fees and other costs of defending any action, that Iris Biotech GmbH may sustain or incur as a result of any act or omission by the buyer, its officers, agents or employees, its successors or assignees, its customers or all other third parties, whether direct or indirect, in connection with the use of any product. For the avoidance of doubt and in the event that Iris Biotech GmbH supplies bespoke or custom product to the buyer‘s design or specification, this indemnity shall extend to include any claim by a third party that the manufacture of the product for the buyer or the use of the product by the buyer infringes the intellectual property rights of any third party.

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General Iris Biotech GmbH shall be entitled to assign or sub-contract all or any of its rights and obligations hereunder. The buyer shall not be entitled to assign, transfer, sub-contract or otherwise delegate any of its rights or obligations hereunder. Any delay or forbearance by Iris Biotech GmbH in exercising any right or remedy under these terms shall not constitute a waiver of such right or remedy. If any provision of these terms is held by any competent authority to be invalid or unenforceable in whole or in part the validity of the other provisions of these terms and the remainder of the provision in question shall not be affected. These terms shall be governed by German Law and the German Courts shall have exclusive jurisdiction for the hearing of any dispute between the parties save in relation to enforcement where the jurisdiction of the German Courts shall be non-exclusive.

Notes

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40

Photochemistry

Index

41

Product code

Product name

RL-2150

Acid-Photo-Linker

RL-1005

Page

Product code

Product name

Page

25

FAA7200

Fmoc-Spr(oNv)-OH

13, 19

AMCA-OSu

30

HAA7645

Glt-Gly-Arg-AMC.HCl

29

RL-2035

ATFB

11

HAA7971

H-Gly-AMC

30

RL-2045

ATFB-NHS

11

HAA3580

H-L-Ala(2-Acd)-OH*HCl

32

PEG2065

Biotin-TEG-ATFBA

11

HAA3570

H-L-Ala(2-Bacd)-OH*HCl

31

BAA1590

Boc-L-Ala(2-Acd)-OH

31

HAA2930

H-L-Ala(2-Furyl)-OH

14

BAA1580

Boc-L-Ala(2-Bacd)-OH

31

HAA1200

H-L-Ala-AMC

28

BAA3650

Boc-L-Lys-AMC*AcOH

28

HAA1174

H-L-Ala-AMC*TFA

29

BAA1660

Boc-L-Phe(4-N=NPh)-OH

22

HAA7630

H-L-Arg-AMC*2HCl

29

BAA3070

Boc-L-Photo-Leucine*DCHA

3

HAA2890

H-L-Asp(AMC)-OH

29

BAA3080

Boc-L-Photo-Lysine

3

HAA9320

H-L-Cys(DMNB)-OH

18

BAA3090

Boc-L-Photo-Methionine*DCHA

4

HAA9270

H-L-Cys(MDNPE)-OH

18

BAA1530

Boc-L-Photo-Phe-OH

4

HAA3200

H-L-Leu-AMC

29

BAA3100

Boc-L-Photo-Proline

5

HAA3710

H-L-Phe(4-N=NPh)-OH*HCl

21

LS-4180

Dabcyl-KTSAVLQSGFRKM-Glu(Edans)-amide

33

HAA3100

H-L-Photo-Leucine*HCl

3

RL-1170

Fmoc-ACA-OH

30

HAA3110

H-L-Photo-Lysine*HCl

3

FAA9180

Fmoc-AMPB-OH

22

HAA3120

H-L-Photo-Methionine*HCl

4

FAA5830

Fmoc-L-Ala(2-Acd)-OH

31

HAA3490

H-L-Photo-Phe-OH

4

FAA5880

Fmoc-L-Ala(2-Bacd)-OH

31

HAA3130

H-L-Photo-Proline*HCl

5

FAA4250

Fmoc-L-Ala(2-Furyl)-OH

15

HAA7740

H-L-Pyr-AMC

29

FAA7945

Fmoc-L-Cys(MDNPE)-OH

18

HAA9255

H-L-Sec(DMNB)-OH*TFA

18

FAA8420

Fmoc-L-Cys(NDBF)-OH

17

HAA9360

H-L-Sec(MDNPE)-OH

18

FAA1975

Fmoc-L-Cys(Npys)-OH

17

HAA9475

H-L-Sec(NPE)-OH*HCl

19

FAA3970

Fmoc-L-Cys(oNv)-OH

17

HAA9465

H-L-Sec(oNB)-OH*HCl

19

FAA4410

Fmoc-L-Glu(EDANS)-OH

34

HAA7760

H-L-Thr-AMC

28

FAA8870

Fmoc-L-hCys(oNv)-OH

19

PEG5000

N3-TFBA-O2Oc

11

FAA1498

Fmoc-L-Lys(Dabcyl)-OH

33

RL-2920

Photo-Benzoic acid

8

FAA8425

Fmoc-L-Lys(NDBFOC)-OH

18

RL-2930

Photo-Benzylamine*HCl

9

FAA7230

Fmoc-L-Lys(Nvoc)-OH

17

RL-2910

Photo-Butylamine

9

FAA7010

Fmoc-L-Phe(4-N=NPh)-OH

22

RL-3410

Photo-Click-Heptanoic acid

8

FDP1240

Fmoc-L-Phe-Aca-OH

28

RL-3720

Photo-Click-Palmitic acid

8

FAA4590

Fmoc-L-Photo-Leucine

3

RL-3760

Photo-Click-Stearic acid

8

FAA4600

Fmoc-L-Photo-Lysine

3

RL-2900

Photo-Hexanoic acid

7

FAA4610

Fmoc-L-Photo-Methionine

4

RL-3740

Photo-Palmitic acid

8

FAA5690

Fmoc-L-Photo-Phe-OH

4

RL-2890

Photo-Pentanoic acid

7

FAA4620

Fmoc-L-Photo-Proline

5

RL-3750

Photo-Stearic acid

8

FAA7350

Fmoc-N(oNv)-Gly-OH

19

RL-2970

Photo-Trimethyl-Lock

13

RL-1026

Fmoc-Photo-Linker

26

PAA2000

tBu-SS-Photo(Fmoc)-Gly-OH

24

BR-5205

Fmoc-Photolabile Resin

26

ZAA1470

Z-L-Arg-L-Arg-AMC*2HCl

30

FAA7190

Fmoc-Spr(oNB)-OH

13

ZAA1480

Z-L-Phe-L-Arg-AMC*HCl

30

Iris Biotech GmbH • Email: info@iris-biotech.de • www.iris-biotech.de • Empowering Peptide Innovation

Notes

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42

Get in Contact Iris Biotech GmbH Adalbert-Zoellner-Str. 1 95615 Marktredwitz Germany

+49 (0) 9231 97121-0 +49 (0) 9231 97121-99 info@iris-biotech.de www.iris-biotech.de

Distribution Partners The list contains the current distributors of Iris Biotech in different regions of the world. The latest list of distribution partners and contact details is available at: www.iris-biotech.de/distribution-partner

China: Chengdu Yoo Technology Co., Ltd.

Japan: BizCom Japan, Inc. Shigematsu & Co., Ltd Cosmo Bio Co., Ltd.

USA & Canada: Peptide Solutions LLC

India, Bangladesh, Oman, Sri Lanka, United Arab Emirates: Sumit Biosciences Pvt Ltd.

Singapore, Thailand, Malaysia, Indonesia, Vietnam, Philippines, Brunei, Burma (Myanmar), Laos, Cambodia, Timor-Leste: SciClix Pte. Ltd.

Iris Biotech GmbH • Email: info@iris-biotech.de • www.iris-biotech.de • Empowering Peptide Innovation

44

Empowering Peptide Innovation