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COURSE N

MEDICINAL CHEMISTRY (Course Organiser: Dr M F Greaney) Dr. Love

Metals in Medicine (5)

Prof. Baxter

Nucleic Acids (5)

Dr. Cockroft

Physical Organic Aspects of Medicinal Chemistry (5)

Dr. Archer

Medicinal Chemistry (5)

Dr. Greaney

Medicinal Chemistry (5)

Dr. Hamilton (Organon)

Industrial Medicinal Chemistry (5)


METALS IN MEDICINE 5 Lectures

Dr. J. Love

AIM To provide an overview of inorganic medicinal chemistry, with particular emphasis on the role of the metal centre(s) and its mode of action, and current trends in the design of bioactive compounds SYNOPSIS This course will focus on the design, synthesis, and effectiveness of transition metal and organometallic compounds in therapeutic and diagnostic medical applications, and will build on previous inorganic chemistry courses. Particular emphasis will be placed on: • Essential elements, chemotherapeutic and diagnostic elements • Platinum, titanium, and other metal anticancer agents • Gold anti-arthritic drugs • Radiopharmaceuticals and imaging agents, targeted radioactive compounds • Contrast agents for magnetic resonance imaging LEARNING OUTCOMES By the end of this five lecture course, the student should have a good understanding of the history and basic concepts of medicinal inorganic chemistry, and should be able to describe in detail synthetic approaches and mechanisms of action of some important metal-based therapeutic and diagnostic agents. READING Medicinal Inorganic Chemistry, Z. Guo, P. J. Sadler, Angew. Chem. Int. Ed., 1999, 38, 1512 Bioinorganic Chemistry: Inorganic Elements in the Chemistry of Life – an introduction and guide, W. Kaim, B. Schwederski, Wiley and Sons, Chichester, 1999


NUCLEIC ACIDS 5 Lectures

Professor R L Baxter

AIMS •

To introduce the students to the structure, chemical properties and synthesis of oligonucleotides and to make them aware that, complex biological phenomena can be understood on a molecular level with common chemical principles.

To give an overview of the biological significance of DNA and RNA and to teach the basics of the processes by which sequence information is passed from DNA to RNA to proteins.

To cover areas of oligonucleotide chemistry as it relates to therapeutic and diagnostic applications.

SYNOPSIS 1.

Nucleic acid structure: a detailed discussion of the structure and physical properties of the functional groups (purine and pyrimidine bases, sugar backbone, phosphodiester linkages) of nucleic acids; double strand formation through base-pairing (Watson-Crick and other); helical structures.

2.

Chemical properties of nucleic acids; comparing DNA with RNA.

3.

Brief biochemistry and molecular biology of DNA: Transcription and Translation; splicing of mRNA. The chemical mechanisms involved in protein synthesis at the ribosome; roles of mRNA and tRNA.

4.

Chemical synthesis of DNA. Introduction to solution methods, Modern approaches by solid phase methods.

5.

Synthesis and study of DNA containing mutagenic bases: challenges for the chemist.

6.

Therapeutic and diagnostic applications: Nucleoside based anti-viral agents, anti-cancer compounds.

7.

Applications of DNA chemistry in synthetic applications

LEARNING OUTCOMES By the end of the five lecture course, the student should have an understanding of the biological significance of RNA and DNA, a basic understanding of oligonucleotide chemistry and an appreciation on how it relates to therapeutic and diagnostic applications. READING For background reading use a general biochemistry textbook (e.g. Stryer, Lehninger and Abeles) Nucleic Acids in Chemistry and Biology, G.M. Blackburn and M.J. Gait, Oxford University Press, 1996 (2nd editon) Chemistry of Biomolecules, R.J. Simmons, RSC, 1992


PHYSICAL ORGANIC ASPECTS OF MEDICINAL CHEMISTRY 5 Lectures

Dr. S. L. Cockroft

AIMS & LEARNING OUTCOMES

This course will explore the role of physical organic chemistry in understanding the relationships between the physicochemical and biological properties of pharmaceutical agents. By the end of the course you will appreciate the importance of structure/activity relationships in modern-day drug design and development. SYNOPSIS 1. Quantifying Drug-Receptor Interactions: ● van der Waals interactions ● electrostatic interactions ● the α/β hydrogen bonding scale ● solvophobic effects ● enthalpy-entropy compensation 2. Solubility & Lipophilicty: ● absolute solubility ● effects of crystal polymorphism on solubility ● partition coefficients as a measure of lipophilicity (logPo/w) ● the pH partition hypothesis ● distribution coefficients (logDo/w) ● membrane partitioning (logDmem) 3. Substituent Effects on Drug Properties: ● lipophilicity (π constants and ClogPo/w) ● pKa ● Hammett substituent constants ● hydrogen bonding ● proximity effects 4. Drug Distribution, Metabolism & Pharmacokinetics (DMPK): ● absorption ● distribution ● metabolism ● excretion ● differences based on administration route 5. Chemoinformatics in Drug Discovery & Design: ● Quantitative Structure Activity Relationships (QSAR) ● database profiling (the origin of Lipinski’s ‘Rule of 5’ for good drug likeness) ● efficient exploration of physical property space in drug screening RECOMMENDED READING ‘Modern Physical Organic Chemistry’ Eric V. Anslyn and Dennis D. Dougherty, University Science Books, 2004 ‘Quantifying Intermolecular Interactions: Guidelines for the Molecular Recognition Toolbox’ Christopher A. Hunter, Angewandte Chemie International Edition, 2004, 43, 5310-5324 ‘Pharmacokinetics and Metabolism in Drug Design’ Dennis A. Smith, Han Van De Waterbeemd, Don K. Walker, Raimund Mannhold, Hugo Kubinyi, Gerd Folkers, Wiley-VCH Verlag GmbH, 2001


MEDICINAL CHEMISTRY 5 Lectures 5 Lectures

Dr Archer Dr M F Greaney

AIMS •

To build on the basis of the previous course.

To indicate how a knowledge of biological processes can lead to rational drug design.

To explore synthetic routes to the target systems.

SYNOPSIS This course builds on the previous third year course and will emphasise the current approaches to rational design of pharmaceutical products by consideration of drug-receptor interactions. The synthetic routes, and biological implications, of the major therapeutic agents Zantac and Cimetidine (anti-ulcer), Captopril/Enalapril (ACE inhibitors) will be discussed. Inhibition of protein processing by enzymes will be developed as a general concept for future pharmaceuticals. LEARNING OUTCOMES By the end of the ten lecture course, the student should have a good understanding of rational approaches towards the design of important drugs including anti-ulcer drugs and ACE inhibitors, and the biological implications of such therapeutic agents. The student should be aware of the use of enzymes to inhibit protein processing as a concept for the design of future pharmaceuticals. READING Comprehensive Medicinal Chemistry, Volumes 1-6, Ed. C. Hansch, P.G. Sammes and J.B. Taylor, Pergamon Press 1990 Organic Chemistry of Drug Discovery and Drug Action, R.B. Silverman, Academic Press, 1992 Medicinal Chemistry, ed. C.R. Ganellin and S.M. Roberts, Academic Press, 1993 Introduction to Medicinal Chemistry, G.L. Patrick, Oxford University Press, 1995 From Bench to Market, W. Cadri, R.D. Fabio, Oxford University Press, 2000


INDUSTRIAL MEDICINAL CHEMISTRY 5 Lectures

Dr N M Hamilton (Organon)

AIMS The aim of the course is to study case histories of the discovery and development of selected important medicinal compounds, and new technologies used within the pharmaceutical industry, from the perspective of industrial researchers who are familiar with these areas. SYNOPSIS Description of routes of administration and their importance in optimising a drug effect. The concepts of prodrugs and soft drugs, and examples with common metabolic pathways. Synthesis and biological activity of steroids including hormonal steroids, neuromuscular blocking agents and modulators of GABAA receptor function. Clinical use and limitations of morphine, chemical modification, simplified morphine derivatives. Multiple opioid receptors including delta and kappa, development of initial lead, opioid leads from high throughput screening, optimisation using solid phase chemistry. LEARNING OUTCOMES (i) Knowledge of common routes of administration of drugs and drug delivery systems. (ii) Knowledge of common metabolic pathways and how they may be exploited in the design of drugs, prodrugs and soft drugs. (iii) Knowledge of the basic body functions controlled by hormonal steroids and also how steroids are exploited for non-hormonal uses, particularly neuromuscular blocking agents. (iv) Ability to discuss the therapeutic potential for GABAA receptor modulators with particular reference to general anaesthetics including steroids. (v) Ability to discuss the importance of new highspeed technologies for the generation of lead compounds and structure-activity relationships, in particular combinatorial chemistry, high throughput screening and automation. (vi) Understanding of the biological importance of opioids as analgesics.

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