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Chemistry 4411

Chemistry 4411: Topics in Medicinal Chemistry

Dr. B. Gregory

Receptors; IUPAC definition; stereochemistry; eutomer and distomer; agonists, partial agonists and antagonists and dose response curves

Amino acids, peptides and proteins; pKa's and ionic status; proteinogenic and some non-proteinogenic biologically-active amino acids; stereochemistry; some relevant reactions of amino acids; enantiomeric and diastereomeric excess definitions; enantioselective (eg Schollkopf methodology) and non-enantioselective synthesis; peptides; some examples; structure determination including Sanger and Edman methods, selective enzymic and chemical cleavage; synthesis including protecting groups, orthogonal propection, coupling methods, solid phase methodology, Menger's synthesis of cyclosporin including Castro cyclization; peptides in medicinal chemistry -1:LHRH, Guillemin and Schally, ICI antagonist design, Zoladex, structure modifications, problems with peptides as drugs; proteins, primary, secondary and tertiary structure, a-helix, b-pleated sheet, b- or reverse turn; b-peptides, Gellman and Seebach and synthesis of b-peptides by Arndt-Eistert homologation; inter- and intramolecular interactions in proteins, some generalizations concerning function of selected amino acids in proteins.

Enzymes, coenzymes, enzyme mechanisms, enzyme inhibitors

Amide hydrolysis, comparison of chemical and enzymic (carboxypeptidase A) mechanisms, Angiotensin converting enzyme, postulated effect of ACE inhibition on blood pressure, Squibb group proposal for ACE mech anism and potential inhibitor structure based on Brazilian arrowhead viper structure, carboxypeptidase mechanism and Byers and Wolfenden "biproduct analogue" ideas, captopril, enalopril (Vasotec); problems with peptide drugs recap and potential solutions - non-cleavable amide bioisosteres, conformational restriction, retro-inverso isomers, etc; Roche products approach to ACE inhibition, cilazapril, synthesis of cilazapril.

Enzymes, some generalizations including stereospecificity eg arginase, binding at transition state, transition state inhibitors eg acetylcholinesterase inhibition and sarin, enzyme-substrate binding, allosteric effects, enzyme classification and IUPAC nomenclature-info. Catalytic antibodies and Landry's work at Columbia.

Coenzymes and vitamins; brief overview of sugars, vitamin B1, thiamine pyrophosphate and its mechanistic involvement in glycolysis (pyruvic acid to acetylcoenzyme A) and pentose phosphate cycle (transketolase mechanism); vitamin B6, pyridoxal phosphate, mechanisms for transamination, dehydration, racemization and decarboxylation; D-alanine racemase as a target, fluoroalanine, cycloserine, alafosfalin, prodrugs; L-aromatic amino acid decarboxylase enzymes as targets, Parkinson's disease, L-Dopa, carbidopa, benzserazide, selegiline, Parkinson's inducers and ester reversal, mechanism-based enzyme inactivators, ornithine decarboxylase, eflornithine; NAD+, NADP+, NADH and NADPH, dehydrogenase enzymes, H transfer stereochemistry, pro-R and pro-S, re and si; Folic acid and related compounds, C1 transfer, biosynthesis of tetrahydrofolic acid in bacteria and in mammals, Amadori rearrangemnt, sulfa drugs, antimetabolites, antitumour agents based on folic acid, dihydrofolate reductase (DHFR) inhibition, DHFR/NADPH/methotrexate (MTX) ternary complex X-ray structure, binding of MTX, mechanism and stereochemistry of CH2 and H transfer in thymidylate biosynthesis, polyglutamates, biological effects of structural variation of folic acid structure, selective inhibition of bacterial and protozoal (malarial parasite) DHFR, pyrimethamine, trimethoprim and related compounds, leprosy.

Miscellany: stages in drug development, pharmacophore identification, carrier groups, bioisosteric replacement, classical and non-classical bioisosteres, examples of use, structural variation vs. biological activity in some organophosphorus compounds - anticancer agents to nerve gases, toxicity, dose response curves, LD50 and ED50, lipophilicity and transport, drug administration and absorption, ionization and absorption, termination of drug activity, metabolism - phase I and phase II - generalizations and some examples, NIH shift.

Case study: anti-ulcer drug development, histamine H1, H2 and H3 receptors, gastric acid production, histamine H2 receptor antagonists, histamine - ionic and tautomeric equilibria, development and synthesis of cimetidine, ranitidine, other approaches to gastric acid control eg omeprazole, Helicobacter pylorii involvement and treatment.

Nucleic acids: structure of nucleosides including C-nucleosides, nucleotides, DNA, including A, B and Z-forms, biosynthesis of purine and pyrimidine nucleotides and comparison with chemical synthesis including acyclonucleosides, PALA-a multi-substrate analogue inhibitor, overview of DNA replication, drugs interfering with replication including topoisomerase I inhibitors (camptothecin analogues eg topotecan, GI 147211); topoisomerase II inhibitors - ellipticine analogues, amsacrine, NSC 628679, GL-331, daunorubicin, menogaril, NK611; quinolone antibacterials, ciprofloxacin, fleroxacin, norfloxacin; intercalating agents, effect on DNA phys. props., anthracyclines, pirarubicin, amsacrine analogues, non-classical intercalators eg bisantrene HCl; drugs capable of DNA strand scission - anthracyclines, enediynes eg neocarzinostatin, esperamicins, dynemicin A, calicheamicins, analogues, Bergman reaction, benzene diradical generation mechanism in enediynes and mechanisms of strand scission; groove binding agents netropsin, distamycin, FCE 24517, Lown's lexitropsins; alkylating agents, mechanism of substitution in bis-chloroethylamines, historical development, melphalan, chlorambucil, cyclophosphamide, mitomycin C and mechanism of DNA alkylation, bioreductive activation, CC 1065, pyrrolo[1,4]benzodiazepines eg tomayamicin.

Nucleoside analogues as antineoplastic and/or antiviral agents: tiazofurin and mode of action; modification to sugar, Ara-C, Ara-A (vidarabine) and adenosine deaminase inhibitors eg covidarabine; viruses and mechanism of virus infections, approaches to antiviral agents - modified bases eg Idoxuridine, Ribavirin, acylonucleosides, acylovir and reasons for selectivity, chain termination, carbanucleosides and carba-acyclonucleosides, Vectavir, Famiciclovir, Valaciclovir, Cidofovir; retroviruses, reverse transcriptase (RT), AIDS and HIV, non-nucleoside RT inhibitors eg TIBO derivatives, revirapine, delaviridine, Merck compounds eg L 697661, drug combinations, nucleoside antivirals including RT inhibitors, AZT and synthesis, dideoxynucleosides, 3-TC (Epivir), oxetanocin and carbacyclic analogues; HIV protease inhibitors, substrate, non-cleavable amide mimics, saquinavir, indinavir, ritonavir, opportunistic infections in AIDS patients and useful drugs.

Antibacterial agents: summary of drug types already covered, Gram staining, bacterial cell wall/membrane structure for Gram positive and negative bacteria, penicillin and the b-lactam antibiotics, historical development, structure variation and nomenclature,; semisynthetics, cephalosporins, nocardicins, thienamycin, its problems and solution, cilastatin, imipenem; b-lactamase inhibitors, clavulanic acid, augmentin, carbenin, meropenem, fropenam; moxalactam and interesting structural features, monobactams, ceftazidime, carbacephems; peptidoglycans, biosynthesis in S. aureus and interference by alafosfalin, D-cycloserine, phosphonomycin, b-lactams, vancomycin, PBP's; new approaches eg SQ 26517, obafluorin, lactivicin, oxamazins, pyrazolidinones, semisynthetic glycopeptides.

Last updated 3rd July 2001