Thymidylate synthase inhibitor design

Fig. 8. Thymidylate synthase inhibitors designed to fit into the A/, AJ -methylenetetrahydrofolate binding site. The best inhibitors from each class are the classical antifolate TS inhibitor (31), the naphthostyril-based lead compound (32), and the tetrahydroquinoline-based lead compound (33), iC values (in nAI)...

Fig. 7. Thymidylate synthase inhibitors designed to bind in the cofactor-binding site using crystal structure of coli enzyme complexed with 5-fluoro-2 -deoxyuridylate (35).

Fig. 26.17 Structure-based design of thymidylate synthase inhibitors, (a) The coenzyme 5,10-methylenete-trahydrofotate. (b) The classical antifolate CB3717. (c) Interactions of the pteridine moiety of CB3717 with active site residues Asp169 and Ala263 and with wat430, a bound water molecule. For explanation, see text. (Adapted, with permission, from Reich, S.H. and Webber, S.E. (1993) Perspect. Drug Dis. Des. 1 371-390. 1993 Escom Science Publishers B.V.)...

Fig. 26.18 Structure-based design of thymidylate synthase inhibitors, (a) Drug lead 2-methyl-2-desamino-/ / °-propargyl-5,8-dideazafolic acid, (b) Derivative lacking the CO-L-glutamate mpiety. (c) Designed diphenylsulfone derivative, (d) AG85, a designed A7-sulfonylindole derivative selected for clinical evaluation.

Fig, 26.19 Structure-based design of thymidylate synthase inhibitors de novo design of a novel lead structure. See text for explanation. 

Figure 12 Design paradigm used in the structure-based discovery of thymidylate synthase inhibitors. ...

The 6-methylacetylamino-l,2,3,4-tetrahydroquinoline, after nitration and separation of isomers, following reduction and deprotection, gave the 7-amino-6-methylamino derivative, which cyclized with cyanogen bromide. Alkylation of the cyclization products afforded inhibitors of thymidylate synthase, 5-substituted 2-amino-l//-l-methyl-5,6,7,8-tetrahydroimidazo[4,5-g]quinolines 136, designed for use in iterative protein crystal analysis (Scheme 42) (92JMC847). 

Fig. 1.4 The increase in thymidylate synthase inhibition activity obtained from an initial hit identified as a disulphide-bound enzyme adduct and optimised to a reversible potent 330nM inhibitor using crystal structure-guided design.

R. W. Ward, J. White, E. W. Moomaw, C. A. Bartlett, and C. A. Morse, Structure-based design of lipophilic quinazoline inhibitors of thymidylate synthase, J. Med. Chem. 39 904 (1996). 

Varney MD, Marzoni GP, Palmer CL, Deal JG, Webber S, Welsh KM, Bacquet RJ, Bartlett CA, Morse CA, Booth CLJ, Herrmann SM, Howland EF, Ward RW, White J. Crystal-structure-based design of Benz[cd]indole-containing inhibitors of thymidylate synthase. JMed Chem 1992 35 663-676. 

Human thymidylate synthase (TS) A 5-substituted lH-benzo cd indol-2-one scaffold was designed de novo based on a key interaction pattern identified from previous X-ray analyses, and on a GRID analysis of the TS crystal structure. X-ray analysis of the complex with a newly designed, low micromolar derivative revealed unmet interactions, and suggested the replacement of a lactam carbonyl by an amidine functionality, ultimately leading to a low nanomolar TS inhibitor selected for clinical trials. i36 ... 

Fig. 6. Chemical structures of inhibitors of thymidylate synthase designed based on modifications of 5,10-methylene tetrahydrofolate (a) ZD1694, (b) OSI1843U89. (c) CB3717 (34).

Varney, M.D., Marzoni, G.P., Palmer, C.L., et al. (1992) Crystal-structure-based design and synthesis of benz[cd]indole-containing inhibitors of thymidylate synthase. J. Med. Chem. 35, 663-676. 

Thymidylate synthase (TS) catalyses the methylation of deoxyuridylate to thymidylate using 5,10-methylenetetra-hydrofolate (Fig. 26.17a) as a coenzyme. TS inhibitors have potential as chemotherapeutic agents for the treatment of cancer as TS provides the sole biosynthetic source of thymidylate, a precursor in DNA biosynthesis. The design of TS inhibitors is a superb example of structure-based dmg design. The reader is urged to read the original papers, which describe the work in great detail. °... 

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