- Design and Synthesis of Novel 6,7-Imidazotetrahydroquinoline Inhibitors of Thymidylate Synthase Using Iterative Protein Crystal Structure Analysis
-
Antifolate inhibitors of thymidylate synthase (TS) have primarily been based on the structure of folic acid.This paper describes the identification and development of novel 6,7-imidazotetrahydroquinoline TS inhibitors by iterative ligand design, synthesis, and crystallographic analysis of protein-inhibitor complexes.Beginning with a high-resolution crystal structure of E. coli TS (TS, EC 2.1.1.45), an imidazotetrahydroquinoline inhibitor was designed de novo to occupy the folate binding pocket.Structural modifications of the initial compound 1h (Ki ca. 5 μM human/E. coli TS) were then made on the basis of feedback from additional cocrystal structures and activity data.An amino group in the 2-position of the imidazole was found to increase the potency of the series by 1-2 orders of magnitude.Other substitutions on the imidazole ring (1-CH3, 2-CH3, 2-NHCH3, 2-SCH3) generally led to weaker inhibition.Additional improvements in activity were obtained by modification of the substituents on the tetrahydroquinoline nitrogen, bringing the Ki of three of the compounds below 15 nM against the human TS enzyme.The compounds were tested for cytotoxicity and were shown to inhibit the growth of three tumor cell lines in vitro.
- Reich, Siegfried H.,Fuhry, Mary Ann M.,Nguyen, Dzuy,Pino, Mark J.,Welsh, Katherine M.,et al.
-
p. 847 - 858
(2007/10/02)
-
- Crystal-Structure-Based Design and Synthesis of Benzindole-Containing Inhibitors of Thymidylate Synthase
-
The X-ray crystal-structure-based design, synthesis, and biological activity of a novel family of benzindole-containing inhibitors of thymidylate synthase (TS) are described.The structure-activity of the lead compound was studied by conceptually dividing the molecule into four regions and independently optimizing the substituents for each region.Combination of favored substituents for each region led to inhibitors with Ki's against the human enzyme in the range of 10-20 nM.Thymidine shift experiments suggested that the cytotoxic properties of the best enzyme inhibitors were due to TS targeting in cells.The inhibitors were synthesized from substituted 6-aminobenzindol-2(1H)-ones by alkylation with both a simple alkyl group and a substituted benzylic portion.The 2,6-diaminobenzindoles were prepared from the corresponding lactams by conversion to the thiolactam, alkylation to the methylated thiolactam, and then displacement with a substituted or unsubstituted amine.
- Varney, Michael D.,Marzoni, Gifford P.,Palmer, Cindy L.,Deal, Judith G.,Webber, Stephanie,et al.
-
p. 663 - 676
(2007/10/02)
-