Synthesis and Biological Evaluation of Novel 2,6-Diaminobenz[cd]indole Inhibitors of Thymidylate Synthase Using the Protein Structure as a Guide

1995 ◽  
Vol 38 (11) ◽  
pp. 1892-1903 ◽  
Author(s):  
Michael D. Varney ◽  
Cindy L. Palmer ◽  
Judith G. Deal ◽  
Stephanie Webber ◽  
Katherine M. Welsh ◽  
...  
Keyword(s):  
Protein Structure ◽  
Thymidylate Synthase ◽  
Biological Evaluation ◽  
Synthesis And Biological Evaluation

scholarly journals Sulfamide antifolates inhibiting thymidylate synthase: synthesis, enzyme inhibition and cytotoxicity.

2002 ◽  
Vol 49 (2) ◽  
pp. 407-420 ◽  
Author(s):  
Krzysztof Pawełczak ◽  
Maciej Makowski ◽  
Michał Kempny ◽  
Jolanta M Dzik ◽  
Barbara Gołos ◽  
...  
Keyword(s):  
Thymidylate Synthase ◽  
Growth Inhibitor ◽  
Biological Evaluation ◽  
Hymenolepis Diminuta ◽  
Ehrlich Carcinoma ◽  
Thymidylate Synthases ◽  
Glutamic Acid Residue ◽  
Synthase Inhibitor ◽  
New Compounds ◽  
Synthesis And Biological Evaluation

Synthesis and biological evaluation are described of seven new analogues (3-9) of two potent thymidylate synthase inhibitors, 10-propargyl-5,8-dideazafolate (1) and its 2-methyl-2-deamino congener ICI 198583 (2). While the new compunds 3 and 4 were analogues of 1 and 2, respectively, containing a p-aminobenzenesulfonyl residue in place of the p-aminobenzoic acid residue, the remaining 5 new compounds were analogues of 4 with the L-glutamic acid residue replaced by glycine (5), L-valine (6), L-alanine (7), L-phenylglycine (8) or L-norvaline (9). The new analogues were tested as inhibitors of thymidylate synthases isolated from tumour (Ehrlich carcinoma), parasite (Hymenolepis diminuta) and normal tissue (regenerating rat liver) and found to be weaker inhibitors than the parent 10-propargyl-5,8-dideazafolic acid. Selected new analogues, tested as inhibitors of growth of mouse leukemia L 5178Y cells, were less potent than the parent 10-propargyl-5,8-dideazafolic acid. Substitution of the glutamyl residue in compound 4 with L-norvaline (9) resulted in only a 5-fold stronger thymidylate synthase inhibitor, but a 40-fold weaker cell growth inhibitor.

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