Non-glutamate Type Pyrrolo[2,3-d]pyrimidine Antifolates. I: Synthesis and Biological Properties of Pyrrolo [2,3-d] pyrimidine Antifolates Containing Tetrazole Congener of Glutamic Acid

Abstract

Either the α- or γ-carboxyl group of the glutamic acid moiety of N-[4-[3-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yh]propyl]benzoyl]-L-glutamic acid (lb, TNP-351) and its related compound (la) was replaced with a 1H-tetrazole ring, and the inhibitory effects of the resulting compounds on dihydrofolate reductase (DHFR) and the growth of murine fibrosarcoma Meth A cells were examined. The γ-tetrazole analogs (2) were found to be much more potent DHFR inhibitors than TNP-351, and strongly inhibited the growth of Meth A cells. On the other hand, the a-tetrazole analogs (3) were much less active against Meth A cells, even though their DHFR-inhibitory activity was comparable to that of TNP-351. These findings suggest that the a-carboxyl group plays an important role in effective uptake via the reduced folate carrier, and a novel DHFR inhibitor could be obtained by chemically modifying the γ-carboxyl moiety while leaving the a-carboxyl group intact. © 1995, The Pharmaceutical Society of Japan. All rights reserved.