jm980081y_si_001.pdf (110.85 kB)
Structure-Based Design and Synthesis of Lipophilic 2,4-Diamino-6-Substituted Quinazolines and Their Evaluation as Inhibitors of Dihydrofolate Reductases and Potential Antitumor Agents
journal contribution
posted on 1998-08-12, 00:00 authored by Aleem Gangjee, Anup P. Vidwans, Anil Vasudevan, Sherry F. Queener, Roy L. Kisliuk, Vivian Cody, Ruming Li, Nikolai Galitsky, Joe R. Luft, Walter PangbornThe synthesis and biological activities of 14 6-substituted 2,4-diaminoquinazolines are reported.
These compounds were designed to improve the cell penetration of a previously reported series
of 2,4-diamino-6-substituted-pyrido[2,3-d]pyrimidines which had shown significant potency and
remarkable selectivity for Toxoplasma gondii dihydrofolate reductase (DHFR), but had much
lower inhibitory effects on the growth of T. gondii cells in culture. The target N9−H analogues
were obtained via regiospecific reductive amination of the appropriate benzaldehydes with 2,4,6-triaminoquinazoline, which, in turn, was synthesized from 2,4-diamino-6-nitroquinazoline. The
N9−CH3 analogues were synthesized via a regiospecific reductive methylation of the corresponding N9−H precursors. The compounds were evaluated as inhibitors of DHFR from
human, Pneumocystis carinii, T. gondii, rat liver, Lactobacillus casei, and Escherichia coli,
and selected analogues were evaluated as inhibitors of the growth of tumor cells in culture.
These analogues displayed potent T. gondii DHFR inhibition as well as inhibition of the growth
of T. gondii cells in culture. Further, selected analogues were potent inhibitors of the growth
of tumor cells in culture in the in vitro screening program of the National Cancer Institute
with GI50s in the nanomolar and subnanomolar range. Crystallographic data for the ternary
complex of hDHFR−NADPH and 2,4-diamino-6-[N-(2‘,5‘-dimethoxybenzyl)-N-methylamino]pyrido[2,3-d]pyrimidine, 1c, reveal the first structural details for a reversed N9−C10 folate
bridge geometry as well as the first conformational details of a hybrid piritrexim−trimetrexate
analogue.