Conformationally restricted tricyclic analogues of lipophilic pyrido[2,3-d]pyrimidine antifolates

被引：1

作者：

Gangjee, A ^{[1
]}

Mavandadi, F

Queener, SF

机构：

[1] Duquesne Univ, Grad Sch Pharmaceut Sci, Div Med Chem, Pittsburgh, PA 15282 USA

[2] FibroGen, S San Francisco, CA 94080 USA

[3] Indiana Univ, Sch Med, Dept Pharmacol & Toxicol, Indianapolis, IN 46202 USA

来源：

JOURNAL OF HETEROCYCLIC CHEMISTRY | 2001年 / 38卷 / 01期

关键词：

D O I：

10.1002/jhet.5570380132

中图分类号：

O62 [有机化学];

学科分类号：

070303 ; 081704 ;

摘要：

The effect of conformational restriction of the C9-N10 bridge on inhibitory potency and selectivity of trimetrexate against dihydrofolate reductase, was studied. Specifically three nonclassical tricyclic 1,3-diamino-8-(3',4',5'-trimethoxybenzyl)-7,9-dihydro-pyrrolo[3,4-c]pyrido[2,3-d]pyrimidin-6(5H,8H)-one (4), 1,3-diamino-8-(3',4',5'-trimethoxybenzyl (5) and 1,3-diamino-(8H)-(3',4',5'-trimethoxybenzyl)-7,9-dihydro-pyrrolo[3,4-c]pyrido[2,3-d]pyrimidine (7) antifolates were synthesized. The tricyclic analogues 4 and 5 were obtained via the regiospecific cyclocondensation of the beta -keto ester 17 with 2,4,6-triaminopyrimidine. The analogue 7 was obtained via reduction of the lactam 4 with borane in tetrahydrofuran. Compounds 4, 5 and 7 were evaluated as inhibitors of dihydrofolate reductase from Pneumocystis carinii, Toxoplasma gondii and rat liver. All three compounds were more selective than trimetrexate against Pneumocystis carinii dihydrofolate reductase and significantly more selective than trimetrexate against Toxoplasma gondii dihydrofolate reductase compared with rat liver dihydrofolate reductase.

引用

页码：213 / 220

页数：8

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