Conformationally restricted tricyclic analogues of lipophilic pyrido[2,3-d]pyrimidine antifolates [1a,b]

A. Gangjee, F. Mavandadi, Sherry Queener

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Abstract

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)-9-hydro-pyrrolo [3,4-c]pyrido[2,3-d]pyrimidin-6-(8H)-one (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 cyclo-condensation of the β-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 liven 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.

Original languageEnglish (US)
Pages (from-to)213-220
Number of pages8
JournalJournal of Heterocyclic Chemistry
Volume38
Issue number1
StatePublished - 2001

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Folic Acid Antagonists
Tetrahydrofolate Dehydrogenase
Trimetrexate
Rats
Boranes
Lactams
Liver
Condensation
Esters
pyrido(3,2-d)pyrimidine

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Conformationally restricted tricyclic analogues of lipophilic pyrido[2,3-d]pyrimidine antifolates [1a,b]. / Gangjee, A.; Mavandadi, F.; Queener, Sherry.

In: Journal of Heterocyclic Chemistry, Vol. 38, No. 1, 2001, p. 213-220.

Research output: Contribution to journalArticle

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abstract = "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)-9-hydro-pyrrolo [3,4-c]pyrido[2,3-d]pyrimidin-6-(8H)-one (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 cyclo-condensation of the β-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 liven 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.",
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