Novel 2,4-diamino-5-substituted-pyrrolo[2,3-d]pyrimidines as classical and nonclassical antifolate inhibitors of dihydrofolate reductases

Aleem Gangjee, Farahnaz Mavandadi, Sherry Queener, John J. McGuire

Research output: Contribution to journalArticle

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Abstract

Eight novel, nonclassical, antifolate 2,4-diamino-5-(anilinomethyl)pyrrolo[2,3-d]pyrimidines, 1-8, with 3′,4′,5′-trimethoxyphenyl, 3′,4′-dimethoxyphenyl, 2′,5′-dimethoxyphenyl, 4′-methoxyphenyl, 2′,5′-diethoxyphenyl, 3′,4′-dichlorophenyl, 1′-naphthyl, and phenyl substituents were synthesized as potential inhibitors of dihydrofolate reductases (DHFRs). The classical analogue N-[4-[N-[(2,4-diaminopyrrolo[2,3-d]pyrimidin-5-yl)methyl]amino]benzoyl]-L- glutamic acid (9) was also synthesized as an inhibitor of DHFR and an antitumor agent. The classical and nonclassical analogues were obtained via reductive condensations of the key intermediate 2,4-diamino-5-cyanopyrrolo[2,3-d]pyrimidine (12) with the appropriate substituted aniline or (p-aminobenzoyl)-L-glutamate followed by reduction of the intermediate Schiff bases with NaCNBH3. Compounds 1-9 were evaluated in vitro as inhibitors of rat liver (rl), Pneumocystis carinii (pc), and Toxoplasma gondii (tg) DHFRs. The nonclassical analogues were significantly selective against tgDHFR (vs rat liver DHFR), ranging from 7- to 92-fold. The inhibitory activity was lower in pcDHFR and rlDHFR (IC50s > 10-5 M) than in tgDHFR (IC50s = 10-6 M). The classical analogue had inhibitory activity similar to that of methotrexate (MTX) against the growth of human leukemia CCRF-CEM, A253, and FaDu squamous cell carcinoma (SCC) of the head and neck cell lines. Further evaluation of 9 against CCRF-CEM and its sublines having defined mechanisms of MTX resistance demonstrated that the analogue utilizes the reduced folate/MTX-transport system and primarily inhibits DHFR and poly-γ-glutamylation plays a role in its mechanism of action. Compound 9 was found to be 3-fold more efficient than aminopterin as a substrate for human folylpolyglutamate synthetase.

Original languageEnglish
Pages (from-to)2158-2165
Number of pages8
JournalJournal of Medicinal Chemistry
Volume38
Issue number12
StatePublished - 1995

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Folic Acid Antagonists
Tetrahydrofolate Dehydrogenase
Methotrexate
Liver
Rats
Glutamic Acid
Aminopterin
Pneumocystis carinii
Schiff Bases
Toxoplasma
Folic Acid
Antineoplastic Agents
Condensation
Leukemia
Cells
Cell Line
Substrates
Growth
Pyrrolo(2,3-d)pyrimidine

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Novel 2,4-diamino-5-substituted-pyrrolo[2,3-d]pyrimidines as classical and nonclassical antifolate inhibitors of dihydrofolate reductases. / Gangjee, Aleem; Mavandadi, Farahnaz; Queener, Sherry; McGuire, John J.

In: Journal of Medicinal Chemistry, Vol. 38, No. 12, 1995, p. 2158-2165.

Research output: Contribution to journalArticle

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abstract = "Eight novel, nonclassical, antifolate 2,4-diamino-5-(anilinomethyl)pyrrolo[2,3-d]pyrimidines, 1-8, with 3′,4′,5′-trimethoxyphenyl, 3′,4′-dimethoxyphenyl, 2′,5′-dimethoxyphenyl, 4′-methoxyphenyl, 2′,5′-diethoxyphenyl, 3′,4′-dichlorophenyl, 1′-naphthyl, and phenyl substituents were synthesized as potential inhibitors of dihydrofolate reductases (DHFRs). The classical analogue N-[4-[N-[(2,4-diaminopyrrolo[2,3-d]pyrimidin-5-yl)methyl]amino]benzoyl]-L- glutamic acid (9) was also synthesized as an inhibitor of DHFR and an antitumor agent. The classical and nonclassical analogues were obtained via reductive condensations of the key intermediate 2,4-diamino-5-cyanopyrrolo[2,3-d]pyrimidine (12) with the appropriate substituted aniline or (p-aminobenzoyl)-L-glutamate followed by reduction of the intermediate Schiff bases with NaCNBH3. Compounds 1-9 were evaluated in vitro as inhibitors of rat liver (rl), Pneumocystis carinii (pc), and Toxoplasma gondii (tg) DHFRs. The nonclassical analogues were significantly selective against tgDHFR (vs rat liver DHFR), ranging from 7- to 92-fold. The inhibitory activity was lower in pcDHFR and rlDHFR (IC50s > 10-5 M) than in tgDHFR (IC50s = 10-6 M). The classical analogue had inhibitory activity similar to that of methotrexate (MTX) against the growth of human leukemia CCRF-CEM, A253, and FaDu squamous cell carcinoma (SCC) of the head and neck cell lines. Further evaluation of 9 against CCRF-CEM and its sublines having defined mechanisms of MTX resistance demonstrated that the analogue utilizes the reduced folate/MTX-transport system and primarily inhibits DHFR and poly-γ-glutamylation plays a role in its mechanism of action. Compound 9 was found to be 3-fold more efficient than aminopterin as a substrate for human folylpolyglutamate synthetase.",
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