Novel 2,4-Diamino-5-substituted-pyrrolo[2,3-d]pyrimidines as Classical and Nonclassical Antifolate Inhibitors of Dihydrofolate Reductases
| Autor: | Farahnaz Mavandadi, John J. McGuire, Aleem Gangjee, Sherry F. Queener |
|---|---|
| Rok vydání: | 1995 |
| Předmět: |
chemistry.chemical_classification
Bicyclic molecule Pyrimidine biology Stereochemistry Aminopterin Chemical synthesis chemistry.chemical_compound Pyrimidines Enzyme chemistry Enzyme inhibitor Drug Discovery Antifolate Dihydrofolate reductase Tumor Cells Cultured biology.protein medicine Folic Acid Antagonists Humans Molecular Medicine Peptide Synthases medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 38:2158-2165 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm00012a016 |
| Popis: | 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-dipyrimidin-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 NaCNBH 3 . 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 (IC 50 s > 10 -5 M) than in tgDHFR (IC 50 s = 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 |
| Databáze: | OpenAIRE |
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