2-amino-4-oxo-5-substituted-pyrrolo[2,3-d]pyrimidines as nonclassical antifolate inhibitors of thymidylate synthase

Aleem Gangjee, Farahnaz Mavandadi, Roy L. Kisliuk, John J. McGuire, Sherry F. Queener

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

Six novel 2-amino-4-oxo-5-[(substituted phenyl)sulfanyl]pyrrolo[2,3- d]pyrimidines 7-12 were synthesized as potential inhibitors of thymidylate synthase (TS) and as antitumor and/or antibacterial agents. The analogues contain a 5-thio substituent with a phenyl, 4'-chlorophenyl, 3',4'- dichlorophenyl, 4'-nitrephenyl, 3',4'-dimethoxyphenyl, and 2'-naphthyl on the sulfur, and were synthesized from the key intermediate 2-(pivaloylamino)-4- oxo-6-methylpyrrolo[2,3-d]-pyrimidine, 17. Appropriately substituted aryl thiols were appended to the 5-position of 17 via an oxidative addition reaction using iodine, ethanol, and water under conditions which also resulted in the deprotection of the 2-amino group. The compounds were evaluated against human, Lactobacillus casei, Escherichia coli, Streptococcus faecium, and Pneumocystis carinii (pc) TSs and against human, rat liver (rl), pc, and Toxoplasma gondii (tg) DHFRs. The nonclassical analogues with the 3',4'-dichloro and the 4'-nitro substituents in the side chain (9 and 10) were more potent than N-[4-[N-[(2-amino-3,4-dihydro-4-oxo-6- quinazolinyl)methyl]-N-prop-2-ynylamino]benzeyl]-L-glutamic acid (PDDF, 1) and N-[5-[N-[(3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl]-N- methylamino]-2-thenoyl]-L-glutamic acid (ZD1694, 2) against human TS. Analogues with the 4'-chloro, 3',4'-dimethoxy, and naphthyl side chains (8, 11 and 12) were more potent than the unsubstituted phenyl analogue (7) but less than 2, 9, and 10 by 1 order of magnitude. They were all poor inhibitors of human, rl, and pc DHFRs (IC50 = 10-5 M) but moderate inhibitors (IC50 = 10-6 M) of tg DHFR. The 4-nitro analogue, 10 (EC50 1.5 μM), was comparable to PDDF in its potency as an inhibitor of the growth of the FaDu human squamous cell carcinoma cell line.

Original languageEnglish (US)
Pages (from-to)4563-4568
Number of pages6
JournalJournal of Medicinal Chemistry
Volume39
Issue number23
DOIs
StatePublished - Nov 26 1996

    Fingerprint

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this