Novel 5-substituted pyrrolo[2,3- d ]pyrimidines as dual inhibitors of glycinamide ribonucleotide formyltransferase and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase and as potential antitumor agents

Yiqiang Wang, Shermaine Mitchell-Ryan, Sudhir Raghavan, Christina George, Steven Orr, Zhanjun Hou, Larry H. Matherly, Aleem Gangjee

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

A new series of 5-substituted thiopheneyl pyrrolo[2,3-d]pyrimidines 6-11 with varying chain lengths (n = 1-6) were designed and synthesized as hybrids of the clinically used anticancer drug pemetrexed (PMX) and our 6-substituted thiopheneyl pyrrolo[2,3-d]pyrimidines 2c and 2d with folate receptor (FR) α and proton-coupled folate transporter (PCFT) uptake specificity over the reduced folate carrier (RFC) and inhibition of de novo purine nucleotide biosynthesis at glycinamide ribonucleotide formyltransferase (GARFTase). Compounds 6-11 inhibited KB human tumor cells in the order 9 = 10 > 8 > 7 > 6 = 11. Compounds 8-10 were variously transported by FRα, PCFT, and RFC and, unlike PMX, inhibited de novo purine nucleotide rather than thymidylate biosynthesis. The antiproliferative effects of 8 and 9 appeared to be due to their dual inhibitions of both GARFTase and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase. Our studies identify a unique structure-activity relationship for transport and dual target inhibition.

Original languageEnglish (US)
Pages (from-to)1479-1493
Number of pages15
JournalJournal of Medicinal Chemistry
Volume58
Issue number3
DOIs
StatePublished - Feb 12 2015

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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