6-Substituted Pyrrolo[2,3-d]pyrimidine Thienoyl Regioisomers as Targeted Antifolates for Folate Receptor α and the Proton-Coupled Folate Transporter in Human Tumors

Lei Wang, Adrianne Wallace, Sudhir Raghavan, Siobhan M. Deis, Mike R. Wilson, Si Yang, Lisa Polin, Kathryn White, Juiwanna Kushner, Steven Orr, Christina George, Carrie O'Connor, Zhanjun Hou, Shermaine Mitchell-Ryan, Charles E. Dann, Larry H. Matherly, Aleem Gangjee

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

2-Amino-4-oxo-6-substituted-pyrrolo[2,3-d]pyrimidine antifolate thiophene regioisomers of AGF94 (4) with a thienoyl side chain and three-carbon bridge lengths [AGF150 (5) and AGF154 (7)] were synthesized as potential antitumor agents. These analogues inhibited proliferation of Chinese hamster ovary (CHO) sublines expressing folate receptors (FRs) α or β (IC50s < 1 nM) or the proton-coupled folate transporter (PCFT) (IC50 < 7 nM). Compounds 5 and 7 inhibited KB, IGROV1, and SKOV3 human tumor cells at subnanomolar concentrations, reflecting both FRα and PCFT uptake. AGF152 (6) and AGF163 (8), 2,4-diamino-5-substituted-furo[2,3-d]pyrimidine thiophene regioisomers, also inhibited growth of FR-expressing CHO and KB cells. All four analogues inhibited glycinamide ribonucleotide formyltransferase (GARFTase). Crystal structures of human GARFTase complexed with 5 and 7 were reported. In severe combined immunodeficient mice bearing SKOV3 tumors, 7 was efficacious. The selectivity of these compounds for PCFT and for FRα and β over the ubiquitously expressed reduced folate carrier is a paradigm for selective tumor targeting.

Original languageEnglish (US)
Pages (from-to)6938-6959
Number of pages22
JournalJournal of Medicinal Chemistry
Volume58
Issue number17
DOIs
StatePublished - Sep 10 2015

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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