2. Academic Validation
  3. 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

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

  • J Med Chem. 2015 Sep 10;58(17):6938-59. doi: 10.1021/acs.jmedchem.5b00801.
Lei Wang 1,  Adrianne Wallace 2,  Sudhir Raghavan 1,  Siobhan M Deis 3,  Mike R Wilson 4,  Si Yang 1,  Lisa Polin 2 4,  Kathryn White 2 4,  Juiwanna Kushner 2 4,  Steven Orr 2,  Christina George 2,  Carrie O'Connor 2,  Zhanjun Hou 2 4,  Shermaine Mitchell-Ryan 4,  Charles E Dann 3rd 3,  Larry H Matherly 2 4 5,  Aleem Gangjee 1
Affiliations

Affiliations

  • 1 Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University , 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, United States.
  • 2 Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute , 110 East Warren Avenue, Detroit, Michigan 48201, United States.
  • 3 Department of Chemistry, Indiana University , Bloomington, Indiana 47405, United States.
  • 4 Department of Oncology, Wayne State University School of Medicine , Detroit, Michigan 48201, United States.
  • 5 Department of Pharmacology, Wayne State University School of Medicine , Detroit, Michigan 48201, United States.
PMID: 26317331 DOI: 10.1021/acs.jmedchem.5b00801
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.

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