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
  • 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.