2. Academic Validation
  3. Tumor Targeting with Novel 6-Substituted Pyrrolo [2,3-d] Pyrimidine Antifolates with Heteroatom Bridge Substitutions via Cellular Uptake by Folate Receptor α and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis

Tumor Targeting with Novel 6-Substituted Pyrrolo [2,3-d] Pyrimidine Antifolates with Heteroatom Bridge Substitutions via Cellular Uptake by Folate Receptor α and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis

  • J Med Chem. 2016 Sep 8;59(17):7856-76. doi: 10.1021/acs.jmedchem.6b00594.
Lalit K Golani 1,  Adrianne Wallace-Povirk 2,  Siobhan M Deis 3,  Jennifer Wong 3,  Jiyuan Ke 4,  Xin Gu 4,  Sudhir Raghavan 1,  Mike R Wilson 5,  Xinxin Li 1,  Lisa Polin 2 5,  Parker W de Waal 4,  Kathryn White 2 5,  Juiwanna Kushner 2 5,  Carrie O'Connor 2,  Zhanjun Hou 2 5,  H Eric Xu 4 6,  Karsten Melcher 4,  Charles E Dann 3rd 3,  Larry H Matherly 2 5 7,  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 Laboratory of Structural Sciences and Laboratory of Structural Biology and Biochemistry, Van Andel Research Institute , 333 Bostwick Avenue NE, Grand Rapids, Michigan 49503, United States.
  • 5 Department of Oncology, Wayne State University School of Medicine , Detroit, Michigan 48201, United States.
  • 6 Key Laboratory of Receptor Research, VARI-SIMM Center, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai 201203, People's Republic of China.
  • 7 Department of Pharmacology, Wayne State University School of Medicine , Detroit, Michigan 48201, United States.
PMID: 27458733 DOI: 10.1021/acs.jmedchem.6b00594
Abstract

Targeted antifolates with heteroatom replacements of the carbon vicinal to the phenyl ring in 1 by N (4), O (8), or S (9), or with N-substituted formyl (5), acetyl (6), or trifluoroacetyl (7) moieties, were synthesized and tested for selective cellular uptake by folate receptor (FR) α and β or the proton-coupled folate transporter. Results show increased in vitro antiproliferative activity toward engineered Chinese hamster ovary cells expressing FRs by 4-9 over the CH2 analogue 1. Compounds 4-9 inhibited de novo purine biosynthesis and glycinamide ribonucleotide formyltransferase (GARFTase). X-ray crystal structures for 4 with FRα and GARFTase showed that the bound conformations of 4 required flexibility for attachment to both FRα and GARFTase. In mice bearing IGROV1 ovarian tumor xenografts, 4 was highly efficacious. Our results establish that heteroatom substitutions in the 3-atom bridge region of 6-substituted pyrrolo[2,3-d]pyrimidines related to 1 provide targeted antifolates that warrant further evaluation as Anticancer agents.

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