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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

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posted on 2016-07-26, 00:00 authored by Lalit K. Golani, Adrianne Wallace-Povirk, Siobhan M. Deis, Jennifer Wong, Jiyuan Ke, Xin Gu, Sudhir Raghavan, Mike R. Wilson, Xinxin Li, Lisa Polin, Parker W. de Waal, Kathryn White, Juiwanna Kushner, Carrie O’Connor, Zhanjun Hou, H. Eric Xu, Karsten Melcher, Charles E. Dann, Larry H. Matherly, Aleem Gangjee
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 49 over the CH2 analogue 1. Compounds 49 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.