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Publication Abstract from PubMed

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) alpha and beta or the proton-coupled folate transporter. Results show increased in vitro anti-proliferative activity toward engineered Chinese hamster ovary cells expressing FRs by 4-9 over the CH2 analog 1. Compounds 4-9 inhibited de novo purine biosynthesis and glycinamide ribonucleotide formyltransferase (GARFTase). X-ray crystal structures for 4 with FRalpha and GARFTase showed that the bound conformations of 4 required flexibility for attachment to both FRalpha 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.

Tumor Targeting with Novel 6-Substituted Pyrrolo [2,3-d] Pyrimidine Antifolates with Heteroatom Bridge Substitutions Via Cellular Uptake by Folate Receptor alpha and the Proton-coupled Folate Transporter and Inhibition of De Novo Purine Nucleotide Biosynthesis.,Golani LK, Wallace-Povirk A, Deis SM, Wong JE, Ke J, Gu X, Raghavan S, Wilson MR, Li X, Polin LA, de Waal PW, White K, Kushner J, O'Connor CE, Hou Z, Xu HE, Melcher K, Dann Iii CE, Matherly LH, Gangjee A J Med Chem. 2016 Jul 26. PMID:27458733^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.