Fluorine-Substituted Pyrrolo[2,3-d]Pyrimidine Analogues with Tumor Targeting via Cellular Uptake by Folate Receptor α and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis,Journal of Medicinal Chemistry

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Fluorine-Substituted Pyrrolo[2,3-d]Pyrimidine Analogues with Tumor Targeting via Cellular Uptake by Folate Receptor α and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis
Journal of Medicinal Chemistry ( IF 7.3 ) Pub Date : 2018-04-27 00:00:00 , DOI: 10.1021/acs.jmedchem.8b00408
Manasa Ravindra ₁ , Mike R. Wilson _{1,

2} , Nian Tong ₁ , Carrie O’Connor ₂ , Mohammad Karim ₁ , Lisa Polin _{2,

3} , Adrianne Wallace-Povirk ₂ , Kathryn White _{2,

3} , Juiwanna Kushner _{2,

3} , Zhanjun Hou _{2,

3} , Larry H. Matherly _{2,

3,

4} , Aleem Gangjee ₁

Affiliation

Novel fluorinated 2-amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidine analogues 7–12 were synthesized and tested for selective cellular uptake by folate receptors (FRs) α and β or the proton-coupled folate transporter (PCFT) and for antitumor efficacy. Compounds 8, 9, 11, and 12 showed increased in vitro antiproliferative activities (∼11-fold) over the nonfluorinated analogues 2, 3, 5, and 6 toward engineered Chinese hamster ovary and HeLa cells expressing FRs or PCFT. Compounds 8, 9, 11, and 12 also inhibited proliferation of IGROV1 and A2780 epithelial ovarian cancer cells; in IGROV1 cells with knockdown of FRα, 9, 11, and 12 showed sustained inhibition associated with uptake by PCFT. All compounds inhibited glycinamide ribonucleotide formyltransferase, a key enzyme in the de novo purine biosynthesis pathway. Molecular modeling studies validated in vitro cell-based results. NMR evidence supports the presence of an intramolecular fluorine–hydrogen bond. Potent in vivo efficacy of 11 was established with IGROV1 xenografts in severe compromised immunodeficient mice.

更新日期：2018-04-27

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