Tumor Targeting with Novel Pyridyl 6-Substituted Pyrrolo[2,3-d]Pyrimidine Antifolates 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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Tumor Targeting with Novel Pyridyl 6-Substituted Pyrrolo[2,3-d]Pyrimidine Antifolates 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 6.8 ) Pub Date : 2018-02-09 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01708
Manasa Ravindra ₁ , Adrianne Wallace-Povirk ₂ , Mohammad A. Karim ₁ , Mike R. Wilson ₂ , Carrie O’Connor ₂ , Kathryn White ₂ , Juiwanna Kushner ₂ , Lisa Polin _{2,

3} , Christina George ₂ , Zhanjun Hou _{2,

3} , Larry H. Matherly _{2,

3,

4} , Aleem Gangjee ₁

Affiliation

Tumor-targeted specificities of 6-substituted pyrrolo[2,3-d]pyrimidine analogues of 1, where the phenyl side-chain is replaced by 3′,6′ (5, 8), 2′,5′ (6, 9), and 2′,6′ (7, 10) pyridyls, were analyzed. Proliferation inhibition of isogenic Chinese hamster ovary (CHO) cells expressing folate receptors (FRs) α and β were in rank order, 6 > 9 > 5 > 7 > 8, with 10 showing no activity, and 6 > 9 > 5 > 8, with 10 and 7 being inactive, respectively. Antiproliferative effects toward FRα- and FRβ-expressing cells were reflected in competitive binding with [³H]folic acid. Only compound 6 was active against proton-coupled folate receptor (PCFT)-expressing CHO cells (∼4-fold more potent than 1) and inhibited [³H]methotrexate uptake by PCFT. In KB and IGROV1 tumor cells, 6 showed <1 nM IC₅₀, ∼2–3-fold more potent than 1. Compound 6 inhibited glycinamide ribonucleotide formyltransferase in de novo purine biosynthesis and showed potent in vivo efficacy toward subcutaneous IGROV1 tumor xenografts in SCID mice.

更新日期：2018-02-09

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