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

摘要

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 [~(3)H]folic acid. Only compound 6 was active against proton-coupled folate receptor (PCFT)-expressing CHO cells (～4-fold more potent than 1 ) and inhibited [~(3)H]methotrexate uptake by PCFT. In KB and IGROV1 tumor cells, 6 showed 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.