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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 &gt; 9 &gt; 5 &gt; 7 &gt; 8, with 10 showing no activity, and 6 &gt; 9 &gt; 5 &gt; 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 &lt;1 nM IC 50 , ∼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.

journal of medicinal chemistry

Tumor Targeting with Novel Pyridyl 6-Substituted Pyrrolo[2,3-<i>d</i>]Pyrimidine Antifolates via Cellular Uptake by Folate Receptor α and the Proton-Coupled Folate Transporter and Inhibition of <i>De Novo</i> Purine Nucleotide Biosynthesis

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