One of the major hurdles in cancer therapy is the inability of chemotherapy agents to selectively target tumor cells over normal tissues.  The multi-enzyme-targeted anticancer drug pemetrexed (PMX) suffers from dose-limiting toxicity due to its membrane transport by the reduced folate carrier (RFC) which is ubiquitously expressed in normal and tumor cells. We recently reported a series of 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolates. The most active of this series (AG71 ) included a 4 carbon bridge and a thienoyl ring and was selectively transported into cells by folate receptors (FRs) and the proton-coupled folate transporter (PCFT) (but not RFC) whereupon it inhibited de novo purine biosynthesis at the level of glycinamide ribonucleotide formyltransferase (GARFTase). AG71  was highly active toward both KB and IGROV1 tumors; in SCID mice with KB tumors, AG71  was also highly active against both early and advanced stage tumors. Based on our results with AG71 , a series of 6-substituted pyrrolo[2,3-d]pyrimidines with side chain variations in the bridge were designed and synthesized as analogs of AG71 . These analogs are part of the SAR study of FRa and/or PCFT transport and GARFTase inhibition. The analogs were tested for anti-proliferative effects on KB human tumor cells and on Chinese hamster ovary (CHO) sublines engineered to individually express RFC (PC43-10), PCFT (R2/PCFT4), and FRa (RT-16). Analogs synthesized in this study showed subnanomolar IC50 values against KB tumor cells in culture. Drug effects were completely abolished by excess folic acid establishing FR-mediated uptake. Similar to AG71 , no RFC activity is observed for these compounds. Whereas PMX is a multi-targeted agent with inhibitory effects on both de novo thymidylate and purine nucleotide biosynthetic pathways, the anti-proliferative effects of these compounds were abolished by adenosine but not thymidine, establishing exclusive inhibition of purine biosynthesis. The design, synthesis and biological activities of these analogs will be discussed.

Design, synthesis, and biological evaluation of 6-substituted pyrrolo[2,3-<i>d</i>]pyrimidines as potent inhibitors of tumors expressing folate receptors via GARFTase inhibition

244th National Meeting (2012)

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Design, synthesis, and biological evaluation of 6-substituted pyrrolo[2,3-d]pyrimidines as potent inhibitors of tumors expressing folate receptors via GARFTase inhibition