Pemetrexed (PMX, Alimta: total annual sale of 2.28 billion dollars in 2016) is the current standard for treating malignant pleural mesothelioma and non-small cell lung cancer. Despite being a blockbuster drug, PMX suffers from neutropenia as a dose-limiting toxicity in part due to its non-selective transport by the reduced folate carrier (RFC). RFC is expressed ubiquitously in normal tissues and tumor cells. Unlike RFC, folate receptors (FRα and FRβ) and the proton coupled folate transporter (PCFT) show limited expression in normal tissues. In normal tissues, FRα (eg. renal tubule) is inaccessible to circulating chemotherapeutic agents and FRβ (eg. thymus) is nonfunctional. On the other hand, FRs are overexpressed in malignancies such as ovarian cancer (FRα) and in myeloid leukemia (FRβ), where they are accessible to circulation. PCFT functions optimally between pH range 5.5 – 6.9 which mimics the acidic microenvironment of solid tumors and becomes non-functional at physiological pH (7.2 - 7.4). Hence agents targeting FRs and/or PCFT selectively over RFC are expected to have superior safety profile as novel cytotoxic targeted cancer chemotherapeutics. PMX is a 5-substituted pyrrolo[2,3-d]pyrimidine linked to a phenyl glutamate side chain via a two carbon bridge. Our previously reported 5-substituted pyrrolo[2,3-d]pyrimidines with phenyl side chains and three (AGF126) or four carbon (AGF127) linkers, when compared with PMX showed potent KB tumor cell inhibition with very little or no selectivity for FRα, FRβ or PCFT over RFC. To improve selectivity, we designed and synthesized 5-substituted pyrrolo[2,3-d]pyrimidines with a pyridine side chain and two-(AGF324), three- (AGF315) and four- (AGF317) carbon bridges. AGF315 and AGF317 showed outstanding selectivity for FRα (32- and 22- fold, respectively), FRβ (226- and 55- fold, respectively) and moderate selectivity for PCFT (6- and 3- fold, respectively) over RFC with potent KB tumor cell inhibition (IC50 = 15.9 nM and 2.51 nM, respectively). To our knowledge, this is the first example of 5-substituted pyrrolo[2,3-d]pyrimidine analogs with remarkable (&gt; 10 fold) selectivity for both FRα and FRβ over RFC in in vitro studies compared to PMX. The design, synthesis, and biological evaluation of these pyridine analogs will be presented.

Novel 5-substituted pyrrolo[2,3-d]pyrimidines with pyridine glutamate side chain as selective folate receptors and proton-coupled folate transporter substrates: Potential targeted chemotherapeutic agents

254th National Meeting (2017)

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