The two most important hurdles in cancer chemotherapy are toxicity due to inability of the therapeutic agent to selectively target tumor cells and chemotherapeutic resistance common to single agent therapy. Pemetrexed (PMX), the multi-enzyme targeted anticancer drug has dose-limiting toxicity due to its transport by the ubiquitously expressed reduced folate carrier (RFC). We recently reported a series of 5-substituted pyrrolo[2,3-d]pyrimidine classical antifolates that inhibit folate receptor (FR) expressing tumor cells (KB and IGROV1) at nanomolar IC50 values by selective uptake. The target enzymes were confirmed to be glycinamide ribonucleotide formyl transferase (GARFTase) and aminoimidazole carboxamide ribonucleotide formyl transferase (AICARFTase) having little to no DHFR (dihydrofolate reductase) or thymidylate synthase (TS) inhibitory activity. To determine the impact of the distance between the scaffold and the side chain phenyl on multi-target inhibition as well as selectivity, a series of classical 5-substituted pyrrolo[2,3-d]pyrimidines with varying bond lengths were designed and synthesized. The synthesis and in vitro evaluation of these compounds as substrates for folate transporters- RFC, FR and proton coupled folate transporter (PCFT) and as inhibitors of GARFTase, AICARFTase, TS and DHFR will be presented.

Design, synthesis, and biological evaluation of pemetrexed homologs as multi-enzyme antifolates selectively targeting the folate receptor

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.