Cancer chemotherapy is in urgent need of agents devoid of dose-limiting toxicities (DLTs) and drug resistance. Targeted chemotherapy utilizes selective uptake by transporters expressed in tumor cells to circumvent DLTs. Multi-enzyme inhibition can evade tumor resistance by attacking two or more targets in tumor cells. The folate receptors (FRs) are functionally overexpressed in several tumor cells including ovarian cancers and the proton-coupled folate transporter (PCFT) is the principal folate transporter in the acidic micro-environment of solid tumors. The reduced folate carrier (RFC) is ubiquitously expressed major tissue folate transporter, and is non-functional in acidic environment. Substrates of folate transporters inhibit one or more of the following intracellular enzymes that catalyze one-carbon transfer during purine/pyrimidine biosynthesis: glycinamide ribonucleotide formyl transferase (GARFTase), aminoimidazole carboxamide ribonucleotide formyl transferase (AICARFTase), thymidylate synthase (TS) and dihydrofolate reductase (DHFR). DLTs due to non-selective RFC mediated transport, and tumor resistance are the drawbacks of currently used drugs such as methotrexate (MTX) and pemetrexed (PMX). Our previous reports demonstrated that scaffold hopping and 2C bridge extension to 3C and 4C in 6-5 fused aroyl glutamates that are structurally and mechanistically distinct from MTX and PMX, improve antitumor potency and selectivity ( selectively inhibit FR/PCFT over RFC over-expressing KB and IGROV1 tumor cells at sub-nM to nM IC50 values due to GARFTase and/or AICARFTase inhibition). We recently reported that fluorine substitution on the phenyl side chain, ortho(o-) to the glutamate improves potency and selectivity of our pyrrolo[2,3-d]pyrimidine analogs. Fluorine substitution can lower binding energies and/or favor the bound conformation by a multitude of effects such as intramolecular F-H bonding, halogen bonding, dipole interactions and steric effects. In the current report we extend the rational design of 6-substituted pyrrolo[2,3-d]pyrimidine analogs to explore the effects on the biological activity by replacing the o-fluorophenyl side chain with o-methylphenyl (steric), o-trifluoromethylphenyl (steric and electronic) and pyrimidyl (electronic) side chains. Novel compounds in this series have a remarkable picomolar inhibition of tumor cells. The molecular modeling, synthesis, NMR studies for F-H bonding and in vitro evaluation will be presented.

Targeted antitumor agents for the inhibition of one-carbon metabolism associated with purine biosynthesis: Altering sterics, electronics and conformation for tumor selectivity and potency

254th National Meeting (2017)

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