Defense Date


Graduation Date

Spring 5-11-2018


One-year Embargo

Submission Type


Degree Name



Medicinal Chemistry


School of Pharmacy

Committee Chair

Aleem Gangjee

Committee Member

Marc W. Harrold

Committee Member

Kevin Tidgewell


antifolate, PYRROLO[2, 3-d]PYRIMIDINE, furo, 5-substituted


In last few decades many folate analogs have been discovered and several compounds are successfully being used as anticancer agents. Methotrexate (MTX), pemetrexed (PMX), raltitrexed (RTX): are a few examples of classical antifolates that are currently in clinical use. Although these compounds are widely used, all of them show dose limiting toxicity due to their non-specific transport into normal cells as well as malignant cells. Currently, clinically used classical antifolates suffer from this disadvantage because there is no way to selectively transport them into malignant cells. Currently available antifolates are transported via reduced folate career (RFC) as well as Folate receptors (FRs) and/or Proton coupled folate transporter (PCFT). Because RFC is ubiquitous in the human body, the dose limiting toxicity is unavoidable for an antifolate if it is a substrate for RFC. To circumvent this challenge with antifolate chemotherapy, it is necessary to develop agents which are selective for the cancerous tissues. Exploiting the site specificity of FRs and/or the acidic pH specificity of PCFT, the goal of developing targeted antifolate agents could be achieved. This approach of selective transport into tumor cells via FRs and/or PCFT and over RFC targets inhibition of GARFTase dependent salvage pathway for purine biosynthesis inside the tumor. Based on this premise, five 5-substituted pyrrolo[2,3-d]pyrimidines have been designed, synthesized and characterized. Among them four are novel compounds and one is a previously reported compound. The previously reported compound has never been tested for FR/PCFT-GARFTase selectivity before, and therefore was of interest and was synthesized. To investigate the role of side chain aromatic group in the folate analogs, phenyl, fluorophenyl and furan groups have been placed in the linker region. The compounds comprise of different aliphatic linker chain length from 2C to 5C. To test selectivity, FR and PCFT transport have been studied. and GARFTase inhibitory assay will be conducted.