DESIGN AND SYNTHESIS OF FUSED PYRIMIDINES AS SINGLE AGENTS WITH COMBINATION CHEMOTHERAPY POTENTIAL, AS TUBULIN POLYMERIZATION AND ONE-CARBON METABOLISM INHIBITORS FOR CANCER

This dissertation describes the design, synthesis, and biological evaluation of bicyclic fused pyrimidines as single agents with combination chemotherapy potential with both antiangiogenic and cytotoxic effects. The dissertation also discusses one-carbon metabolism inhibitors and tumor targeting proteolysis targeting chimeras (PROTACs). In cancer chemotherapy, the two major limitations are the dose-limiting toxicities of clinically used agents and the development of resistance to the treatment. Combination chemotherapy with antiangiogenic agents and microtubule targeting agents has shown an advantage against both these drawbacks. Single agents with both antiangiogenic activity and cytotoxicity would afford a therapy that circumvents pharmacokinetic problems of multiple agents, avoid drug-drug interactions, lower the drug dose, decrease overlapping toxicities, and delay or prevent tumor cell resistance. The work in this dissertation discusses the development of fused pyrimidines, aimed to inhibit tubulin polymerization as well as act as antiangiogenic agents which inhibit one or more of the receptor tyrosine kinases (RTKs)- vascular endothelial growth factor receptor-2 (VEGFR2), platelet-derived growth factor receptor-β (PDGFRβ) and epidermal growth factor receptor (EGFR). This work also reviews the synthesis of bicyclic thieno[3,2-d]pyrimidines and pyrrolo[2,3-d]pyrimidines as microtubule targeting agents (MTAs). Cancer cells transport folates through reduced folate carrier (RFC), proton-coupled folate transporter (PCFT) and folate receptors (FRs). Tumor targeting through PCFT and FRs, over RFC is particularly valuable to selectively target the cancer cells over normal cells. The absence of X-ray crystal structure for RFC makes it challenging to design these compounds. Clinically used antifolates, such as pemetrexed has three major disadvantages: (i) transport by RFC; (ii) dependence on its polyglutamylation for potency; and (iii) development of resistance due to mutagenesis in the target enzyme (thymidylate synthase). This dissertation focuses on the development of substituted-pyrazolo[4,3-d]pyrimidines and thieno[3,2-d]pyrimidines to combat the above-mentioned drawbacks of clinically used antifolates. The work described herein discusses our efforts to obtain agents with the potential of inhibiting multiple intracellular targets for 1C metabolism, eventually preventing the de novo purine biosynthesis for cancer cells. PROTACs are heterobifunctional small molecules that employ the ubiquitin proteasome system to degrade the target protein of interest. In this dissertation, PROTACs using antifolate as the targeting agent have been reported. Novel synthetic effort has been developed to design pyrrolo[3,2-d]pyrimidine analogs with a cereblon E3 ligase recruiting moiety to generate tumor-specific PROTACs for 1C metabolism inhibition