Discovery of Pyrimidine-based Heterocycles as Single Agents With Combination Chemotherapy Potential And As Inhibitors Of Purine Nucleotide Biosynthesis For The Treatment of Cancer
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- combination; chemotherapy; pyrimidine; tubulin; antifolate; cancer; Heterocyclic Compounds; Organic Chemicals; Other Chemicals and Drugs
This dissertation describes the design, synthesis and biological evaluation of monocyclic and bicyclic pyrimidine-base heterocycles as single agents with combination chemotherapy potential having both antiangiogenic effects and cytotoxic effects. This dissertation also describes selective tumor targeting with 5-substituted pyrrolo[2,3-d]pyrimidines analogs with heteroatom bridge substitution as GARFTase inhibitors.The work in this dissertation is centered on identifying structural features that are necessary for inhibition of tubulin polymerization as well as for inhibition of 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) in single entities. Single agents with both antiangiogenic activities as well as cytotoxicity would afford agents that circumvent pharmacokinetic problems of multiple agents, avoid drug-drug interactions, could be used at lower doses to alleviate toxicity, be devoid of overlapping toxicities, and delay or prevent tumor cell resistance.This work reviews the synthesis of substituted monocyclic pyrimidines as well as pyrrolo[2, 3-d]pyrimidines. This work also reviews the synthesis of multi-transporter (PCFT and FR) selective 5-substituted pyrrolo[2, 3-d]pyrimidines as GARFTase inhibitors circumventing both dose-limiting toxicity and tumor resistance associated with most prescribed antitumor agents like pemetrexed.