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I) The Development of Deoxycytidine Kinase Inhibitors with Nanomolar Affinity and Improved Metabolic Stability, II) The Synthesis of Ferrocene-Containing Monomers and Biodegradable Polymers Using Azide-Alkyne Click Chemistry and Ring Opening Polymerization

Abstract

Small molecule dCK inhibitors, in combination with pharmacological perturbations of de novo dNTP biosynthetic pathways, can eliminate acute lymphoblastic leukemia cells in animal models. Our group’s previous lead dCK inhibitors had a short half-life in vivo. Part I of this dissertation presents the development of new dCK inhibitors with improved pharmacokinetic properties. Guided by crystal structures of dCK in complex with the lead compound and with derivatives, we delineated the sites of the inhibitor for modification. Crystal structure of the complex between dCK and the racemic mixture of our new lead compound indicated that the R- isomer is responsible for kinase inhibition. This was corroborated by kinetic analysis of the purified enantiomers, which showed that the R-isomer has >60-fold higher affinity than the S-isomer for dCK. This new lead compound has significantly improved metabolic stability, making it a prime candidate for dCK-inhibitor based therapies against hematological malignancies and, potentially, other cancers.

Part II presents a strategy for functionalizing biodegradable polymers with ferrocene. Small molecule drugs containing ferrocene play an important role in current cancer research, as these novel chemotherapeutics possess redox activity and have the ability to quench damaging free radicals. Current drugs that quench free radicals have adverse side effects, and dosage limits render them less effective in radiotherapy. In the search of more potent and/or selective radioprotective agents, ferrocene functionalized monomers were synthesized via azide-alkyne “click” cycloaddition. Potentially environmentally friendly ferrocene-containing polycarbonates were synthesized via ring opening polymerization (ROP), and they were characterized via NMR spectroscopy, gel permeation chromatography (GPC), thermal analysis, and electrochemical studies.

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