| This dissertation details my efforts towards the design and development of novel small molecules anti-cancer agents including joint efforts with a host of colleagues and collaborators.;The introduction, Chapter 1, provides a brief overview of the current "Hallmarks of Cancer." This is a list of characteristics acquired during tumorigenesis, which provide the targets for us to develop. In this sojourn, we hav utilized a wide spectrum of strategies and technigues to develop specific drugs. These efforts are described in this thesis.;Chapter 2 describes the computational fragment-based design, synthesis, and biological validation of a series of novel inhibitors of the enzyme dUTPase as potential anti-cancer agents.;Chapter 3 details the design, synthesis, biological evaluation, and molecular modeling studies of novel CXCR2 antagonists.;Chapter 4 reports the synthesis and structure-activity relationship of a series of small molecules capable of disrupting the protein-protein interaction between transcription factor MEF2 and class IIa HDACs.;Chapter 5 outlines our efforts to optimize a series of analogs of the FDA-approved cyclooxygenase-2 (COX-2) inhibitor CelebrexRTM (celecoxib), that have anti-cancer properties an devoid of COX-2 activity and the efforts of our collaborators to characterize the efficacy of these agents in a variety of models and therapeutic combinations are also summarized. |
