Cancer is a major health concern in the United States where it is the second most common cause of death. It is characterized by uncontrollable cell division and abnormal growth. Although a number of drugs with validated targets are available in the clinic, many cancers develop multidrug resistance, and consequently, existing treatments lose their effectiveness. Hence, there is an urgent and unmet need for newer anticancer agents with better clinical profiles. This two-part dissertation will utilize two different targets to discover anticancer agents.

In the first part, the interplay of the androgen receptor, estrogen receptor and the enzyme CYP7B1 in prostate tissue has been exploited to design and synthesize potential inhibitors of CYP7B1 that can be used for chemoprevention and treatment of prostate cancer. The enzyme inhibition assays that are currently in progress will help validate this enzyme as a novel target for combating prostate cancer.

The second part incorporates the evolution of a synthetic route to the tubulysin antimitotic tetrapeptide scaffold which has then been used in the systematic design and synthesis of simplified analogs as well as some tubulysin natural products. The biological data generated from these focused libraries has aided the establishment of systematic structure-activity relationships. Additional cytotoxicity and tubulin polymerization inhibition data will help define a minimum pharmacophore for this family of cytotoxic peptides and guide the design of analogs with better physico-chemical properties. A series of fluorescent labels have also been synthesized to study the interaction of these molecules with the target tubulin protein.