The design and synthesis of novel proteasome inhibitors : studies on the synthesis of nagelamide M and analogs, the synthesis of rapamycin based proteasome inhibitors, and the synthesis of TCH based molecular probes for binding site determination

"The two primary physiologic mechanisms for the recycling of amino acids from no-longer needed or damaged proteins are autophagy and enzymatically via the proteasome. Inhibition of the proteasome has emerged as the preeminent means for treating cancers that constitutively overproduce proteins, particularly multiple myeloma. Two drugs currently available for the treatment of multiple myeloma, BortezomibTM and KyprolisTM, inhibit the proteasome by binding to the catalytically active sites through a competitive mechanism. While initially effective, over time the resistance that is typical of competitive binders emerges, and relapse rates are currently measured at 97 %, with the average survival time after being one year. Additionally the most common side effect is neuropathy, which typically does not abate after discontinuation of chemotherapy. The current state of the art demonstrates the need not only for new proteasome inhibitors, but inhibitors that act through a different mechanism. The Tepe group was the first to develop such a molecule, imidazolines of the TCH-series, which bind to the proteasome via a noncompetitive mechanism. The details of the interaction of these molecules with the proteasome have been extensively studied, but the location of the binding site remains elusive. In this work, several molecular probes were designed and synthesized (two diazirine photoaffinity-TCH hybrids and a biotin-TCH hybrid) to elucidate the location of the binding site. Currently biological testing is underway. Additionally, a library of analogs based on the natural product rapamycin were designed and synthesized. An analog was discovered that was equipotent to the natural product itself, which could be synthesized on a gram scale in three steps from commercially available materials. To discover the binding site of these molecules, a diazirine photoaffinity probe was designed and synthesized. Enough biological data was generated to refine the library and design and synthesize a second generation of the analogs; currently biological testing of these analogs is underway. Lastly, extensive studies on the total synthesis of the pyrrole-imidazole natural product nagelamide M were designed and performed. These studies relied mainly on the use of C-H activation to functionalize a methylene C-H bond adjacent to a heteroatom. None of the key reactions were successful, and the synthesis stalled at an early stage. Overall this thesis describes several advances in the areas of drug discovery and proteasome inhibition, and perhaps most excitingly access to molecules that could elucidate the binding site of the TCH molecules."--Pages ii-iii.