Design and Synthesis of OSW-1 Analogs and Other Bioactive Small Molecules for Potential Therapeutic Applications

Abstract

OSW-1 is a cholestane glycoside natural product with potent anti-proliferative activity, broad spectrum anti-viral activity, and a novel mechanism of action. The OSW-1’s cellular targets are oxysterol-binding protein (OSBP) and OSBP-related protein 4 (ORP4). Recently, OSBP has been determined to execute an essential role in the proliferation of many classes of pathogenic viruses. ORP4 has been determined, also recently, to be a driver of cellular proliferation and to be a precision cancer target. The main project of this dissertation research is focused on using organic synthesis to produce new synthetic routes to access new OSW-1-derived compounds. To better understand the compound’s mechanism of action and molecular pharmacology, a set of OSW-1 probe analogs were designed and produced. To further the potential development of OSW-1-derived therapeutic compounds, a new approach for the rapid and convergent synthesis of a diverse library of OSW-1 analogs based on a new scaffold was developed. This new approach to OSW-1 analogs synthesis will allow for the future production of analogs with selective affinity for OSBP or ORP4 and improved pharmacological properties. Additionally, a set of stable-isotopically-labeled anti-cancer agents were synthesized to allow the absolute quantification of the drug inside the individual cancer cells through a new mass spectrometry technique. The last project describes the design and synthesis of a retinaldehyde’s analog with high selectivity for retinaldehydrogenase (RALDH) enzymes. This novel compound could form the basis for the development of new treatments for blindness caused by pathological myopia.