Concise synthesis methods to aminosterols and sterol N-glycosides for the development of new OSW-1-derived scaffolds

Abstract

Abstract The cholestane glycoside natural product compound OSW-1 has both broad spectrum antiviral activity and potent antiproliferative activity. OSW-1 is a high affinity ligand of both oxysterol-binding protein (OSBP) and OSBP-related protein 4 (ORP4). OSBP has been implicated in viral disease replication, and ORP4 has been shown to play a critical role in cancer cell survival. The synthesis and structural complexity of OSW-1, in combination with its indiscriminate targeting of both OSBP and ORP4, have limited its drug development and the study of its molecular pharmacology. Herein, a new, three-component synthesis approach (i.e. steroid component, side-chain component, and disaccharide component) to produce E-ring azacycle OSW-1-scaffolds was development and pursued. Identification of the new E-ring azacycle OSW-1 scaffold was guided by the development of a putative molecular model of OSW-1 interacting within the oxysterol-binding protein pocket. The new three-component approach to new E-ring azacycle OSW-1-derived scaffolds required the development of two new synthetic methods. The first method required a direct and easily diversified route to 22-aminosterols. A direct, tunable two-component stereoselective formation of either C16-C17-ene-22-aminosterol or 17-hydroxyl-22-aminosterol, using an imino-ene/aza-Prins reaction, was successfully developed. The mechanism of this Lewis acid-mediated imino-ene/aza-Prins reaction was explored. The second new method required for the three-component approach to OSW-1-scaffolds was the development of a novel amine glycosylation method. An atypical application of the Fukuyama-Mitsunobu reaction was successfully developed into an aminosterol N-glycosylation method that affords high yields of coupled 22-aminosterol and the OSW-1 arabinose-xylose-disaccharide. The new reaction methods developed can be generally used to access other aminosterol scaffolds and aminoglycoside carbohydrate-containing compounds. These new methods were used to synthesize a new C-22-aminoglycosylated OSW-1 analog, demonstrating the application of these methods in the synthesis of a complex molecular target. The newly developed methods have laid the fundamental groundwork of the three-component approach to produce E-ring azacyle OSW-1 scaffolds. These new scaffolds will be pursued in the future to rapidly produce new analog compounds for antiviral and anticancer drug development.