I. Synthesis of Aryl C-Nucleosides and Retinoid Analogs II. Investigation into Docking Studies of Bisabosqual Analogs

Abstract

Currently, there are three major approaches used for the synthesis of aryl C-2-deoxyriboses. The first approach uses a common sugar derivative developed by Kool, 1,2-dideoxy-3,5-O-p-toluoyl-alpha-1-chloro-D-ribofuranose. The second approach uses Woski's 2-deoxyribonolactone glycal. The third approach uses a functionalize sugar involving tin reagents developed by Daves. All three methods have certain drawbacks. In efforts to finding a more efficient and alternative approach to making aryl C-deoxynucleosides, we developed a nine step synthetic route from commercially available inexpensive starting materials. In humans, epidermal keratinocytes are unique in their ability to convert Vitamin A1 (retinol) into Vitamin A2 (3,4-didehydroretinol). Each of these alcohols can be further metabolized to generate retinoid acids which serve as transcription factor ligands which can alter epidermal homeostasis. Currently unknown are the panel of genes which each of these ligands modulates. As a prerequisite for assessing the impact of each acid, their metabolism must be compared. For these purposes 3,4-didehydroretinoic acid and 3H-3,4-didehydroretinoic acid were synthesized. One important step in the biosynthesis involving the formation of cholesterol is the NADPH-requiring enzyme squalene synthase. Recently, four new squalene synthase inhibitors were found, they are Bisbosqual A, B, C and D. Using Discovery Studio from Accelrys, protein ligand docking studies were carried out on Bisabosqual A,B,C and D to understand the IC50 data reported by Minagawa. Insights into these studies were used to design Bisabosqual analogs for future synthesis.