Design And Synthesis Of Natural Product Analogs Of Stevioside And Synthetic Analogs Of Retinoic Acid

Abstract

Part I Stevioside is a natural product from the Stevia rebaudiana Bertoni plant native to South America. It is one of the major steviol glycosides, with rebaudioside A as the other main natural product, isolated from the Stevia plant and comprises 5 – 22% by weight from the dried plant leaves. These natural products are commercially sold as natural sweeteners with reports of being 200 to 300 times sweeter than table sugar. Steviol glycosides are made up of a tetracyclic diterpene, also called ent-kaurene, core structure attached to varying sugar chains at the A ring carboxyl group or C-ring hydroxyl group; Stevioside contains three glucose molecules while rebaudioside A contains four glucose molecules. The stevioside diterpene serves as novel template for analog development and exploration because there are numerous directions to diversify the different rings, mainly the A, C and D rings, within the molecule. Stevioside undergoes enzymatic or basic hydrolysis to form the steviol acid, which rearranges to the isosteviol acid under acidic conditions via a Wagner-Meerwein methyl shift of the bridging carbon. These two diterpenes were further explored via a diversity-oriented synthetic approach to yield other diterpene scaffolds from which compound libraries were synthesized in order to explore novel chemical space. Testing of the libraries demonstrate initial activity in several biological assays, thus proving that the ent-kaurene core scaffold is a viable starting point to elicit biological activity and for therapeutic development. Part II Through the efforts by the National Institutes of Health, research is being conducted to develop non-hormonal reversible male contraceptive agents. Current forms of male contraception include a temporary barrier by means of condoms or permanent surgical sterilization. Their unpopularity and the unmet need for something more tolerable have led to the development of non-hormonal male contraceptive agents targeting the retinoic acid receptor alpha (RAR) nuclear receptor. Previous research has shown that RAR disrupts spermatogenesis during mitosis and the administration of RAR agonists to Vitamin A deficient mice, which is similar to RAR gene knockout mice, reversed infertility effects. Given these promising results, we designed and synthesized retinoids for the development of RAR antagonists. Four compounds were produced and assayed for activity in RAR as well as selectivity against RAR beta (RAR) and RAR gamma (RAR).