Oxamidation of Unsaturated Hydrozamates: Diastereoselectivity and Synthetic Application.

Oxamidation of Unsaturated Hydrozamates: Diastereoselectivity and Synthetic Application

Synthesis and biological activity of naturally occurring a-glucosidase inhibitors

In addition to their clinical importance in the treatment of type II diabetes, a-glucosidase inhibitors have attracted considerable attention from the synthetic community because of their profound effect on an array of cellular processes, including N-linked glycoprotein processing and maturation, oligosaccharide metabolism, and cell–cell and cell–virus recognition. Over the past decade, a number of structurally novel naturally occurring a-glucosidase inhibitors which do not conform to the classical iminosugar mold have been identified, including zwitterionic thiosugars and marine organosulfates. While these natural products are important leads in the development of new classes of glucosidase inhibitors, they have also attracted considerable attention as synthetic targets in of themselves. This article reviews the recent literature concerning the synthesis of these emerging natural product families, as well as the preparation of those polyhydroxylated alkaloids more traditionally associated with anti-a-glucosidase activity. 176 references are cited

Structure–Activity Relationships of Spectinamide Antituberculosis Agents: A Dissection of Ribosomal Inhibition and Native Efflux Avoidance Contributions

Spectinamides are a novel class of antitubercular agents with the potential to treat drug-resistant tuberculosis infections. Their antitubercular activity is derived from both ribosomal affinity and their ability to overcome intrinsic efflux mediated by the Mycobacterium tuberculosis Rv1258c efflux pump. This study explores the structure–activity relationships through analysis of 50 targeted spectinamides. Compounds are evaluated for ribosomal translational inhibition, MIC activity in Rv1258c efflux pump deficient and wild type tuberculosis strains, and efficacy in an acute model of tuberculosis infection. The results of this study show a narrow structure–activity relationship, consistent with a tight ribosome-binding pocket and strict structural requirements to overcome native efflux. Rationalization of ribosomal inhibition data using molecular dynamics simulations showed stable complex formation for halogenated spectinamides consistent with the long post antibiotic effects observed. The lead spectinamides identified in this study demonstrated potent MIC activity against MDR and XDR tuberculosis and had desirable antitubercular class specific features including low protein binding, low microsomal metabolism, no cytotoxicity, and significant reductions in bacterial burdens in the lungs of mice infected with M. tuberculosis. The structure–activity relationships detailed here emphasize the need to examine efflux-mediated resistance in the design of antituberculosis drugs and demonstrate that it is possible to overcome intrinsic efflux with synthetic modification. The ability to understand the structure requirements for this class has produced a variety of new substituted spectinamides, which may provide useful alternative candidates and promote the further development of this class