The process of small molecule and natural product glycorandomization developed by Thorson and coworkers has been validated as one of the first simple, efficient and general glycosylation strategies for small molecule and macromolecular therapeutics. Given its broad utility and documented impact on improving the specificity, mechanism and ADME properties of drug leads, the glycorandomization technology platform is expected to revolutionize the future of drug discovery. Centrose, LLC, a company based upon this technology platform, will use the patented glycorandomization and neoglycorandomization technologies to develop breakthrough products to treat cancer with an anticipated future expansion into the infectious disease market. The ability to further accelerate and simplify the revolutionary glycorandomization process via automation will radically enhance the impact of glycorandomization upon the future of drug discovery. This phase I SBIR proposal specifically targets PA-06-012 (Manufacturing Processes of Medical, Dental, and Biological Technologies; SBIR R43/R44) and presents a systematic approach toward the development of a prototype (designated the `glycolator') for fully-automated neoglycorandomization drug discovery. Within the early Phase I timeline, we specifically seek to delineate the best reaction solvent, reaction heating, reaction mixing and product purification parameters compatible with our selected automation platform - the Gilson GX-271 ASPECTM. These elements will then be combined as the first fully automated `glycolator' and the later Phase I timeline specifically dedicated to assessing the utility of the glycolator for both library construction and preparative scale synthesis of representative neoglycosides. As a potential future Phase II study, we envision an expansion of this automated platform to encompass both automated upstream monosaccharide chemistries and automated downstream chemoselective ligation chemistries - both of which are anticipated to greatly enhance the competitive advantage of the glycorandomization drug discovery technology platform. ? ? ?
