While it is known that the sugar attachments of pharmaceutically important natural products often define theircorresponding biological activity, until recently, efficient methods to alter these essential carbohydrateappendages, and thereby systematically explore their carbohydrate-based structure-activity relationships(SAR), was lacking. In recent years, we have developed two strategies to rapidly glycosylate naturalproducts - in vitro glycorandomization (a chemoenzymatic process) and, more recently,neoglycorandomization (chemoselective-ligation based process). As Lab Program 2 of the University ofWisconsin National Cooperative Drug Discovery Group (UW NCDDG), this proposal outlines a systematicapplication of these two unique strategies toward diversification of a wide range of natural product parentscaffolds (including a number from UW NCDDG Program 1, Professor Shen) with previously indicatedanticancer activities. Specifically, the proposed studies are designed to assess the general applicability ofchemoenzymatic and chemoselective ligation-based glycorandomization to significantly enhance accessiblenatural product-based diversity and, in conjunction with the unique screening and downstream analysiscapabilities of the UW NCDDG, will present perhaps the broadest correlation to date between the biologicalactivity of natural products and the specific contributions invoked by their attached carbohydrates. Moreimportantly, as mandated by the NCDDG, the parent scaffolds were also selected to significantly bias theultimate outcome toward the identification of promising anticancer leads within the intended funding periodand diversity directives will specifically evolve based upon the constant consultation of the novelscreening/biological analysis/clinical components of the UW NCDDG.
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