Abstract

Chemical genetics uses small organic molecules instead of mutations in genes to modulate protein cellular functions, and therefore allows many biological processes to be studied. This approach depends on an adequate supply and identification of compounds that regulate pathways. Diversity-oriented synthesis (DOS) can be used to prepare combinatorial libraries of structurally complex and diverse small molecules. Rather than being directed toward a single biological target, DOS libraries can be used to identify new ligands for a variety of targets.

Natural products provide the inspiration for a variety of strategies used in the DOS of novel small-molecule libraries. Polyketides are a structurally diverse family of natural products with an extremely broad range of biological activities and pharmacological properties. Previous methods for the synthesis of polyketide libraries have focused primarily on stereochemical aspects of the polypropionate subclass, giving little attention to accessing other backbone modifications. Thus, we have developed a strategy to provide efficient access to complex molecules with a wide range of polyketide motifs. With this new strategy in hand, we have synthesized our first small library of 74 stereochemically diverse polyketides falling into six different structural classes. We have developed methods to add increased diversity to our polyketide libraries via stereoselective syntheses of several bifunctional alkyne building blocks. Our synthetic strategy has also allowed us to generate larger, more complex polyketides by carrying out larger scale batch syntheses of selected polyketide fragments, followed by convergent reiterative coupling of these fragments.

Our polyketide library will be evaluated in a range of high-throughput screens through the NIH Small Molecule Repository and collaborations with multiple laboratories. The results of these screens will allow us to begin analyzing the effectiveness of our library design strategy.