Natural products constitute a valuable source of drug leads and tools to probe complex biological systems. Nearly half of the drugs introduced for cancer over the last six decades are natural products or are inspired by natural products. Likewise, around 75% of new antibiotics described over the last 25 years emerged from studies of natural products. Historically, even natural products that are unsuitable as drug candidates have been used to study complex biological systems such as ion channels, microtubules, the cytoskeleton, the cell cycle and protein trafficking among others. Finally, the synthesis of natura products leads to the discovery and development of synthetic methodologies and strategies. These discoveries may be useful more broadly to the field of organic synthesis. Overall, the synthesis and evaluation of natural products provides the opportunity to advance the state of synthetic chemistry, biological understanding, and drug discovery.
Aim 1. Synthesize complex, biologically active, polyaromatic xanthone natural products. We will develop convergent, enantioselective syntheses of polyaromatic xanthone natural products. None of these compounds has been synthesized previously, and all display potent biological activity. For example, the kibdelones, simaomicin a, kigamicin A, actinoplanone, and IB-00208 are low-nM anti-cancer antibiotics with unknown targets. Sch-56036 displays robust antifungal activity, but no molecular target is known. Additionally, we will synthesize the isokibdelones, which inhibit export pumps. These efforts will confirm the structure of the natural products, assign their absolute stereochemistry, and provide access to both the natural products and their derivatives. Moreover, to facilitate our efforts and contribute to practice of organic synthesis, we will develo new methods for the synthesis of isoquinolinones and dihydroisocoumarins; we will explore a novel synthesis of aryl ketenes; we will invent an asymmetric catalytic synthesis of chiral aminals; and we will discover an asymmetric catalytic [4+2] cycloaddition between electron rich dienes and benzopyranones to yield hexahydro-xanthones.
Aim 2. Use genetic and biochemical methods to discover the mechanism of action of xanthone natural products. We will culture Gram-positive bacteria in the presence of increasing concentrations of antibiotic natural products to induce resistance. Mutants showing specific resistance to the natural product will be sequenced to identify the protein or proteins that were mutated to provide resistance.
Aim 3. Use expression profiling to discover the mechanism of action of xanthone natural products. We will determine the expression of 16 highly variable genes in response to sub-lethal concentrations of cytotoxins. The pattern of expression will be compared to the patterns of expression generated by RNAi knockdown of every gene in the human genome, thus correlating the natural product to a specific loss of function. Biochemical experiments will be used to test predicted modes of action.
Small molecules produced by plants, bacteria and fungi, known collectively as natural products, are valuable resources for drug discovery. We will synthesize several natural products with anticancer, antibiotic and/or antifungal activity and learn how they exert their effects. These studies will provide supplies of these natural products for further evaluation, uncover new biological targets for treating cancer or infectious disease, and prompt the discovery of new, broadly useful, synthetic methods.
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