The objectives of this proposed program are to develop ideas and reaction sequences to transform simple, commercially available compounds into structurally complex, biologically active natural products with high efficiency and to investigate the properties of these substances in biological contexts. The underlying theme of the chemical studies described in this application is the design and execution of cascades of reactions that rapidly form the topologically and stereochemically complex structures of two natural products: (1) the promising angiogenesis inhibitor Cortistatin A, and (2) the potent and selective anticancer compound Maoecrystal V. These natural products have genuine potential as chemotherapeutic agents for the treatment of human diseases and molecular architectures that inspire the development of concepts for the benefit of the field of organic synthesis. The new synthesis proposals are rooted in the idea that judicious sequences of fundamental, carbonyl-dependent reactions will enable rapid syntheses of these challenging target molecules. The synthesis pathways developed in this program will be leveraged to gain insights into the biomolecular target selectivities of these fascinating natural products. Lay language: Small molecule drugs for the treatment of human diseases and molecular probes for discovery-based research activities in cell biology are produced by the methods and concepts of chemical synthesis. The significance of this program comes from the powerful ideas and methods that it will develop for achieving short, efficient syntheses of two structurally complex, biologically active natural products and the discoveries of new biomolecular targets for attacking diseases in humans.
The conception and development of powerful strategies and reaction sequences to rapidly form the complex molecular structures of biologically active natural products is one of the frontier activities in the field of chemical synthesis. This program is developing innovative carbonyl-based cascades of cyclizations for use in syntheses of several natural products with properties that could improve human health.
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