Synthesis of Anticancer Pyran Natural Products

研究抗肿瘤天然产物的化学反应性和生物活性对于了解其作用机制和开发治疗和/或预防癌症的新疗法至关重要。本研究项目旨在通过有机合成新策略和新方法的开发和后续应用，开发具有六元氧杂环的生物活性天然产物的高效合成。将寻求产生目标天然产物结构的策略，同时为合成相关化合物家族提供广泛的解决方案。这些研究选择的靶点具有有趣和新颖的分子结构，缺乏重要的先前合成研究，并且在癌症背景下具有良好的生物活性。计划的合成方法被设计为具有催化立体选择性吡喃形成反应，对映选择性合成黄酮，并纳入多个键形成序列。

Investigating the chemical reactivity and biological activity of anti-tumor natural products is vital to understanding their mechanism of action and developing new therapeutics for the treatment and/or prevention of cancer. This research program aims to develop efficient synthesis of biologically active natural products possessing six-membered oxygen heterocycles through the development and subsequent application of new tactics and methodologies for organic synthesis. Strategies that generate the targeted natural products structures while providing broad solutions to synthesizing related families of compounds will be pursued. The targets selected for these investigations possess interesting and novel molecular architecture, lack significant prior synthetic studies, and have promising biological activity in the context of cancer. The planned synthetic approaches are designed to feature catalytic stereoselective pyran-forming reactions, the enantioselective synthesis of flavanones, and incorporate multiple bond forming sequences. The specific goals of this research are: (1) Synthesis of the natural products chrolactomycin and okilactomycin. These antitumor antibiotics possess a unique and highly oxygenated tricyclic core. We will use a new butenolide macrocyclization/conjugate addition approach as the key strategic sequence. (2) Total synthesis of exiguolide (3) Syntheses of flavanone natural products abyssinone II and kurarinone. We will employ a new enantioselective flavanone synthesis catalyzed by chiral thioureas for the syntheses of these compounds. (4) Evaluate all compounds in these studies for their activity against various human tumor cell lines including breast, prostate, colon, and pancreatic cancer. This last aim will be accomplished in a collaboration combining our synthetic knowledge and capabilities acquired in Aims 1-3 with two expert cancer researchers at Northwestern’s Robert H. Lurie Comprehensive Cancer Center and one expert bioorganic chemist at Yale University