Seeking efficiency and innovation in syntheses of bioactive compounds

描述（由申请人提供）：本研究项目的任务是将我们在有机化学方面的专业知识应用于设计和合成新型抗结核、抗生素、抗癌和类固醇候选药物。该计划的每一个科学目标都将寻求化学创新，以追求高调，以天然产品为基础的目标。在Aim I中，我们将开发一种变革性的新策略，以实现从简单前体片段快速灵活地合成各种基于类固醇的候选药物。我们的方法旨在提供许多新的类固醇品种，包括尚未在生物学研究中探索的替代模式。第二目标的目标是应对耐多药结核分枝杆菌菌株对公共卫生造成的日益严重的威胁，以及令人震惊的缺乏新的抗生素候选药物。通过深思熟虑的分子设计和化学合成，我们将基于三环结构发明抗生素和抗结核药物开发工作的新候选物，该结构定义了细菌蛋白质合成抑制剂的胸膜残蛋白类。值得注意的是，与目前已知的胸膜残蛋白家族成员相比，这些候选基因将被设计成具有更高的代谢稳定性。我们将通过研究合作探索我们的新胸膜多肽化合物的稳定性、抗结核活性和广谱抗生素活性。在本提案的第三部分中，我们将完成一个简短而创新的合成高调的天然产物，maoystal V.。2004年，maoystal V被分离出来，由于其对宫颈癌细胞的有效和选择性的细胞毒性活性的报道，引起了生物医学界的极大关注。在此，我们建议采用化学合成的概念和方法来获得大量的天然产物，用于指导阐明maocrystal V的作用机制的合作研究。我们的合成设计也将开辟新的途径，通过该途径获得含有maocrystal V结构关键元素的结构新颖的筛选候选物。

DESCRIPTION (provided by applicant): The mission of this research program is to apply our expertise in organic chemistry to the design and synthesis of novel anti-tubercular, antibiotic, anticancer, and steroid-based drug candidates. Each of the scientific aims of this program will seek chemical innovation in the pursuit of high profile, natural product-based targets. In Aim I, we will develop a transformative new strategy for achieving rapid and flexible syntheses of diverse collections of steroid-based pharmaceutical candidates from simple precursor fragments. Our approach is designed to provide access to many new varieties of steroids, incorporating substitution patterns that have not yet been explored in biological research. The goal of Aim II is to respond to the rising threat to public health caused by multidrug resistant strains of Mycobacterium tuberculosis and the alarming lack of new antibiotic drug candidates. Through thoughtful molecular design and chemical synthesis, we will invent new candidates for antibiotic and antitubercular drug development efforts based on the tricyclic architecture that defines the pleuromutilin class of bacterial protein synthesis inhibitors. Notably, these candidates will be engineered to exhibit enhanced metabolic stability compared to the currently known members of the pleuromutilin family. We will probe the stability, antitubercular activity, and broad-spectrum antibiotic activity of our new pleuromutilin-based compounds through research collaborations. In Aim III of this proposal, we will complete a short and innovative synthesis of the high profile natural product, maoecrystal V. Isolated in 2004, maoecrystal V has attracted significant attention from the biomedical community due to reports of its potent and selective cytotoxic activity against cervical cancer cells. We propose herein to employ the concepts and methods of chemical synthesis to gain access to significant quantities of the natural product for collaborative studies directed toward the elucidation of the mechanism of action of maoecrystal V. Our design for synthesis will also open new avenues by which to access structurally novel screening candidates incorporating key elements of the structure of maoecrystal V.