Seeking efficiency and innovation in syntheses of bioactive compounds

描述(由申请人提供)：该研究计划的使命是将我们在有机化学方面的专业知识应用于新型抗结核、抗生素、抗癌和类固醇候选药物的设计和合成。该计划的每个科学目标都将寻求化学创新，以追求高调的、以天然产品为基础的目标。在目标一中，我们将开发一种变革性的新战略，以实现从简单的前体片段快速和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获得许多新的类固醇品种的途径，包括尚未在生物学研究中探索的替代模式。AIM II的目标是应对结核分枝杆菌多重耐药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候选抗生素药物。通过深思熟虑的分子设计和化学合成，我们将发明基于三环结构的抗生素和抗结核药物开发的新候选药物，该结构定义了细菌蛋白质合成抑制剂中的截胸素类。值得注意的是，与目前已知的截胸素家族成员相比，这些候选基因将被设计成表现出更强的代谢稳定性。我们将通过研究合作，探索我们新的截胸素类化合物的稳定性、抗结核活性和广谱抗生素活性。在这项提案的目标III中，我们将完成备受瞩目的天然产物毛晶V的简短创新合成。毛晶V于2004年分离出来，由于其对宫颈癌细胞的有效和选择性细胞毒活性的报道而引起了生物医学界的极大关注。在这里，我们建议使用化学合成的概念和方法来获得大量的天然产物，用于合作研究，旨在阐明毛晶V的作用机理。我们的合成设计也将开辟新的途径，通过它来获得含有毛晶V结构的关键元素的结构新颖的候选筛选。 与公共健康相关：化学合成的进步使人们能够设计和生产结构独特的分子，这些分子选择性地调节生物过程，并具有作为治疗人类疾病的分子疗法的巨大潜力。通过化学合成方面的创新进展，这项研究计划将为药物开发努力创造新的抗生素、抗结核、抗癌和类固醇候选药物。这里描述的方法的力量在于它们不仅能够产生已知的治疗剂，而且能够产生具有改进的治疗属性的新型的、特定的修饰分子。

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. PUBLIC HEALTH RELEVANCE: Advances in chemical synthesis enable the design and production of structurally unique molecules that selectively modulate biological processes and have great potential as molecular therapeutics for the treatment of human diseases. Through innovative advances in chemical synthesis, this research program will create new antibiotic, anti-tubercular, anticancer, and steroid-based candidates for drug development efforts. The power of the approaches described herein lie in their ability to create not only known therapeutic agents, but also novel, specifically modified molecules with improved therapeutic properties.