Synthetic and translational studies of antitumor and antimicrobial natural products

抗肿瘤和抗菌天然产物的合成和转化研究

• 批准号: 10392862
• 负责人: Seth B. Herzon
• 金额: $ 58.12万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10392862
• 关键词: Adenocarcinoma; Affinity; Antibiotics; Antineoplastic Agents; Area; Bacterial Infections; Binding; Biological; Cancer Cell Growth; Carbohydrates; Chemicals; Chemistry; Clinical; Colorectal Cancer; DNA; DNA Binding; Development; Diterpenes; Drug resistance; Esters; Exhibits; Funding; Glycolates; Goals; Infection; Interruption; Iodides; Malignant Neoplasms; Methods; Molecular; Natural Products; Reaction; Reagent; Research; Resistance; Ribosomes; Route; Site; Skeleton; Structure; Structure-Activity Relationship; Tropolone; Work; bioactive natural products; cancer therapy; carbapenem-resistant Enterobacteriaceae; chemical synthesis; cytotoxicity; insight; lomaiviticin A; mouse model; natural antimicrobial; pathogen; pleuromutilin; pre-clinical; preclinical evaluation; prevent; programs; translational study

PROJECT SUMMARY/ABSTRACT: Our research program seeks to elucidate the mechanism of action and structure–function relationships of bio- active natural products, toward treatments for drug-resistant bacterial infections and cancer. The development of syntheses that enable precise manipulation of each class of molecules, with correlated insights into mecha- nism, are the unifying goals of each project. A major effort involves discovering new pleuromutilin antibiotics to treat drug-resistant Gram-negative infections. Pleuromutilins are bivalent molecules with a glycolic ester resi- due and a tricyclic skeleton that bind the P and A sites of the bacterial ribosome, respectively. While the gly- colic acid ester has been extensively optimized, limitations in chemistry have historically prevented exploitation of the tricyclic core. We developed semisynthetic and fully synthetic approaches to core-modified pleuromu- tilins; we have thereby synthesized derivatives with potencies exceeding the natural product. We will further develop this chemistry toward agents to treat carbapenem-resistant Enterobacteriaceae, pathogens for which few existing antibiotics are effective. Resistance to pleuromutilins is slow to develop; a long-term goal involves understanding the molecular basis of this durability. A second area of focus is the pimarane diterpenes known as the myrocins. Myrocins exhibit antiproliferative effects in murine models of adenocarcinoma. The structure of the active form of myrocins, their biological target, and their mechanism of action, are unknown. We have developed a powerful annulation strategy that allows us to prepare myrocins in nine steps from commercial reagents. We will use this chemistry to elucidate their target and mechanism of action, and thereby access optimized derivatives for preclinical evaluation. In a third project we seek to complete a total chemical synthe- sis of lomaiviticin A, a glycosylated bacterial metabolite that inhibits cancer cell growth at pM concentrations. We established that the cytotoxicity of lomaiviticin derives from induction of double-strand breaks in DNA; elu- cidated its mode of DNA binding; and determined the mechanism of cleavage. We have recently neared com- pletion of a total chemical synthesis of lomaiviticin; using this synthesis as a springboard, we will prepare car- bohydrate-modified derivatives with increased DNA affinity, sequence selectivity, and increased stability. Two new reactions discovered en route to lomaiviticin – an interrupted Barton vinyl iodide synthesis and a method for the stereocontrolled construction of attached rings – will be further developed. Finally, we will advance our studies of gukulenin A, a pseudodimeric α-tropolone natural product with nM activity against colorectal cancer. We will complete the synthesis of gukulenin, elucidate its structure-function relationships, and identify its bio- logical target. Two new methods for the synthesis of highly-substituted α-tropolones will be developed during the funding period. We have established an extensive network of collaborators to advance the translational aspects of each project. These studies also advance basic chemistry through strategy and reaction develop- ment, and will deliver new preclinical candidates to treat cancer and drug-resistant infections.

项目摘要/摘要： 我们的研究计划旨在阐明生物的作用和结构 - 功能关系的机理 活跃的天然产物，用于治疗耐药细菌感染和癌症。发展 可以精确操纵每类分子的合成，并与机械的见解相关 nism是每个项目的统一目标。一项重大努力涉及发现新的胸膜素抗生素 治疗耐药的革兰氏阴性感染。胸膜素是二价分子，具有乙醇酯晶状体 分别结合细菌核糖体的P和A位点的三环骨架和三环骨架。而Glyce- 绞痛酯已经广泛优化，化学的局限性在历史上阻止了剥削 三轮车芯。我们开发了半同步和完全合成的方法，用于核心修饰的胸膜 - tilins;因此，我们具有超过天然产物的衍生物的合成衍生物。我们将进一步 开发这种化学物质，以治疗耐碳青霉烯的肠杆菌科，病原体 现有的抗生素很少有效。对胸膜素的耐药性发育缓慢。长期目标涉及 了解这种耐用性的分子基础。第二个重点是已知的匹米烷二萜 作为肉豆蔻蛋白。肉豆蔻蛋白暴露于腺癌鼠模型中的抗增殖作用。结构 在活性形式的肉豆蔻蛋白中，它们的生物学靶标及其作用机理是未知的。我们有 制定了一种强大的环境策略，使我们能够在商业上从九个步骤中准备mrocos 试剂。我们将使用这种化学反应来阐明其目标和作用机理，从而访问 优化的衍生物用于临床前评估。在第三个项目中，我们试图完成总化学合成 - Lomaivitic蛋白A的SI，一种糖基化的细菌代谢产物，可在PM浓度下抑制癌细胞的生长。 我们确定洛氏素毒素的细胞毒性源自DNA中双链断裂的诱导。 el 固定其DNA结合模式；并确定切割机理。我们最近接近了 洛氏素化素的总化学合成;使用此合成作为跳板，我们将准备汽车 - 具有增加DNA亲和力，序列选择性和稳定性增加的河水改性衍生物。二 新反应在通往洛氏素毒素的途径 - 一种中断的巴顿乙烯基碘化物合成和一种方法 对于随机控制的连接环的构造 - 将进一步开发。最后，我们将推进我们的 Gukulenin A的研究，一种针对大肠癌的NM活性的伪二聚体α-转基因生产。 我们将完成古库烯素的合成，阐明其结构功能关系，并确定其生物 逻辑目标。在合成高度取代的α-传统的两种新方法中将开发 资金期。我们已经建立了广泛的合作者网络，以推动翻译 每个项目的各个方面。这些研究还通过策略和反应发展推动了基本化学 - 并将提供新的临床前候选者，以治疗癌症和抗药性感染。