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: 9922967
• 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/9922967
• 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.

项目总结/摘要： 我们的研究计划旨在阐明生物活性物质的作用机制和结构-功能关系。 活性天然产物，用于治疗耐药细菌感染和癌症。发展 的合成，使每一类分子的精确操作，与相关的洞察机制， nism是每个项目的统一目标。一个主要的努力涉及发现新的截短侧耳素抗生素， 治疗耐药革兰氏阴性菌感染。截短侧耳素是具有乙醇酯树脂的二价分子， 分别结合细菌核糖体的P和A位点的Due和三环骨架。当Gly- 结肠酸酯已经被广泛优化，化学上的限制在历史上阻止了开发 三环核心的我们开发了半合成和全合成的方法，以核心修饰的胸膜， tilin;我们因此合成了具有超过天然产物的效力的衍生物。我们将进一步 开发这种化学制剂以治疗碳青霉烯类耐药肠杆菌科， 现有的抗生素很少有效。对截短侧耳素的耐药性发展缓慢;长期目标包括 了解这种耐久性的分子基础。第二个重点领域是已知的海松烷二萜 就像myrocins一样。Myrocins在小鼠腺癌模型中表现出抗增殖作用。结构 myrocins的活性形式，其生物学靶标及其作用机制尚不清楚。我们有 开发了一种强大的成环策略，使我们能够从商业化制备myrocins的九个步骤 试剂我们将利用这种化学反应来阐明它们的目标和作用机制，从而获得 用于临床前评价的优化衍生物。在第三个项目中，我们试图完成一个总的化学合成- 洛麦维他星A（一种在pM浓度下抑制癌细胞生长的糖基化细菌代谢物）的姐妹作用。 我们确定洛麦替星的细胞毒性来源于DNA双链断裂的诱导; elu- 确定了它与DNA的结合方式，并确定了它的切割机制。最近，我们已经接近了... 全化学合成的洛麦维他星的一部分;使用此合成作为跳板，我们将准备汽车， 具有增加的DNA亲和力、序列选择性和增加的稳定性的碳水化合物修饰的衍生物。两 在洛麦维他星的合成过程中发现的新反应--间歇式巴顿乙烯基碘合成和方法 立体控制的结构连接环-将进一步发展。最后，我们将推进 研究gukulenin A，一种具有nM抗结直肠癌活性的假二聚体α-托酚酮天然产物。 我们将完成gukulenin的合成，阐明其结构-功能关系，并鉴定其生物活性。 逻辑目标本论文的主要工作是发展两种新的高取代度α-环庚三烯酚酮的合成方法， 融资期。我们已经建立了广泛的合作者网络，以推进翻译 每个项目的各个方面。这些研究还通过战略和反应发展推进基础化学- 并将提供新的临床前候选药物来治疗癌症和耐药感染。