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.

项目概要/摘要： 我们的研究计划旨在阐明生物的作用机制和结构功能关系 活性天然产品，用于治疗耐药细菌感染和癌症。发展历程 能够精确操纵每一类分子的合成，以及对机械的相关见解 nism，是每个项目的统一目标。一项重大努力包括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酸酯残基的二价分子 due 和三环骨架分别结合细菌核糖体的 P 和 A 位点。虽然gly- 胆酸酯已被广泛优化，化学上的限制历来阻碍了开发 三环核心。我们开发了半合成和全合成方法来核心修饰胸膜 蒂林斯；因此，我们合成了效力超过天然产物的衍生物。我们将进一步 开发这种化学物质来治疗耐碳青霉烯类肠杆菌科细菌，其病原体 现有的抗生素很少是有效的。对截短侧耳素的耐药性发展缓慢；长期目标涉及 了解这种耐久性的分子基础。第二个重点领域是已知的吡玛烷二萜 如myrocins。 Myrocins 在小鼠腺癌模型中表现出抗增殖作用。结构 多球菌素的活性形式、其生物靶点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，使我们能够通过九步从商业化制备 myrocin 试剂。我们将利用这种化学来阐明它们的目标和作用机制，从而获得 用于临床前评估的优化衍生物。在第三个项目中，我们寻求完成整个化学合成 lomaiviticin A 的 sis，它是一种糖基化细菌代谢物，在 pM 浓度下可抑制癌细胞生长。 我们确定 Lomaiviticin 的细胞毒性源自诱导 DNA 双链断裂；洗脱- 阐明了其DNA结合方式；并确定了裂解机制。我们最近已经接近 完成洛马维霉素的全化学合成；使用这种合成作为跳板，我们将准备汽车- 二水合物修饰衍生物具有更高的 DNA 亲和力、序列选择性和稳定性。二 在制备 Lomaiviticin 的过程中发现了新反应——一种间断的 Barton 碘乙烯合成方法和方法 用于连接环的立体控制结构 - 将得到进一步开发。最后，我们将推进我们的 gukulenin A 的研究，一种假二聚体 α-托酚酮天然产物，具有 nM 抗结直肠癌活性。 我们将完成gukulenin的合成，阐明其结构与功能关系，并鉴定其生物活性 逻辑目标。期间将开发两种合成高取代α-托酚酮的新方法 资助期限。我们建立了广泛的合作者网络来推进转化 每个项目的各个方面。这些研究还通过策略和反应开发来推进基础化学。 并将提供新的临床前候选药物来治疗癌症和耐药感染。