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蛋白的作用机制和结构-功能关系。 活性天然产品，用于抗药性细菌感染和癌症的治疗。最新进展 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。一项主要的努力包括发现新的切割胸膜的抗生素来 治疗耐药的革兰氏阴性感染。侧耳多肽是具有乙醇酸酯树脂的二价分子-- 分别与细菌核糖体的P和A位点结合的DUE和三环骨架。而甘油- 结肠酸脂得到了广泛的优化，化学方面的限制历来阻碍了开采 三环核心的。我们开发了半合成和全合成的方法来修饰核心胸膜- Tilins；我们因此合成了效力超过天然产品的衍生物。我们将进一步 开发这种化学药物来治疗碳青霉烯耐药的肠杆菌科细菌，其病原体 现有的抗生素很少是有效的。对胸膜多替林的耐药性发展缓慢；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pimarane二萜。 就像我的火箭。Myrocins在小鼠腺癌模型中显示出抗增殖作用。该结构 关于myrocins的活性形式，它们的生物靶标和作用机制尚不清楚。我们有 开发了一种强大的环化策略，允许我们在商业上用9个步骤制备myrocins 试剂。我们将利用这种化学来阐明它们的靶标和作用机制，从而获得 用于临床前评估的优化衍生品。在第三个项目中，我们试图完成一个完全的化学合成- 洛麦维菌素A的SIS，一种糖基化的细菌代谢物，在PM浓度下抑制癌细胞生长。 我们证实，洛麦维星的细胞毒性来自于诱导DNA双链断裂； 确定了其与DNA的结合方式，并确定了其切割机制。我们最近接近了COM- 完成了洛麦维星的全化学合成；以此合成为跳板，我们将制备CAR- 二水修饰的衍生物具有更高的DNA亲和力、序列选择性和更高的稳定性。二 洛麦维星合成过程中发现的新反应--一种中断的巴顿碘乙烯基合成方法 对于立体控制施工的附环--将进一步发展。最后，我们将推进我们的 具有NM抗结直肠癌活性的伪二聚体α-tropolone天然产物古苦素A的研究。 我们将完成古苦素的合成，阐明其结构与功能的关系，并对其进行生物活性鉴定。 合乎逻辑的目标。将开发两种合成高取代α-托洛酮的新方法 资助期。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促进了基础化学的发展。 该公司将提供治疗癌症和耐药感染的新的临床前候选药物。