Synthetic and Mechanistic Studies of Myrocin Antitumor Agents

Myrocin抗肿瘤药物的合成及作用机制研究

• 批准号: 9259036
• 负责人: Christos Economou
• 金额: $ 3.76万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-16 至 2020-01-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9259036
• 关键词: Alkylating Agents; Alkynes; Antibiotics; Antineoplastic Agents; Antitumor Natural Products; Area; Biocompatible Materials; Biological; Biological Models; Biological Process; Bleomycin; Breast Cancer Treatment; Cancer Biology; Cell Line; Cell physiology; Cellular biology; Chemicals; Chemistry; Clinical Trials; Complex; Cyclization; DNA; DNA Alkylation; DNA Markers; DNA Repair; Development; Diterpenes; Duocarmycin Antibiotic; Evaluation; Family; Goals; In Vitro; Ketones; Lead; Length; Malignant Neoplasms; Malignant neoplasm of pancreas; Mission; Mitomycins; Modernization; Natural Products; Nature; Oligonucleotides; Organic Chemistry; Pathway interactions; Pharmaceutical Preparations; Phase; Play; Property; Reaction; Reporting; Research; Route; Scheme; Source; Structure; Time; United States National Institutes of Health; Validation; analog; anticancer activity; antineoplastic antibiotics; antitumor agent; cancer therapy; chemotherapeutic agent; chemotherapy; crosslink; design; drug discovery; enantiomer; improved; in vitro Model; insight; malignant stomach neoplasm; model development; novel; preclinical evaluation; repaired; research and development; small molecule; standard of care; success; tool; tumor

Project Summary This proposal outlines a synthetic route to the antitumor natural product (−)-myrocin B (1, Figure 1).1 1 has never before been synthesized, though the related metabolite (+)-myrocin C (2, Figure 1)2,3 has been prepared.4,5 1 and 2 possess antibiotic properties and anticancer activity in vivo1–3,6 and 1 has been shown to be more active than 2.1 However, a comprehensive evaluation of the biological activity of either 1 or 2 has not been undertaken. In vitro model studies7 conducted on synthetic 2 suggest that these natural products may cross-link of DNA, but no experimental evidence using isolated oligonucleotides in vitro or seeking markers of DNA alkylation in culture have been disclosed. DNA-reactive agents comprise a considerable portion of the modern chemotherapeutic arsenal.8–11 Moreover, the purported mechanism of action of 1 and 2 closely resembles that of the illudin family of natural products12–17, a derivative of which (irofulven, 3, Figure 1)18,19 advanced to Phase II and III clinical trials as a chemotherapeutic for the treatment of breast, gastric, and pancreatic cancers, among others.12,20 The development of 3 exemplifies the underexplored potential of DNA cross- linking natural products as a viable source of chemotherapeutic agents. Total synthesis of 1 represents an essential first step in translational development toward a potential novel chemotherapeutic. Ready access to 1 could also provide a chemical tool for biological studies involving DNA cross-linking, which may ultimately result in further insight into important biological processes such as DNA repair. With biological evaluation and translational development of 1 as the ultimate goal, the synthetic route toward 1 is designed to be scalable and concise. The overall strategy centers on joining two complex cyclohexyl fragments through a robust acetylide addition, with a subsequent Heck-type cyclization envisioned to construct the final carbocyclic ring of the target. Specific aims entail: 1) development of syntheses of the two cyclohexyl precursor fragments of 1, 2) synthesis of the model system and analogue 4, and 3) completion of the synthesis of 1 using conditions developed for synthesis of 4. As projected, the total synthesis of 1 should be achieved in 15 steps. The long-term goals of this project include intensive mechanism of action studies of 1, design and synthesis of analogues for structure–function studies, elucidation of the activity and cell line selectivities of 1, and validation of 1 as a lead for translational development. Figure 1. The myrocins (1, 2), irofulven (3), and the analogue 4     CH3 H X CH OH O CH3 3 H CH3 OHCH3 HO OH O CH3 H CH3 O O OH O CH H 3 O OH O O X = O, (−)-myrocin B (1) X = H,H, (+)-myrocin C (2) irofulven (3) (−)-myrocin B analogue (4)

项目摘要 该提案概述了抗肿瘤天然产物（-）-myrocin B的合成路线（1，图1）。1 1以前从未被合成过，尽管相关的代谢产物（+）-myrocin C（2，图1）2，3已经被合成。 4、5、1和2在体内具有抗生素性质和抗癌活性。1 - 3、6和1具有 已被证明比2.1更活跃，然而，生物学的综合评价 1或2的活动尚未进行。对合成2进行体外模型研究7 表明这些天然产物可能会交联DNA，但没有实验证据表明， 已经公开了体外分离的寡核苷酸或在培养物中寻找DNA烷基化的标记。 DNA反应剂在现代化疗药物库中占相当大的比例。8 - 11 此外，1和2的据称作用机制非常类似于ILUDIN家族的作用机制。 天然产物12 - 17，其衍生物（irofulven，3，图1）18，19进入II期和III期 作为治疗乳腺癌、胃癌和胰腺癌的化学治疗剂的临床试验， 12，20 3的发展证实了DNA交叉的潜力尚未得到充分开发， 连接天然产物作为化疗剂的可行来源。1的全合成 代表了翻译发展到潜在小说的重要的第一步 化疗。容易获得1也可以为生物研究提供化学工具 涉及DNA交联，这可能最终导致进一步了解重要的生物学 例如DNA修复。 以1的生物学评价和转化开发为最终目标， toward 1的设计是可扩展的和简洁的。整体战略的核心是将两个复杂的 环己基片段通过一个强大的乙炔加成，随后Heck型环化 设想构建靶的最终碳环。具体目标包括：1）发展 1的两个环己基前体片段的合成，2）模型体系的合成， 类似物4，和3）使用为合成4开发的条件完成1的合成。作为 根据预测，1的全面综合应分15个步骤实现。 该项目的长期目标包括深入研究1、设计和 用于结构-功能研究、活性阐明和细胞系的类似物的合成 选择性为1，并且验证1作为转化开发的先导。 图1. myrocins（1，2），irofulven（3）和类似物4 CH3 H X CH OH O CH 3 3 H CH3 OHCH3 胡浩 O CH3 H CH3 O O OH O CH H 3 O OH O O X = O，（−）-myrocin B（1） X = H，H，（+）-myrocin C（2）irofulven（3）（-）-myrocin B类似物（4）