Synthetic and Mechanistic Studies of Myrocin Antitumor Agents

项目摘要 该提案概述了一条合成抗肿瘤天然产物(−)的路线--myrocin B(1，图1)。 1以前从未被合成过，尽管相关的代谢物(+)-myrocin C(2，图1)2，3 4，5，1和2在活体1-3，6和1中具有抗菌性能和抗癌活性 已经显示出比2.1更活跃，然而，综合评价生物 尚未执行%1或%2的活动。体外模型研究7在合成的2 表明这些天然产物可能会使DNA发生交联，但没有实验证据表明 已经公开了在体外分离的寡核苷酸或在培养中寻找DNA烷基化的标记。 DNA反应剂是现代化疗药物的重要组成部分。8-11 此外，1和2的所谓作用机制与伊鲁丁家族的作用机制非常相似。 天然产物12-17，其衍生物(irofulven，3，图1)18、19进入第二和第三阶段 作为乳腺癌、胃癌和胰腺癌化疗药物的临床试验， 在其他方面。12，20 3的发展例证了DNA杂交的潜力尚未被发掘。 将天然产品作为一种可行的化疗药物来源。1，2，4，6，6，6，6-三甲基-4-甲基-4，4，4，5，5，5，5，5，5，6，6，5，6，6，6，6，6，6，6，6，6，5，6，6，6，6，5，6，6，6，5，6，5，6，6，5，5，5，5，6，6，5，5，5，4，4，4，4，4，4，5，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，5，4，4，4，4，4，5，4，4，5，4，5，5，5，4，5，4，5，5，5 代表着翻译发展向潜在小说迈出的重要的第一步 化疗药物。随时访问1也可以为生物学研究提供化学工具 涉及DNA交联，这最终可能导致对重要生物学的进一步洞察 DNA修复等过程。 以生物学评价和1的翻译开发为最终目标，合成路线 “朝向1”被设计为可伸缩且简洁。总体战略以联合两个综合体为中心 通过强健的乙炔加成，与随后的Heck环化反应，得到环己基片段 构筑目标的最终碳环。具体目标包括：1)发展 1的两个环己基前体片段的合成，2)模型体系的合成和 类似物4，以及3)使用为合成4而开发的条件完成1的合成。 根据预测，1-甲基-4-甲氧基丙烷的全合成应分15步完成。 该项目的长期目标包括深入的行动机制研究1，设计和 用于结构和功能研究的类似物的合成、活性和细胞系的阐明 选择性为1，并确认1为翻译开发的领导者。 图1.myrocins(1，2)、irofulven(3)和类似物4 第三章CH3 H X CH OH O CH3 3. H-CH3 流行性出血热3 HO OH O CH3 H CH3 O O OH O CH H 3-O-OH O O X=O，(−)-麦角菌素B(1) X=H，H，(+)-麦角菌素C(2)伊罗富芬(3)(−)-麦角菌素B类似物(4)

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)