Asymmetric Total Synthesis of Vindoline and Novel Analogues

描述(申请人提供)：长春花碱和长春新碱是长春花碱家族的成员，最初是从马达加斯加长春花长春花叶中分离出来的。在临床上，长春花碱被用于治疗霍奇金淋巴瘤和非霍奇金淋巴瘤、膀胱癌和乳腺癌。与此同时，长春新碱被用于治疗白血病、淋巴瘤和小细胞肺癌。不幸的是，广泛的使用导致了癌症的出现，这种耐药性主要是通过跨膜蛋白磷酸糖蛋白(PGP，也称为MDR1)的作用而产生的。4这项研究项目的广泛目标是开发长春花碱的第二代不对称化学合成方法，长春花碱是长春花碱和长春新碱的“较低”亚单位。该合成路线以跨环[4+2]/[3+2]环加成反应为关键步骤，建立了四个环和六个立体中心，具有完全的非对映选择性。这一反应构成了之前在博格实验室开发的方法的延伸，涉及到级联的分子内变体。10d拟议的长春花碱合成路线还将允许构建长春花碱和长春新碱类似物，这些类似物不能通过修改母药结构来获得。所有新的类似物都将接受对野生型和耐药癌细胞的活性测试，最终目标是识别出一种对耐药细胞株的活性优于亲本药物的类似物。 与公共卫生相关：该项目旨在开发一种有效的长春花碱的合成，并随后开发抗癌药物长春花碱和长春新碱的新型类似物。通过这些努力制备的类似物将被筛选出抗癌活性，以寻找对耐药细胞系具有增强细胞毒性的候选药物。

DESCRIPTION (provided by applicant): Vinblastine and vincristine are members of the Vinca alkaloid family originally isolated from the leaves of the Madagascan periwinkle Catharanthus roseus (L.) G. Don.1 Both compounds have been used clinically for over 40 years and represent one of the most important contributions that the field of natural products chemistry has made to cancer chemotherapy.2 In the clinic, vinblastine is used in curative combination regimens for the treatment of Hodgkin's and non-Hodgkin's lymphomas, bladder cancer and breast cancer. Vincristine, meanwhile, finds use in the treatment of leukemia, lymphomas and small cell lung cancer. Unfortunately, widespread use has led to the emergence of cancers with resistance that is imparted primarily by the action of the transmembrane protein phosphoglycoprotein (Pgp, also known as MDR1).4 The broad goal of this research project is to develop an efficient second-generation asymmetric chemical synthesis of vindoline, which constitutes the "lower" subunit of vinblastine and vincristine. The proposed synthetic route features, as the key step, a transannular [4+2]/[3+2] cycloaddition cascade reaction that establishes four rings and six stereocenters with complete diastereoselectivity. This reaction constitutes an extension of methodology previously developed in the Boger lab involving an intramolecular variant of the cascade.10d The proposed synthetic route to vindoline will also allow for the construction of vinblastine and vincristine analogues that are not accessible by modification of the parent drug structure. All new analogues will be tested for activity against both wild-type and resistant cancer cells with the ultimate goal being identification of an analogue with activity against resistant cell lines superior to that of the parent drugs. PUBLIC HEALTH RELEVANCE: This project aims to develop an efficient synthesis of vindoline and, subsequently, novel analogues of the cancer drugs vinblastine and vincristine. Analogues prepared through these efforts will be screened for anticancer activity in the search for a candidate with enhanced cytotoxicity against resistant cell lines.