Vindoline and Vinblastine

描述(申请人提供)：基于1，3，4-恶二唑的串联[4+2]/[3+2]环加成级联，以及最近开发的一步铁(III)促进的长春花碱与长春花碱的仿生偶联和随后的氧化反应，详细介绍了长春花碱和临床上重要的抗肿瘤药物长春花碱的非对映选择性、不对称全合成和长春花碱的研究。将继续开展这些研究，以合成和评价包含以前难以接近的深层次结构变化的长春花碱类似物；将进一步深入了解铁(III)促进长春花碱与长春花碱仿生偶联的机制；将进一步扩大获得独特长春花碱类似物的途径；将研究和开发两种新的替代长春花碱类似物的方法，以扩大可合成获得的长春花碱类似物的范围；将建立对长春花碱和长春新碱与微管蛋白结合、抑制微管形成以及抑制细胞有丝分裂和肿瘤细胞生长所必需的结构特征的关键见解。这些研究不仅将对长春花碱抗肿瘤特性的结构-功能关系有一个基本的了解，而且有望继续从研究中涌现出效力、选择性、疗效和/或抗癌特性得到改善的药物。

DESCRIPTION (provided by applicant): Studies on the diastereoselective, asymmetric total synthesis of vindoline and the clinically important antitumor drug vinblastine are detailed based on the implementation of a tandem [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazoles, and a recently developed single step Fe(III)-promoted biomimetic coupling and subsequent oxidation reaction of vindoline with catharanthine. Extensions of these studies to the synthesis and evaluation of vinblastine analogues containing previously inaccessible deep-seated structural changes will be pursued, new insights into the mechanism of the biomimetic Fe(III)-promoted coupling of vindoline with catharanthine will be established further expanding access to unique vinblastine analogues, two new alternatives to existing coupling methods will be examined and developed expanding the range of synthetically accessible vinblastine analogues available for examination, and key insights into the structural features of vinblastine and vincristine integral to their binding to tubulin, inhibition of microtubulin formation, and inhibition of cell mitosis and tumor cell growth will be established. Not only will a fundamental understanding of the structure-function relationships of vinblastine's antitumor properties emerge from the studies, but drugs with improved potency, selectivity, efficacy, and/or tumor resistance profiles can be expected to continue to emerge from the studies.