Vindoline and Vinblastine

描述（由申请人提供）：基于1,3,4-二唑的串联[4+2]/[3+2]环加成级联的实现，以及最近开发的单步Fe（III）促进的vindoline与catharanthine的仿生偶联和随后的氧化反应，详细研究了vindoline和临床重要的抗肿瘤药物长春碱的非对映选择性、不对称全合成。将这些研究扩展到含有以前无法获得的深层结构变化的长春花碱类似物的合成和评价，将建立对仿生Fe（III）促进的长春花碱与catharanthine偶联机制的新见解，进一步扩大获得独特的长春花碱类似物的途径。将研究和开发现有偶联方法的两种新替代方法，扩大可用于检测的合成长春碱类似物的范围，并建立对长春碱和长春新碱与微管蛋白结合、抑制微管蛋白形成、抑制细胞有丝分裂和肿瘤细胞生长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，而且还有望从这些研究中继续出现效力、选择性、有效性和/或肿瘤耐药性更高的药物。

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.