Vindoline and Vinblastine

文多林和长春花碱

• 批准号: 8309097
• 负责人: DALE L BOGER
• 金额: $ 32.73万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-10 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8309097
• 关键词: Address; Alkaloids; Binding; Biological; Biological Factors; Biomimetics; Cells; Clinical; Clinical Treatment; Coupling; Development; Diels Alder reaction; Dose; Dose-Limiting; Esters; Evaluation; Indoles; Investigation; Malignant Neoplasms; Methodology; Methods; Mitosis; Multi-Drug Resistance; Myelosuppression; Organic Synthesis; Oxadiazoles; Pharmaceutical Preparations; Plant Leaves; Preparation; Property; Qualifying; Reaction; Resistance; Resistance profile; Route; Secure; Seminal; Staging; Structure; Structure-Activity Relationship; Time; Toxic effect; Tubulin; Vinblastine; Vinca; Vincristine; Vindoline; Weight; analog; antitumor drug; base; catharanthine; cell growth; cost; cycloaddition; improved; insight; neoplastic cell; neurotoxicity; novel; novel strategies; oncology; overexpression; oxidation; protein protein interaction; tumor

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.

描述（由申请人提供）：基于 1,3,4-恶二唑的串联 [4+2]/[3+2] 环加成级联的实施，以及最近开发的单步 Fe(III) 促进的仿生偶联和 随后文多灵与长春质发生氧化反应。将这些研究扩展到包含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估，将建立对仿生 Fe(III) 促进的长春花碱与长春花碱偶联机制的新见解，进一步扩大对独特长春花碱类似物的获取，将检查和研究现有偶联方法的两种新替代方法 开发扩大了可用于检查的合成长春花碱类似物的范围，并将建立对长春花碱和长春新碱与微管蛋白结合、抑制微管蛋白形成以及抑制细胞有丝分裂和肿瘤细胞生长不可或缺的结构特征的关键见解。研究不仅可以对长春花碱的抗肿瘤特性的结构与功能关系有一个基本的了解，而且可以预期这些研究将继续出现具有改进的效力、选择性、功效和/或肿瘤抗性特征的药物。