Vindoline and Vinblastine

文多林和长春花碱

• 批准号: 8178689
• 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/8178689
• 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. PUBLIC HEALTH RELEVANCE: Fundamentally new approaches to the synthesis of vinblastine and vincristine, clinically employed antitumor drugs, will be developed, unique insights into the mechanism of a key biosynthetic (biomimetic) coupling reaction will emerge from the studies, a fundamental understanding of the interaction of vinblastine/vincristine with its biological target (tubulin) will be defined, and new drugs that further improve on the potency, selectivity, and efficacy of the clinically used natural products will be discovered including those that are active against vinblastine-resistant and multidrug-resistant (MDR) tumors.

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，以及最近开发的一步Fe（III）促进的仿生偶联和随后的文多林与长春质碱的氧化反应，详细描述了文多林和临床重要的抗肿瘤药物长春碱的非对映选择性、不对称全合成的研究。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碱类似物的合成和评价，将建立对仿生Fe（III）促进的文多林与长春质碱偶联机制的新见解，进一步扩大对独特长春碱类似物的获得，将研究和开发现有偶联方法的两种新的替代方法以扩大可用于研究的合成可获得的长春碱类似物的范围，并且将建立对长春碱和长春新碱与微管蛋白结合、微管蛋白形成的抑制以及细胞有丝分裂和肿瘤细胞生长的抑制所必需的结构特征的关键见解。不仅将从研究中对长春碱的抗肿瘤特性的结构-功能关系有基本的了解，而且可以预期从研究中继续出现具有改进的效力、选择性、功效和/或肿瘤抗性谱的药物。 公共卫生相关性：从根本上新的方法来合成长春碱和长春新碱，临床上使用的抗肿瘤药物，将开发，独特的见解，关键的生物合成的机制，通过这些研究，将出现（仿生）偶联反应，将确定对长春碱/长春新碱与其生物靶点（微管蛋白）相互作用的基本理解，并将进一步改善其效力，选择性，将发现临床上使用的天然产物的功效，包括那些对长春碱抗性和多药抗性（MDR）肿瘤有活性的天然产物。