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）：基于串联[4+2]/[3+2] Cyctodition Cascade详细详细介绍了Vindoline和临床上重要的抗肿瘤药物葡萄糖葡萄糖的研究研究的研究，并详细介绍了1,3,4-oxadiazAdiazadiazAdiazadiazAdiazadiazAdiazAdiazadiazAdiazAdiazAdiazAdiazAdiazAdiazAdiazAdia-fe（III）。 Vindoline与Catharanthine的随后氧化反应。 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开发了可用于检查的合成葡萄碱类似物的范围，以及对葡萄蛋白与小管蛋白结合，抑制微管蛋白的结合的重要见解，并建立了细胞和肿瘤细胞生长的抑制。对研究的葡萄碱性抗肿瘤特性的结构 - 功能关系的基本了解不仅会从研究中出现，而且具有提高效力，选择性，功效和/或肿瘤耐药性谱的药物将继续从研究中继续出现。