Cytotoxic & MDR-Active Alkaloids-Synthesis & Evaluation

细胞毒性

• 批准号: 6692208
• 负责人: Joseph Paul Konopelski
• 金额: $ 26.43万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6692208
• 关键词: Cytotoxic; MDR; Active; Alkaloids; Synthesis

DESCRIPTION (provided by applicant): The principle objectives of this research project are the synthesis, in enantiomerically pure form, of diazonamide A (revised structure, 1) and N-methylwelwitindolinone C isothiocyanate (2). The specific aims will focus on six challenges: 1. The first aim is an efficient synthesis of the desired stereochemistry at the C10/C11 centers as an advanced fragment leading to diazonamide A. Aryllead(IV) compounds are highly selective and mild reagents for the production of quaternary centers. Our studies in this area have been especially fruitful. 2. The second aim is the execution of an effective aryl-aryl coupling reaction to set the C16/C18 bond. Organometallic technology can be employed to perform this aryl-aryl coupling reaction. Many such examples exist in the literature, and our own studies concur with this assessment. 3. The third aim is the efficient synthesis of the bis-oxazole system in conjunction with generation of the macrobicyclic structure of diazonamide A. Cyclodehydration of a N-acyI-D-aminoketone will effectively generate the C29 through C31 oxazole, whereas the C26 through C28 chlorooxazole can be effectively prepared via a [3+2] cycloaddition strategy. 4. The fourth aim is the efficient synthesis of the entire ring system of N-methylwelwitindolinone C isothiocyanate. An intramolecular conjugate addition reaction between C3 and C16, coupled with an efficient intermolecular coupling of the indole C4 position with C11, will efficiently generate the central sevenmembered ring of 2. 5. The fifth aim is the successful synthesis of the C11/C12 array of stereocenters in Nmethylwelwitindolinone C isothiocyanate. Directed introduction of functionality at C12 from C11 will allow both centers to be developed simultaneously. 6. The sixth specific aim is the synthesis of selected derivatives of both these targets for biological testing and evaluation. Collaborations for testing have been established. Diazonamide A is a cytotoxic agent and Nmethylwelwitindolinone C isothiocyanate is a multidrug resistance (MDR) reversal agent. Only a vigorous synthetic program toward these natural products and selected derivatives will allow for their full examination both as biological agents for cell cycle study and as possible therapeutics.

描述（由申请人提供）：本研究项目的主要目标是合成对映体纯形式的重氮酰胺A（修订结构，1）和N-甲基异吲哚啉酮C异硫氰酸酯（2）。具体目标将集中在六个挑战：1。第一个目标是在C10/C11中心有效合成所需的立体化学，作为导致重氮酰胺A的高级片段。芳基铅（IV）化合物是用于产生季中心的高选择性和温和的试剂。我们在这方面的研究特别富有成果。2.第二个目的是进行有效的芳基-芳基偶联反应以固定C16/C18键。可以采用有机溶剂技术来进行该芳基-芳基偶联反应。文献中有许多这样的例子，我们自己的研究也同意这一评估。3.第三个目的是有效合成双恶唑体系，同时生成重氮酰胺A的大双环结构。N-酰基-D-氨基酮的环化脱水将有效地产生C29至C31恶唑，而C26至C28氯恶唑可以通过[3+2]环加成策略有效地制备。4.第四个目标是高效合成N-甲基异吲哚啉酮C异硫氰酸酯的整个环系。C3和C16之间的分子内共轭加成反应，再加上吲哚C4位置与C11的有效分子间偶联，将有效地产生2的中心七元环。5.第五个目标是成功合成N-甲基维吲哚啉酮C异硫氰酸酯的C11/C12立体中心阵列。从C11直接引入C12的功能将允许两个中心同时开发。6.第六个具体目标是合成这两种靶标的选定衍生物用于生物测试和评估。已经建立了测试合作。重氮酰胺A是一种细胞毒性药物，N甲基维吲哚啉酮C异硫氰酸酯是一种多药耐药（MDR）逆转剂。只有对这些天然产物和选定的衍生物进行强有力的合成计划，才能将它们作为细胞周期研究的生物制剂和可能的治疗方法进行全面检查。