NEW THERAPEUTICS FROM PORPHYRINS, ACETOGENINS, AND THEIR CONJUGATES

卟啉、乙酰丙酮及其结合物的新疗法

• 批准号: 6313792
• 负责人: CHARLES MICHAEL DRAIN
• 金额: $ 5.95万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6313792
• 关键词: antineoplastics; biological products; chemical structure function; combinatorial chemistry; drug design /synthesis /production; drug discovery /isolation; drug screening /evaluation; furans; lactones; neoplasm /cancer photoradiation therapy; porphyrins

There is considerable interest in the development of more selective anti- tumor agents as well as chemo-therapeutics for multi-drug resistant cancers. Conventional approaches have focused on therapeutic agents which selectively The acetogenins are a new class of naturally occurring agents which has shown potent activity against a number of cancerous cell lines, excellent selectivity in certain cases, and promising efficacy results with xenografts on athymic mice. In another direction, Photo Dynamic Therapy (PDT) has emerged as a promising treatment. However, there are many problems with the present PDT technology (based on porphyrins), including poor selectivity, poor solubility, and the dosaging is complicated by the presence of a variety of compounds such as multimers. In connection with the design of more effective PDT and traditional anti- tumor agents, synthetic methods will be developed for a variety of porphyrins (Type 1), and analogues of the THF-acetogenins (Type II). A methodology targeting a set of porphyrin-acetogenin conjugate molecules (Type III) will also be developed. Type II targets have been designed to utilize the structural features of the acetogenins to facilitate delivery and impact selectivity to PDT agents. new porphyrins will be discovered via a combinatorial chemistry approach, while the strategy for the acetogenins will be a divergent one centering on the initial synthesis of versatile relay compounds. In addition to the specific research directions, this proposal is aimed at the development of the scientific infrastructure at Hunter College for the education and to training of the undergraduate and graduate students. This project will also serve to broaden the research interests of the faculty and to provide the impetus for initiatives in multi-disciplinary research. These goals will be achieved through the very theme of this project, the necessary collaboration between the Drain and Mootoo groups, and the formal workshops and special topic courses which are part of the overall program for Molecular Mechanisms of Disease (MMD).

对开发更具选择性的抗肿瘤剂以及用于多药耐药癌症的化学治疗剂有相当大的兴趣。传统的方法集中在选择性的治疗剂上。乙酸配基是一类新的天然存在的试剂，其显示出对许多癌细胞系的有效活性，在某些情况下具有优异的选择性，并且在无胸腺小鼠的异种移植物中具有有希望的功效结果。在另一个方向，光动力疗法（PDT）已成为一种有前途的治疗方法。然而，目前的PDT技术（基于卟啉）存在许多问题，包括选择性差、溶解性差，并且由于存在多种化合物如多聚体而使剂量复杂化。为了设计更有效的PDT和传统的抗肿瘤药物，将开发各种卟啉（1型）和THF-乙酸原类似物（II型）的合成方法。还将开发一种针对一组卟啉-丙酮配基缀合物分子（III型）的方法。II型靶标已被设计成利用乙酸配基的结构特征来促进递送并影响对PDT剂的选择性。新的卟啉将通过组合化学方法被发现，而对于乙酸配基的策略将是以多功能中继化合物的初始合成为中心的发散策略。除了具体的研究方向外，该提案还旨在发展亨特学院的科学基础设施，用于本科生和研究生的教育和培训。该项目还将扩大教师的研究兴趣，并为多学科研究的举措提供动力。这些目标将通过本项目的主题，Drain和Mootoo小组之间的必要合作，以及作为疾病分子机制（MMD）整体计划一部分的正式研讨会和专题课程来实现。