NEW THERAPEUTICS FROM PORPHYRINS, ACETOGENINS, AND THEIR CONJUGATES

人们对开发更具选择性的抗肿瘤药物以及治疗多药耐药癌症的化疗药物非常感兴趣。传统的治疗方法主要集中在治疗药物上，其中选择性的乙酰生素是一类新的自然产生的药物，已经显示出对一些癌细胞株的有效活性，在某些情况下表现出良好的选择性，并在裸鼠身上的异种移植上取得了有希望的疗效。在另一个方向，光动态疗法(PDT)已经成为一种有前途的治疗方法。然而，目前的光动力学技术(基于卟啉)存在着选择性差、溶解性差、多聚体等多种化合物的存在使给药复杂等问题。为了设计更有效的光动力疗法和传统的抗肿瘤药物，将开发各种卟啉(类型1)和四氢呋喃-乙酰基类似物(类型II)的合成方法。还将开发一种针对一组卟啉-乙酰生素共轭分子(类型III)的方法学。第二类靶标被设计成利用乙酰生素的结构特征来促进对PDT试剂的递送和影响选择性。新的卟啉将通过组合化学方法被发现，而乙酰生素的策略将是一种发散的策略，其核心是多用途继电化合物的初始合成。除了具体的研究方向外，这项建议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。这项计划还将有助于拓宽教员的研究兴趣，并推动多学科研究的倡议。这些目标将通过这个项目的主题、DRAIN和Mootoy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。

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).