NEW THERAPEUTICS FROM PORPHYRINS, ACETOGENINS, AND THEIR CONJUGATES

人们对开发更有选择性的抗肿瘤药物以及针对多重耐药癌症的化学疗法非常感兴趣。醋酸原素是一类天然存在的新型药物，对许多癌细胞系具有有效的活性，在某些情况下具有良好的选择性，并且在胸腺小鼠的异种移植中具有良好的疗效。在另一个方向上，光动力疗法（PDT）已经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，溶解度差，以及多种化合物（如多聚物）的存在使给药复杂化。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 -乙酰素类似物（II型）的合成方法。还将开发一种针对卟啉-乙酰素偶联分子（III型）的方法。II型靶标被设计为利用醋酸原的结构特征来促进对PDT药物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，而乙酰素的策略将是一种以合成多用途接力化合物为中心的发散策略。除了具体的研究方向外，本提案还旨在发展亨特学院的科学基础设施，以教育和培养本科生和研究生。此项目亦有助扩大学院的研究兴趣，并推动多学科研究。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总体方案一部分的正式讲习班和专题课程来实现。

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).