MICROWAVE SYNTHESIS OF ARYLPHOSPHONIUM SALTS BOUND TO FLUORESCENT MARKERS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 芳基膦盐(APS)具有细胞毒性。它们表现出与抗生素一样的结构-活性关系(SARS)，在DNA结合、酶抑制和对恶性肿瘤细胞的杀伤力方面。这些亲脂性阳离子很容易通过细胞膜。相对于正常细胞线粒体，它们优先聚集在恶性细胞的线粒体中，以应对较大的电荷梯度。这一特性已被用来将DNA烷化剂输送到恶性肿瘤细胞的线粒体中。APS在体外和体内均表现为对乙酰胆碱酯酶的抑制作用。它们是牛血清胺氧化酶、蛋白激酶C和HIV整合酶等的竞争性抑制剂。在一个正在进行的合作项目中，AP被证明可以调节DNA毒性，该项目的初步结果已经公布。DNA结合也从熔化曲线移动、电泳迁移率和我们实验室进行的电子结合研究中得到证明。我们将进行协作实验，以探索APS的具体毒性机制。我们将合成与荧光分子结合的APS，含有共价结合抗生素APS的聚合物，用于新的DNA结合和毒性实验的APS，以及新型APS离子液体。AutoDock和HyperChem将用于计算APS-DNA相互作用。荧光标记化合物将用于利用荧光显微镜观察APS在细胞内的定位和分散。将对聚合物AP进行抗菌活性测试，并将其并入适合制造医疗管材、袋子和容器的塑料中。新的单体APS将在DNA复制毒性研究以及熔融和电泳实验中进行筛选。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Arylphosphonium salts (APS) are cytotoxic. They exhibit structure-activity relationships (SARs) as antibiotics, in DNA binding, enzyme inhibition and in lethality to malignant cells. These lipophilic cations easily pass across cell membranes. They preferentially accumulate in the mitochondria of malignant cells in response to the larger charge gradient relative to normal cell mitochondria. This property has been exploited to deliver DNA alkylating agents into mitochondria of malignant cells. APS exhibit SARs for in vitro and in vivo inhibition of acetylcholinesterase. They are competitive inhibitors of bovine serum amine oxidase, protein kinase C and HIV integrase, among others. APS have been shown to modulate DNA toxicity in a collaborative project underway, for which preliminary results have been published. DNA binding is also evidenced by melting curve shifts, electrophoresis mobility and in silico binding studies done in our laboratories. We will do collaborative experiments to explore the specific mechanisms for toxicity of APS. We will synthesize APS bound to fluorescent molecules, polymers containing covalently bound antibiotic APS, APS for new DNA binding and toxicity experiments, and novel APS ionic liquids. AutoDock and HyperChem will be used to calculate APS-DNA interactions. The fluorescent-labeled compounds will be used to observe localization and dispersion of APS into cells using fluorescent microscopy. Polymeric APS will be tested for antibacterial activity and incorporated into plastics suitable for the fabrication of medical tubing, bagging and containers. New monomer APS will be screened in a continuation of DNA-replication toxicity studies and in melting and electrophoresis experiments.