MICROWAVE SYNTHESIS OF ARYLPHOSPHONIUM SALTS BOUND TO FLUORESCENT MARKERS

微波合成与荧光标记物结合的芳基磷盐

• 批准号: 8360079
• 负责人: John Charles Williams
• 金额: $ 1.07万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360079
• 关键词: Acetylcholinesterase; Alkylating Agents; Anti-Bacterial Agents; Antibiotics; Behavioral Research; Binding; Biomedical Research; Calorimetry; Cell division; Cell membrane; Cells; Complex; Computer Simulation; Crystallization; DNA; DNA Binding; DNA biosynthesis; Drops; Electrophoresis; Enzyme Inhibition; Enzymes; Estrogen Receptors; Exhibits; Funding; Grant; HIV Integrase; Life; Medical; Metabolism; Mitochondria; National Center for Research Resources; Organic Synthesis; Plastics; Polymers; Principal Investigator; Protein Kinase C; Publishing; Reporting; Research; Research Infrastructure; Resources; Roentgen Rays; Salts; Source; Structure; Structure-Activity Relationship; Students; Testing; Titrations; Toxic effect; United States National Institutes of Health; bovine serum amine oxidase; cancer cell; cost; cytotoxic; macromolecule; melting; microwave electromagnetic radiation; polypeptide; receptor binding; research study; solid state; uptake

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Microwave assisted organic synthesis (MAOS) is being employed to synthesize cytotoxic arylphosphonium salts (APS). APS exhibit structure-activity relationships as antibiotics, in DNA binding, enzyme inhibition and against malignant cells. They cross cell membranes and accumulate in mitochondria of malignant cells. They deliver DNA alkylating agents into cancer cells, inhibit acetylcholinesterase, bovine serum amine oxidase, protein kinase C and HIV integrase. Among possible consequences are disruption of metabolism and cell division from blocked enzymes and interference with replication. A report of the latter with student co-authors has been published. APS effects in DNA melting, electrophoresis, and isothermal titration calorimetry are being studied. A student co-authored article on in silico APS-estrogen-receptor binding has been published. We will do further experiments at RIC and Brown EPSCoR on toxicity mechanisms of APS. We have synthesized new APS-fluorescent conjugates and observed their uptake by live cells. We have prepared APS polymers and graft polymers that are antibiotic. AutoDock, HyperChem and eHitsLightning will and are being used to calculate APS-DNA interactions. Polymeric APS will be tested further for antibacterial activity for potential use in medical plastics. New APS will be screened for DNA-replication toxicity. A crystallization project to make complexes for X-ray structure determination is underway and crystals have been isolated from DNA-APS hanging-drop experiments. Solid-state polypeptide synthesis will provide polypeptides for conjugates to APS and for DNA complexing studies. Triphenyltriazoles will be synthesized and incorporated into polypeptide co-polymers to make antibiotic and/or biodegradable macromolecules.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其他NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 微波辅助有机合成法（MAOS）被用来合成具有细胞毒性的芳基磷盐（APS）。APS在DNA结合、酶抑制和抗恶性细胞等方面表现出与抗生素类似的构效关系。它们穿过细胞膜并积聚在恶性细胞的线粒体中。它们将DNA烷化剂递送到癌细胞中，抑制乙酰胆碱酯酶、牛血清胺氧化酶、蛋白激酶C和HIV整合酶。可能的后果包括代谢和细胞分裂因酶被阻断而中断，以及复制受到干扰。后者与学生合著的一份报告已经出版。APS在DNA解链、电泳和等温滴定量热法中的作用正在研究中。 发表了一篇关于计算机模拟APS-雌激素受体结合的学生合著文章。我们将在RIC和Brown EPSCoR对APS的毒性机制做进一步的实验。我们已经合成了新的APS-荧光缀合物，并观察了它们的摄取活细胞。 我们已经制备了APS聚合物和具有抗菌性的接枝聚合物。AutoDock、HyperChem和eHitsLightning将被用于计算APS-DNA相互作用。 将进一步测试聚合APS的抗菌活性，以用于医疗塑料的潜在用途。将筛选新APS的DNA复制毒性。一个结晶项目，使复合物的X-射线结构测定正在进行中，晶体已分离出DNA-APS悬滴实验。 固态多肽合成将为APS的缀合物和DNA络合研究提供多肽。将合成三苯基三唑并将其掺入多肽共聚物中以制备抗生素和/或可生物降解的大分子。