Photochemical Delivery and Metal Mediated Reactions of Bioactive Small Molecules

现在公认的是，气体分子一氧化氮、一氧化碳和二硫化碳是哺乳动物许多生物学功能的重要调节器，更具体地说，是人类的调节器。例如，一氧化氮是血压的调节器，而一氧化氮、一氧化碳和二硫化碳等硫化物在伤口愈合和炎症中发挥关键作用，但仍知之甚少。该项目所代表的持续研究包括两个相关的主题。第一个涉及阐明定义这些物种生理的基本化学，而第二个涉及设计新技术，根据需要将这种生物活性小分子(BSM)递送到特定的生物靶标。前者涉及应用现代仪器来检测这些BSM与生物相关金属中心的化学反应速率，而后者则侧重于利用光作为触发器来控制特定部位BSM释放的时间、位置和剂量。这些项目的研究生和本科生研究人员获得了微纳材料科学、化学生物学、光化学、化学合成和动力学方面的跨学科培训。他们还积极参加K-12外展活动，与当地学校的老师和学生分享他们研究活动的兴奋。NSF化学部的生命过程化学计划将资助加州大学圣巴巴拉分校的Peter C.Ford博士进行跨学科研究，以探索将BSMS NO和CO光化学传递到生理靶点的新策略和前体，并对潜在生物活性分子CS2的传递进行探索性研究。实验方法将包括合成BSM前体和生色团之间的偶联物，包括有机染料和用于单光子和双光子激发的纳米材料。现代光学方法(超快激光研究、共聚焦显微镜等)将评估定量光敏机制并为设计优化提供指导，而体外(细胞培养)研究则提供生物活性的初步测试。在合作研究中，研究人员将探索以聚合物为基础的纳米和微载体，将BSM前体-发色团偶联物输送到特定的生物部位。这样定义的原则应该广泛适用于其他生物活性分子的输送。此外，还将使用停流和闪光光解动力学光谱、计算和协作低温矩阵研究来阐明BSM与生物相关的金属中心底物反应的基本机制。评估这些途径对于确定这些复杂系统的化学/生理关系至关重要。

It is now well established that the gaseous molecules nitric oxide, carbon monoxide and carbon disulfide are important regulators of many biological functions in mammals and, more specifically, in humans. For examples, nitric oxide is a regulator of blood pressure, while nitric oxide, carbon monoxide, and sulfur compounds such as carbon disulfide have key, but still poorly understood, roles in wound healing and inflammation. The continuing research represented by this project encompasses two related topics. The first is concerned with elucidating the fundamental chemistry that defines the physiology of these species, while the second is concerned with designing new technology to deliver such bioactive small molecules (BSMs) to specific biological targets on demand. The former topic involves the application of modern instrumentation to examine rates of the chemical reactions of these BSMs with biologically relevant metal centers, while the latter is focused on utilizing light as a trigger for controlling the timing, location and dosage of BSM release at specific sites. Graduate and undergraduate student researchers in these projects acquire interdisciplinary training in micro- and nano-materials science, chemical biology, photochemistry and chemical synthesis and kinetics. They also are active in K-12 outreach activities, where they share the excitement of their research activities with teachers and students in local schools. With this award, the Chemistry of Life Processes Program in the NSF Chemistry Division is funding Dr. Peter C. Ford from the University of California, Santa Barbara for interdisciplinary investigations into new strategies and precursors for photochemical delivery of the BSMs NO and CO to physiological targets and for exploratory studies into delivery of the potentially bioactive molecule CS2. Experimental methods will include syntheses of conjugates between BSM precursors and chromophores including organic dyes and nano-materials for one- and 2-photon excitation. Modern optical methods (ultra-fast laser studies, confocal microscopy, etc.) will evaluate quantitative photosensitization mechanisms and provide guidelines for design optimization, while in vitro (cell culture) studies provide initial tests of biological viability. In collaborative studies, the investigators will explore polymer-based nano- and micro-carriers for delivery of BSM precursor-chromophore conjugates to specific biological sites. The principles thus defined should be broadly applicable to delivery of other bioactive molecules. In addition, stopped-flow and flash photolysis kinetics spectroscopy, computations and collaborative low temperature matrix studies will be used to elucidate fundamental mechanisms of BSM reactions with biologically relevant metal-centered substrates. Evaluating such pathways is crucial to defining the chemistry/physiology relationships of these complex systems.