Designed Photoactive Metal Nitrosyls for Site-specific NO Delivery

设计用于特定位点 NO 传递的光活性金属亚硝基化合物

• 批准号: 0957251
• 负责人: Pradip Mascharak
• 金额: $ 43.43万
• 依托单位: University of California-Santa Cruz
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0957251&HistoricalAwards=false
• 关键词: Designed; Photoactive; Metal; Nitrosyls; Site

The Chemical Structure, Dynamics and Mechanisms Program of the Division of Chemistry supports the research efforts of Professor Pradip K. Mascharak of the University of California Santa Cruz in studying metal nitrosyl complexes as exogenous NO donors that are activated with light. Such photoactive nitrosyl complexes are employed to deliver NO to chemical, biological and cellular targets on demand. Density functional theory (DFT) and TD-DFT calculations are used in the smart design of metal (Fe, Mn, and Ru) nitrosyls. These computational techniques are used to fine tune the ligand design so that the complexes are sensitive to near infrared light (which is better for photodynamic therapy). The nitrosyl-dye conjugates are used as "trackable NO donors" in tracing NO delivery in cellular targets (malignant sites) and monitoring NO-induced apoptosis (programmed cell death). In order to make the various nitrosyls suitable for site-specific delivery of NO, the group incorporates the metal complexes into different polymer matrices. Nitric oxide (NO) is recognized as a key mediator in a variety of physiological and pathological pathways such as blood pressure regulation, immune response, neurotransmission, and cellular apoptosis. Typical systemic NO drugs (such as glyceryl trinitrate) cannot be used for site-specific NO delivery because of the inexorability of NO release from NO donors. The drug goes everywhere in the body and NO is released via various enzymatic and non-enzymatic (such as pH and temperature) pathways. Light, on the other hand, can control NO release from proper NO donors in a cellular environment. This research project provides insight into the design and synthesis of metal complexes that release NO in response to specific stimuli (light). This goal-oriented project provides an excellent opportunity for graduate and undergraduate students to participate in research at the interface of chemistry and biology.

化学系的化学结构，动力学和机制计划支持Pradip K教授的研究工作。加州大学圣克鲁斯分校的Mascharak博士在研究金属亚硝酰络合物作为外源NO供体的光激活。 这种光活性亚硝酰基复合物用于根据需要将NO递送至化学、生物和细胞靶标。 采用密度泛函理论（DFT）和TD-DFT计算方法，对金属（Fe，Mn，Ru）亚硝基化合物进行了智能设计。 这些计算技术用于微调配体设计，使复合物对近红外光敏感（这对光动力疗法更好）。 亚硝酰基染料缀合物用作“可追踪的NO供体”，用于追踪细胞靶点（恶性部位）中的NO递送并监测NO诱导的细胞凋亡（程序性细胞死亡）。 为了使各种亚硝基适合于位点特异性递送NO，该小组将金属络合物掺入不同的聚合物基质中。 一氧化氮（NO）是血压调节、免疫应答、神经传递和细胞凋亡等多种生理和病理途径中的关键介质。 典型的全身性NO药物（如甘油三硝酸酯）不能用于位点特异性NO递送，因为NO供体释放NO的不可阻挡性。 药物在体内无处不在，NO通过各种酶和非酶（如pH和温度）途径释放。 另一方面，光可以控制细胞环境中适当的NO供体释放NO。 该研究项目提供了对金属络合物的设计和合成的深入了解，这些金属络合物在响应特定刺激（光）时释放NO。 这个以目标为导向的项目为研究生和本科生提供了一个很好的机会，参与化学和生物学接口的研究。