PORPHYRIN SYNTHETIC METHODS FOR BIOORGANIC APPLICATIONS

用于生物有机应用的卟啉合成方法

• 批准号: 6476466
• 负责人: JONATHAN SIDNEY LINDSEY
• 金额: $ 24.88万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-12-01 至 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6476466
• 关键词: Mossbauer spectrometry; Raman spectrometry; biomimetics; blood brain barrier; chemical models; chemical stability; chemical substitution; chemical synthesis; chlorin; enzyme activity; enzyme deficiency; genetically modified animals; heme; laboratory mouse; method development; mitochondria; porphyrins; superoxide dismutase; tissue /cell culture

Porphyrins are the most versatile prosthetic groups in nature. The long-term goals of this proposal are to develop synthetic methodology in porphyrin chemistry that can be used to gain deep insight into the biological properties of porphyrinic molecules and can be exploited in biomimetic and therapeutic porphyrin- mediated processes. The specific aims are as follows: (1) Develop synthetic methods for preparing porphyrins bearing four different meso-substituents (ABCD-poryphyrins). This methodology will provide detailed control of the local porphyrin environment and is crucial for building sophisticated biomimetic systems. (2) Develop simple routes to hydroporphyrin building blocks, including chlorins, bacteriochlorins, isobacteriochlorins, and corrins. This methodology will support studies probing the role of hydroporphyrins in enzymes containing green hemes, sirohemes, F430 and vitamin B12. (3) Construct synthetic models that serve as benchmarks for understanding the properties of the active site (P460) of hydroxylamine oxidase, the most complex heme enzyme known. (4) Synthesize a family of porphyrin-based catalytic superoxide dismutase (SOD) mimics, and evaluate their SOD activity, membrane partitioning, and efficacy in cell culture (or animal models) as a substitute for naturally occurring SODs. A major objective is to target the mitochondria as well as cross the blood-brain barrier. This work will explore the design features that may lead to therapeutic treatment for the large number of human pathologies associated with SOD deficiencies, including pulmonary and cardiovascular diseases, degenerative diseases associated with aging, and neurodegenerative diseases (stroke, Parkinson s, ALS). This proposal involves 5 collaborators (Profs. Bocian, Day, Fridovich, Munck, Scheidt) who perform a variety of physical measurements and biological studies of the synthetic porphyrins prepared by the PI.

卟啉本质上是最通用的假肢群体。该提案的长期目标是开发卟啉化学中的合成方法，这些方法可用于深入了解卟啉分子的生物学特性，并可以在仿生和治疗性卟啉介导的过程中利用。 具体目的如下：（1）开发用于制备四种不同中氧化物（ABCD-Poryphyrins）的卟啉的合成方法。 该方法将提供对局部卟啉环境的详细控制，并且对于建立复杂的仿生系统至关重要。 （2）开发简单的途径，前往氢磷脂的构建块，包括氯蛋白，细菌氯蛋白，等杆菌氯蛋白和Corrins。 该方法将支持研究探测氢磷酸酯在含有绿色下摆，sirohemes，f430和维生素B12的酶中的作用的研究。 （3）构造合成模型，可作为理解羟胺氧化酶（已知最复杂的血红素酶）活性位点（P460）的特性（P460）的特性。 （4）合成一个基于卟啉的催化超氧化物歧化酶（SOD）模拟物的家族，并评估其在细胞培养（或动物模型）中的SOD活性，膜分配和功效，以代替自然存在的SOD。 一个主要目标是针对线粒体以及越过血脑屏障。 这项工作将探讨可能导致与SOD缺乏症相关的大量人类病理的治疗特征，包括肺部和心血管疾病，与衰老以及神经退行性疾病相关的退行性疾病（Stroke，Stroke，Parkinson s，als，Als）。 该提案涉及5名合作者（Bocian教授，Day，Fridovich，Munck，Scheidt），他们对PI制备的合成卟啉进行了多种物理测量和生物学研究。