PORPHYRIN SYNTHETIC METHODS FOR BIOORGANIC APPLICATIONS

用于生物有机应用的卟啉合成方法

• 批准号: 6329668
• 负责人: JONATHAN SIDNEY LINDSEY
• 金额: $ 24.16万
• 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/6329668
• 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.

卟啉是自然界中用途最广泛的假体基团。这项提议的长期目标是开发卟啉化学的合成方法学，该方法学可用于深入了解卟啉分子的生物学性质，并可用于仿生和治疗卟啉介导的过程。具体目标如下：(1)开发合成含四种不同介孔取代基的卟啉(ABCD-卟啉)的方法。这种方法将提供对当地卟啉环境的详细控制，对于建立复杂的仿生系统至关重要。(2)开发简单的方法来构建氢卟啉构建块，包括氯素、细菌素、异细菌碘氯素和科林素。这一方法论将支持探索氢卟啉在含有绿色素、铁血红素、F430和维生素B12的酶中的作用的研究。(3)构建合成模型，作为理解羟胺氧化酶活性部位(P460)性质的基准，羟胺氧化酶是已知的最复杂的血红素酶。(4)合成一类基于卟啉的催化超氧化物歧化酶(SOD)模拟物，并评价其活性、膜分配以及在细胞培养(或动物模型)中作为天然超氧化物歧化酶替代物的效果。一个主要的目标是以线粒体为靶点，并跨越血脑屏障。这项工作将探索可能导致治疗与超氧化物歧化酶缺乏相关的大量人类病理的设计特点，包括肺病和心血管疾病、与衰老相关的退行性疾病以及神经退行性疾病(中风、帕金森S、肌萎缩侧索硬化症)。本提案涉及5位合作者(教授。Bocian，Day，Fridovich，Munck，Scheidt)，他们对PI制备的合成卟啉进行了各种物理测量和生物学研究。