PORPHYRIN SYNTHETIC METHODS FOR BIOORGANIC APPLICATIONS

卟啉是自然界中用途最广的基。本提案的长期目标是发展卟啉化学合成方法，可用于深入了解卟啉分子的生物学特性，并可用于仿生和治疗卟啉介导的过程。具体目的如下：(1)建立含四种不同介面取代基的卟啉（abcd -卟啉）的合成方法。这种方法将提供对局部卟啉环境的详细控制，对于构建复杂的仿生系统至关重要。(2)开发氢卟啉构建块的简单路线，包括氯、细菌氯、等细菌氯和科林斯。这种方法将支持探索氢卟啉在含有绿血红素、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位点（P460）特性的基准，羟胺氧化酶是已知最复杂的血红素酶。(4)合成一个基于卟啉的催化超氧化物歧化酶（SOD）模拟物家族，并评估其SOD活性、膜分配和在细胞培养（或动物模型）中作为天然SOD替代品的功效。一个主要的目标是瞄准线粒体以及穿过血脑屏障。这项工作将探索可能导致大量与SOD缺乏相关的人类疾病的治疗性治疗的设计特征，包括肺部和心血管疾病，与衰老相关的退行性疾病，以及神经退行性疾病（中风，帕金森氏症，ALS）。该提案涉及5名合作者（教授）。Bocian, Day, Fridovich, Munck, Scheidt)对PI制备的合成卟啉进行了各种物理测量和生物学研究。

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.