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.