Our efforts in the area of bioinorganic chemistry of nitric oxide (NO) are directed towards understanding how this small paramagnetic molecule functions in the chemistry of mammalian systems. The growth in interest in NO chemistry can be attributed to the discovery within the last several years that this remarkable small molecule is responsible for a host of biological phenomena such as the maintenance of normal blood pressure, neurotransmission, and DNA damage. Research in our laboratory involves the study of the fundamental chemistry of metal-NO linkages in biomolecules. No such studies have been done previously. Thus, the preparation of a series of NO complexes of metalloporphyrins (of varying electron-donating ability) and metallochlorins of some late first-row transition metals (Mn, Fe, Co) will be pursued. These metals are biologically active in a variety of ligand environments, and the NO complexes of metalloporphyrins/chlorins are potential models for heme-NO and cytochrome-NO interactions. The fundamental chemistry of the resulting product species with electrophilic and nucleophilic reagents to produce new sulfur-nitrogen, carbon-nitrogen, and nitrogen-nitrogen bonds will be investigated. The interaction of nitrosamines and thionitrites with the metalloporphyrins/chlorins will also be studied. Although nitrosamines are of environmental consequence and can be found in food and cigarette smoke, no studies have been conducted on how these carcinogenic molecules bind to metal complexes that may be present in the human body. Thus, the study of how the atoms in the nitrosamines bind to the metal centers in porphyrin-type compounds, and how these interactions control the eventual decomposition and/or activation pathways of the resulting biochemical species will be pivotal to developing new chemical routes for the deactivation of these carcinogens.

R29GM053586

1996-08-01

2002-07-31