The objective of the work described in this proposal is discovery of fundamental chemistry and synthetic methodology for obtaining porphyrin systems of biological interest, with special emphasis on development of completely new methodology for isotope labeling of hemes so as to provide access to unique spectroscopic probes of structure-activity relationships in heme proteins. Methodology will be developed which will permit syntheses of natural hemes regioselectively labeled in predetermined positions with deuterium and carbon-13. Materials deriving from these studies will subsequently be used for NMR, resonance Raman, and other biophysical studies to gain an understanding of heme/apoprotein interactions and structure/function relationships in a variety of biologically important heme proteins such as hemoglobins, myoglobins, cytochromes, oxygenases, and peroxidases. Heme and/or protein dysfunction in heme proteins is the basis for a number of debilitating and often fatal diseases. It is also proposed to synthesize a number of novel heme-type systems which will be incorporated into synthetic redox protein maquettes; these compounds will enable mapping of local dielectric field gradients in protein mimics, and basic principles uncovered should be directly applicable to the more complex natural products. Malaria parasites require human and animal blood solely for its protein component; the toxic heme is polymerized to the insoluble hemozoin (malaria pigment), in order to render it harmless. The mechanisms of heme polymerization will be investigated by studying the nature of the porphyrin linkages in hemozoin, through the synthesis of a variety of model oligomers. Since malaria parasites are rapidly developing resistance to most existing drugs, the mechanism of inhibition of heme polymerization will also be investigated with the intention of finding new potential antimalaria drugs for this disease which kills 1.5 to 2 million people every year. The overall program will use basic science to establish a synthetic rationale and anchor point for spectroscopic methodology being developed to advance our understanding of heme protein function, and of structural and electronic factors which cause several debilitating disease such as anemia and malaria. Deuterium labeled, carbon-13 enriched, and unlabeled porphyrins will be obtained by total synthesis from acyclic precursors. Some methods for such approaches have already been worked out, but improvements and discovery of new methodology, simple and multistep, is planned and anticipated.
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