Porphyrin Synthetic Methods for Bioorganic Applications

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The long-term objective of this proposal is to develop synthetic methodology that can be used to gain deep insight into the biological properties of porphyrinic molecules and can be exploited in diagnostic and therapeutic applications. The term "porphyrinic" encompasses tetrapyrrole macrocycles that are fully unsaturated (porphyrins) or partially reduced (hydroporphyrins; such as chlorins or bacteriochlorins). The specific objective is to develop powerful routes for the synthesis of water-soluble, bioconjugatable porphyrins and hydroporphyrins. Hydroporphyrins absorb strongly in the red/near-IR spectral region, an ideal wavelength of light for deep penetration of cells and tissues. Such compounds are anticipated to have widespread biological applications where active targeting with a red/near-IR label is required, yet hydroporphyrins with the requisite molecular design features have not been available synthetically. The hydroporphyrins will bear one conjugatable handle, one or more water-solubilizing groups, structural features to prevent dehydrogenation and suppress oxidation, and tunable photochemistry via alteration of the centrally coordinated metal. Strategies for the rational synthesis of bacteriochlorins will be developed, including the derivatization of porphyrins, the derivatization of chlorins, and synthesis de novo. In the development of new synthetic routes, attention will be paid to issues of simplicity, scope, and scale, thereby enabling widespread utilization by a broad range of scientists from diverse fields. New molecular motifs will be investigated for achieving water solubility, a key requirement for use in biomolecule labeling studies. The basic science for the use of hydroporphyrin-biomolecule conjugates will be addressed by first characterizing the intrinsic properties of the hydroporphyrins, then characterizing the loading, non-covalent binding, aggregation, photostability, and brightness of hydroporphyrin-antibody conjugates. This work will open the door to applications such as multicolor/multiparameter labeling of cells and intracellular components, and provide a sound basis for the design and development of next-generation molecules for use in diverse therapeutic applications where active-targeting strategies are sought.