Our goal is to synthesize new drugs to combat AIDS, which is taking a large and increasing worldwide medical, social and financial toll. We have preliminary evidence that diverse types of porphyrin ligands and metalloporphyrins are active against the HIV virus in PBM cells. Both precedent and preliminary testing suggest that these compounds often have low toxicity and could readily be introduced clinically. We propose to synthesize new porphyrins to investigate aspects of porphyrin structure and properties which may be important in Improving the efficacy of these compounds as drugs. Correlation of structure and activity of these molecules using information from other projects in this NCDDG proposal will lay the groundwork for the design of improved porphyrin AIDS therapeutic agents. We propose to synthesize for anti-HIV activity and toxicity evaluation prorphyrin species with systematically different properties by changing the peripheral groups of the macrocyclic porphyrin ligand and the metal and its attached axial ligands. A universe of compounds can therefore be synthesized. However, our goal is to target selectively these compounds by recognizing the effects on activity of features such as: a) the nature of the charges (+ or -) on the porphyrin ligand periphery and on the metal and axial ligands: b) the geometric distribution of charges: e) the pKas of the charged groups: d) the partition coefficient, P, of the porphyrin (determined largely by the charge/MW ratio the peripheral substituents, the metal and its axial ligands): e) the steric bulk of the porphyrin ligand and the central metal/axial ligand moiety: f) the coordination number of the complex (i.e., 4-, 5-, 6-coordinate): and g) the types of axial ligands (both labile and nonlabile) bound to the metal. It should be recognized that there will be interplay among these features. Thus, for example, overall steric bulk will depend both on the metal/axial ligand and peripheral group bulk. Rational design of AIDS therapeutic agents is critical because synthesis and testing of new drugs is time-consuming and expensive. Thus, in evaluation of factors a to g above we propose efficient synthetic schemes to prepare representative compounds starting from natural and from completely synthetic compounds. A unifying theme of this NCDDG proposal is the striking correlation between activity and nucleic acid binding. However, some porphyrins may be active by different modalities. Consequently, a long-term objective of this particular program will be to recognize additional mechanisms by which porphyrins exhibit anti-AIDS activity... Our current rationale Is to synthesize and characterize porphyrins and metalloporphyrins that will target cytoplasmic viral RNA and RNA/DNA.
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