Synthesis and characterization of positively charged porphyrin-peptide conjugates.

The total syntheses of 14 porphyrin conjugates containing one to four positively charged amino acids and two distinct linkers are described. All conjugates were fully characterized using spectroscopic methods, and the X-ray structure of a porphyrin isothiocyanate precursor was obtained. In vitro studies using HEp2 cells show that these conjugates have low cytotoxicity (IC50 > 250 microM) and that the extent of their cellular uptake depends significantly on the number, nature, and sequence of amino acids in the peptide, and on the presence of a centrally chelated metal ion. Metal-free conjugates bearing three consecutive arginine residues accumulated the most within cells. On the other hand, the preferential sites of subcellular localization were found to be independent from the number, nature, and sequence of amino acids in the conjugate, the linker, and coordinated metal ion; it is suggested, based on theoretical calculations, that the peptides in these conjugates fold over the porphyrin macrocycle in order to maximize intramolecular hydrophobic interactions.