Synthetic Porphyrinic Macrocycles for Photodynamic Therapy and Other Biological Applications

Abstract

Synthetic porphyrinic macrocycles are invaluable for use in a wide variety of biological applications. Such applications include photodynamic therapy (PDT) for treatment of cancer, age-related macular degeneration (AMD), and microbial infections. Several metal chelates of protoporphyrin IX molecules [Zn(II), Pd(II), In(III), and Ga(III)] were prepared from the corresponding free base porphyrin. The metalloporphyrins were tested for anti-microbial PDT. Metalloporphyrins bearing cationic substituents showed better killing of gram-negative bacteria, whereas the free base porphyrin showed strong activity against gram-positive bacteria.

Porphyrins bearing imidazolium substituents are valuable owing to the positive charge of the imidazolium group, which can impart water solubility to the porphyrin construct. To faciliate synthesis and handling of imidazole-substituted porphyrins, heteronuclear (11B, 15N) NMR spectroscopy was employed to fully characterize the various imidazole-substituted precursors to the porphyrins, including the dialkylboron complexes thereof. Metal chelates of imidazolium-porphyrins [Zn(II), Pd(II), and In(III)] were prepared starting from non-polar trans-AB porphyrins. Imidazolium-porphyrins bearing cationic or anionic substituents were examined for the efficiency of killing cancer cells (e.g., HeLa and CT26 carcinoma cells). The effectiveness of cell killing was observed in the following order: Pd(II) > cationic In(III) > cationic Zn(II) > anionic Zn(II) imidazolium-porphyrin.

Hydroxymethyl-porphyrins and hydroxymethyl-chlorins were synthesized for studies of self-assembly in analogy with the structure and function of the natural pigment bacteriochlorophyll c. Various acyclic precursors containing a hydroxymethyl moiety (e.g., Mukaiyama reagents, 1-acyldipyrromethane) were prepared so that the hydroxymethyl group could be incorporated prior to the formation of the tetrapyrrole macrocycle.

Formyl-chlorins were prepared for studies of the effect of the formyl group on the absorption spectral properties. Both hydroxymethyl-chlorins and formyl-chlorins were synthesized by the palladium-mediated coupling of the corresponding bromo-chlorin. Two routes were employed: (1) synthesis of a hydroxymethyl-chlorin via Stille coupling, followed by PCC-mediated oxidation to access the formyl-chlorin, and (2) palladium-catalyzed reductive carbonylation of a bromo-chlorin to access the formyl-chlorin.

The ability to incorporate imidazole (and imidazolium), hydroxymethyl, and formyl groups at designated sites in porphyrins and chlorins affords valuable methodology for constructing molecular architectures of use in a variety of biological and materials chemistry applications.