The chemistry and evaluation of porphyrin-based potential anticancer agents.

摘要

Towards the goal of synthesizing porphyrin-based radiosensitizers and hypoxia-selective cytotoxins (HSCs) leading to improved cancer treatment modalities, the chemistry of several porphyrin systems (diarylporphyrins, tetraarylporphyrins, and those based on protoporphyrin IX) was investigated. Porphyrin incorporation of nitroaromatic and heterocyclic-N-oxide moieties into porphyrins was the general objective, but additional areas were investigated.;Symmetrical diarylporphyrins incorporating pyridyl, oxidopyridyl-, nitrophenyl and phenyl substituents were synthesized.;Condensation of pyrrole with one or two aldehydes in propionic acid (the Adler method) was used to synthesize several tetraaryiporphyrins containing pyridyl or imidazolyl groups.;Porphyrins containing one to four pyridyl groups were 'N-oxidized' with m-chloroperbenzoic acid to produce five novel (oxidopyridyl)porphyrins and seven porphyrin N-oxides.;New substituents were introduced at the 8,13-positions of protoporphyrin IX dimethylester via the previously reported TlIII-vinyl oxidation product, and a selective deprotection of compound's dimethyl acetal functionalities was developed.;In vitro assays for radiosensitization, hypoxia-selective toxicity, and photosensitization with chinese hamster ovary cells were used to evaluate the potential of selected porphyrins incorporating oxidopyridyl (OPyTrSPhP), 2-nitroimidazolyl (BNImEtPIX) or tirapazamine (TirapPhTrPhP) substituents along with suitable 'reference' compounds.;In general, the porphyrins were non-toxic, and they showed little radiosensitizing or photosensitizing ability; however, TirapPhTrPhP showed a modest radiation SER value (1.5). Some photosensitization was observed with OPyTrSPhP, but its effectiveness was poor in comparison to that of PhotofrinRTM ; some evidence was found for protection from PDT-induced damaged by pyridine N-oxide. Based on the accumulation in cells measured by UV-Vis spectroscopy, BNImEtPIX was accumulated to the greatest degree, but, per microgram of porphyrin delivered, Photofrin IIRTM was accumulated the most and the sulfonatophenyl porphyrins the least. The accumulation data for the liposome-formulated porphyrins obtained via UV-Vis measurements appear to conflict with those from the fluorescence microscopy; some possible explanations are discussed. (Abstract shortened by UMI.).