RESUMO
A novel 5,10,15,20-tetraaryl-21-selenaporphyrin isomer with an inverted pyrrole ring, i.e., 5,10,15, 20-tetraaryl-2-aza-21-carba-22-selenaporphyrin (SeC-TArPH) has been produced by a [3 + 1] condensation of 2, 5-bis(phenylhydroxymethyl)selenophene and 5,10-ditolyltripyrrin. The reaction yielded 5,20-diphenyl-10,15-bis(p-tolyl)-21-selenaporphyrin Se-DPDTPH (19%) and its isomer with an inverted pyrrole ring, i.e., 5,10-diphenyl-15,20-bis(p-tolyl)-2-aza-21-carba-22-selenaporphyrin, SeC-DPDTPH (1%). Mechanistically the synthesis of SeC-DPDTPH requires one beta-condensation at the pyrrole moiety of 5, 10-ditolyltripyrrin instead of the stereotypical alpha-condensation. The identity of inverted selenaporphyrin has been confirmed by high-resolution mass spectrometry and (1)H NMR spectroscopy. A saddle distortion mode for the inverted selenaporphyrin macrocycle SeC-DPDTPH has been determined by X-ray crystallography. NMR spectra are consistent with the existence of tautomeric equilibria that involve three tautomeric species of the neutral form of SeC-DPDTPH. The preference for the tautomer with the labile proton located at the peripheral N(2) nitrogen atom has been detected in pyridine-d(5) solution. The density functional theory (DFT) has been applied to determine the molecular and electronic structure of three tautomers of 2-aza-21-carba-22-selenaporphyrin: 2-N, 23-N, 24-NH, 2-N, 23-NH, 24-N, and 2-NH, 23-N, 24-N formally created from SeC-DPDTPH by a replacement of phenyl and tolyl groups with hydrogen. The total energies calculated using the B3LYP/6-311G//B3LYP/6-311G approach, demonstrate that relative stability of postulated tautomers decreases in the order 2-N, 23-NH, 24-N > 2-N, 23-N, 24-NH > 2-NH, 23-N, 24-N. The small energy differences between tautomeric species suggests their simultaneous presence in equilibrium.
RESUMO
BACKGROUND: Photodynamic therapy may be a promising treatment for patients with tumors. The mechanism of its action is poorly understood and different from the cytotoxic effects induced by antitumor drugs. MATERIALS AND METHODS: New sensitizers, termed as 21-selenaporphyrin (SEP) and 21-thiaporphyrin (STSP) were studied for their photocytotoxicity in vitro against selected human cancer cell lines. This study was followed by in vivo screening of the effect of SEP using an animal tumor model. The activity of the new agents was compared with that of a known photosensitizer, namely chlorin e6. In our selection of the cell lines applied for in vitro study, the possible accessibility and effectiveness of photodynamic therapy (PDT) for treatment of colon and urinary bladder cancers, was considered. RESULTS: New compounds appeared to be not toxic for tested cells in culture, without exposure to light. The STSP exerted in vitro effects comparable with chlorin e6 photocytotoxicity, while SEP appeared to be ineffective. However, in vivo experiments performed in a BFS1 fibrosarcoma tumor model in mice showed that the SEP was at least as much effective as chlorin e6 in the induction of tumor necrosis. In contrast to chlorin e6, SEP-PDT induced no skin sensitization. CONCLUSIONS: Both new sensitizers can be applied in PDT at no risk of skin damage. The mechanism of the action of these two compounds is probably different, i.e. the 21-thiaporphyrin possibly acts directly on tumor cells and the 21-selenaporphyrin via endothelial cells of newly formed tumor vasculature.
