Synthesis of sulfanyl porphyrazines with bulky peripheral substituents – Evaluation of their photochemical properties and biological activity

Abstract

Alkylation reaction of dimercaptomaleonitrile disodium salt with N-(2-bromoethyl)phthalimide in N,N-dimethylformamide, and potassium carbonate led to novel maleonitrile derivative. This compound was used in the Linstead tetramerization reaction in n-butanol in the presence of magnesium n-butoxide towards magnesium(II) sulfanyl porphyrazine with phthalimide peripheral substituents. Its demetallation and subsequent zinc(II) ion insertion led to zinc(II) sulfanyl porphyrazine derivative. All obtained compounds were thoroughly characterized using UV–vis, MS, and 1H and 13C NMR spectroscopy. The purity of macrocycles was assessed using HPLC. Novel symmetrical porphyrazines were found to generate singlet oxygen in N,N-dimethylformamide and dimethyl sulfoxide in low yields. The highest, over 4% yield of singlet oxygen generation, was noted for zinc(II) porphyrazine derivative in DMSO. In the biological study, the cytotoxicities and photocytotoxicities of symmetrical sulfanyl porphyrazines with phthalimide peripheral substituents were compared with lately obtained unsymmetrical sulfanyl tribenzoporphyrazine, 22,23-bis[3,5-bis(3,5- dimethoxybenzyloxy)benzylsulfanyl]tribenzo[b,g,l]porphyrazinato magnesium(II). The in vitro study was performed on androgen-sensitive human prostate adenocarcinoma (LNCaP) and human prostate cancer (PC3) cell lines using MTT assay. The data obtained for liposomal formulations containing sulfanyl porphyrazines with phthalimide substituents indicated their low and light-independent cytotoxicity against cancer cells. On the contrary, the sulfanyl tribenzoporphyrazine was studied in its free form and after incorporation in liposomes. In the free form it revealed moderate photocytotoxicity against both cancer cell lines with IC50 values of 7.71 μM and 8.82 μM for LNCaP and PC3 cells, respectively. Moreover, the liposomal DOTAP : POPC formulation containing sulfanyl tribenzoporphyrazine revealed over 10-fold higher effectiveness reaching the IC50 up to 0.52 μM against LNCaP cancer cells in comparison to its free form. On the contrary, liposomal PG formulation of sulfanyl tribenzoporphyrazine was found to be inactive on the human cancer cells.