Cytotoxicity of New Metal Porphyrinates Based on Chlorophyll a Derivatives

Y. I. Pylina,^a D. M. Shadrin,^a O. G. Shevchenko,^a I. S. Khudyaeva,^b D. V. Belykh,^b@ and I. O. Velegzhaninov^a

^aInstitute of Biology of Komi Scientific Centre of Ural Division RAS, 167982 Syktyvkar, Russia

^bInstitute of Сhemistry of Komi Scientific Centre of Ural Division RAS, 167000 Syktyvkar, Russia

^@Corresponding author E-mail: belykh-dv@chemi.komisc.ru, belykh-dv@mail.ru

DOI: 10.6060/mhc161285b

Macroheterocycles 2017 10(3) 279-288

Chlorophyll a derivatives are frequently used in photodynamic therapy of cancer. They are one of the prospective classes of compounds for screening of chemotherapeutic drugs with increased efficiency due to their malignant neoplasms affinity and dark cytotoxicity. The aim of the present work is to investigate some new porphyrinates of transition metals based on chlorophyll a and to reveal prospective cytostatic anticancer agents. A number of highly toxic compounds have been found. Mechanisms of biological activity of the most effective compound – Zn-13(1)-N-methylamide-15(2),17(2)-dimethyl ester of chlorin е₆ (Zn-1) have been studied. This compound has a threshold pattern of dose-effect relationship in both HeLa and A549 cells. This may be considered as an advantage which increases the efficiency in case of target delivery of the compound to the tumor. Fluorescence microscopy showed that compound Zn-1 is able to penetrate rapidly into the cell. Caspase 3 activity analysis gives evidences of a remarkably early induction of apoptosis (within 3 h from the beginning of exposure). This is confirmed by the presence of separate pool of cells with highly fragmented DNA detected with Comet assay. Analysis of hemolytic activity in mice erythrocytes allows to suggest that biomembranes are the main targets of the Zn-1 compound. Expressions of stress-response genes in HeLa cells after 8 h exposure to Zn-1 indirectly confirms this hypothesis. Thus, new metalloporphyrins have been discovered and their bioactivity has been investigated in vitro.

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