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Photoactivatable cell-selective dinuclear trans-diazidoplatinum(IV) anticancer prodrugs.

Autoři: Shi H., Romero-Canelón I., Hreusova M., Novakova O., Venkatesh V., Habtemariam A., Clarkson G.J., Song J.-I., Brabec V., Sadler P.J.Publikováno : Inorganic Chemistry 57(22), 14409-14420Rok: 2018

A series of dinuclear octahedral PtIV complexes trans,trans,trans-[{Pt(N3)2(py)2(OH)-(OC(O)CH2CH2C(O)NH)}2R] containing pyridine (py) and bridging dicarboxylate (R = -CH2CH2- (1); trans-1,2-C6H10- (2); p-C6H4- (3); -CH2CH2CH2CH2- (4)) ligands have been synthesized and characterized, including the x-ray crystal structures of complexes 1·2MeOH and 4, the first photoactivatable dinuclear platinum(IV) complexes with azido ligands. The complexes are highly stable in the dark, but upon photoactivation with blue light (420 nm), they release the bridging ligand and mononuclear photoproducts. Upon irradiation with blue light (465 nm), they generate azidyl and hydroxyl radicals, detected using a 5,5-dimethyl-1-pyrroline N-oxide electron paramagnetic resonance spin trap, accompanied by the disappearance of the ligand-to-metal charge-transfer (N3 → Pt) band at ca. 300 nm. The dinuclear complexes are photocytotoxic to human cancer cells (465 nm, 4.8 mW/cm2, 1 h), including A2780 human ovarian and esophageal OE19 cells with IC50 values of 8.8−78.3 μM, whereas cisplatin is inactive under these conditions. Complexes 1, 3, and 4 are notably more photoactive toward cisplatin-resistant ovarian A2780cis compared to A2780 cells. Remarkably, all of the complexes were relatively nontoxic toward normal cells (MRC5 lung fibroblasts), with IC50 values >100 μM, even after irradiation. The introduction of an aromatic bridging ligand (3) significantly enhanced cellular uptake. The populations in the stages of the cell cycle remained unchanged upon treatment with complexes in the dark, while the population of the G2/M phase increased upon irradiation, suggesting that DNA is a target for these photoactivated dinuclear PtIV complexes. Liquid chromatography−mass spectrometry data show that the photodecomposition pathway of the dinuclear complexes results in the release of two molecules of mononuclear platinum(II) species. As a consequence, DNA binding of the dinuclear complexes after photoactivation in cell-free media is, in several respects, qualitatively similar to that of the photoactivated mononuclear complex FM-190. After photoactivation, they were 2-fold more effective in quenching the fluorescence of EtBr bound to DNA, forming DNA interstrand cross-links and unwinding DNA compared to the photoactivated FM-190.


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