Triapine Derivatives Act as Copper Delivery Vehicles to Induce Deadly Metal Overload in Cancer Cells.

BIOMOLECULES(2020)

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摘要
Thiosemicarbazones continue to attract the interest of researchers as potential anticancer drugs. For example, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, or triapine, is the most well-known representative of this class of compounds that has entered multiple phase I and II clinical trials. Two new triapine derivatives HL1 and HL(2)were prepared by condensation reactions of 2-pyridinamidrazone and S-methylisothiosemicarbazidium chloride with 3-N-(tert-butyloxycarbonyl) amino-pyridine-2-carboxaldehyde, followed by a Boc-deprotection procedure. Subsequent reaction ofHL(1)andHL(2)with CuCl2 center dot 2H(2)O in 1:1 molar ratio in methanol produced the complexes[Cu-II(HL1)Cl-2]center dot H2O(1 center dot H2O) and[Cu-II(HL2)Cl-2](2). The reaction ofHL(2)with Fe(NO3)(3)center dot 9H(2)O in 2:1 molar ratio in the presence of triethylamine afforded the complex[Fe-III(L-2)(2)]NO3 center dot 0.75H(2)O(3 center dot 0.75H(2)O), in which the isothiosemicarbazone acts as a tridentate monoanionic ligand. The crystal structures ofHL(1),HL(2)and metal complexes 1 and 2 were determined by single crystal X-ray diffraction. The UV-Vis and EPR spectroelectrochemical measurements revealed that complexes 1 and 2 underwent irreversible reduction of Cu(II) with subsequent ligand release, while3showed an almost reversible electrochemical reduction in dimethyl sulfoxide (DMSO). Aqueous solution behaviour of HL1 and 1,as well as of HL2 and its complex2, was monitored as well. Complexes1-3were tested against ovarian carcinoma cells, as well as noncancerous embryonic kidney cells, in comparison to respective free ligands, triapine and cisplatin. While the free ligandsHL(1)andHL(2)were devoid of antiproliferative activity, their respective metal complexes showed remarkable antiproliferative activity in a micromolar concentration range. The activity was not related to the inhibition of ribonucleotide reductase (RNR) R2 protein, but rather to cancer cell homeostasis disturbance-leading to the disruption of cancer cell signalling.
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triapine,amidrazones,isothiosemicarbazones,copper(II),iron(III),cancer signalling
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