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[Ag(L)NO₃] Complexes with 2-Benzoylpyridine-Derived Hydrazones: Cytotoxic Activity and Interaction with Biomolecules.

ABSTRACT: Complexes [Ag(H2BzPh)NO₃] (1), [Ag(H2BzpCH₃Ph)NO₃] (2), [Ag(H2BzpClPh)NO₃] (3), and [Ag(H2BzpNO₂Ph)NO₃] (4) were synthesized with 2-benzoylpyridine benzoylhydrazone (H2BzPh) and its para-methyl-benzoylhydrazone (H2BzpCH₃Ph), para-chloro-benzoylhydrazone (H2BzpClPh), and para-nitro-benzoylhydrazone (H2BzpNO₂Ph) derivatives. Experimental data indicate that the nitrate ligand binds more strongly to the silver center through one of the oxygen atoms, whereas the second oxygen atom from nitrate and the hydrazone oxygen makes much weaker interactions with the metal. Dissociation of nitrate most probably occurs in solution and in biological media. Interestingly, theoretical calculations suggested that when dissociation of the nitrate takes place, all bond orders involving the metal and the atoms from the hydrazone ligand increase significantly, showing that the bonding of nitrate results in the weakening of all other interactions in the metal coordination sphere. Upon complexation of the hydrazones to silver(I), cytotoxicity against B16F10 metastatic murine melanoma cells increased in all cases. Complexes (1-3) proved to be more cytotoxic than cisplatin. All compounds were more cytotoxic to B16F10 cells than to nontumorigenic murine Melan-A melanocyte cells. Interestingly, the selectivity index (SI = IC_{50 non-malignant cells}/IC_{50 tumor cells}) of complex (1), SI = 23, was much higher than that of the parent hydrazone ligand, SI = 9.5. Studies on the interactions of complexes (1-3) with DNA suggested that although (1-3) interact with calf thymus DNA by an intercalative mode, direct covalent binding of silver(I) to DNA probably does not occur. Complexes (1-3) interact in vitro with human serum albumin indicating that these compounds could be transported by albumin.

SUBMITTER: Santos AF

PROVIDER: S-EPMC6130902 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Triethylphosphinegold(I) complexes [Au(HL1)P(CH2CH3)3]PF6 (1), [Au(HL2)P(CH2CH3)3]PF6 (2), and [Au(HL3)P(CH2CH3)3]PF6 (3) were obtained with (E)-2-(1-(2-methyl-5-nitro-1H-imidazol-1-yl)propan-2-ylidene)hydrazinecarbothioamide (HL1), (E)-N-methyl-2-(1-(2-methyl-5-nitro-1H-imidazol-1-yl)propan-2-ylidene)hydrazinecarbothioamide (HL2), and (E)-2-(1-(2-methyl-5-nitro-1H-imidazol-1-yl)propan-2-ylidene)-N-phenylhydrazinecarbothioamide (HL3). All compounds were assayed for their cytotoxic activities against HCT-116 colorectal carcinoma cells under normoxia and hypoxia conditions and against nonmalignant HEK-293 human embryonic kidney cells under normoxia conditions. The thiosemicarbazone ligands HL1-HL3 were inactive against HCT-116 cells under hypoxia but while HL3 was inactive, HL1 and HL2 proved to be cytotoxic to both cell lineages under normoxia conditions. Complexes (1-3) and the triethylphosphinegod(I) precursor proved to be active against both cell lineages in normoxia as well as in hypoxia. While 1 and 3 revealed to be active against HEK-293 and HCT-116 cells, being approximately as active against HCT-116 cells in normoxia as under hypoxia, complex (2) proved to be more active against HCT-116 cells under hypoxia than under normoxia conditions, and more active against HCT-116 cells than against the nonmalignant HEK-293 cells, with the selectivity index, calculated as SI = IC50HEK-293/IC50HCT-116hypoxia, equal to 3.7, similar to the value obtained for the control drug tirapazamine (tirapazamine (TPZ), SI = 4). Although the compounds showed distinct cytotoxic activities, the electrochemical behaviors of HL1-HL3 were very similar, as were the behaviors of complexes (1-3). Complex (2) deserves special interest since it was significantly more active under hypoxia than under normoxia conditions. Hence, in this case, selective reduction of the nitro group in a low oxygen pressure environment, resulting in toxic reactive oxygen species (ROS) and damage to DNA or other biomolecules, might operate, while for the remaining compounds, other modes of action probably occur.

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[Ag(L)NO₃] Complexes with 2-Benzoylpyridine-Derived Hydrazones: Cytotoxic Activity and Interaction with Biomolecules.

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[Ag(L)NO3] Complexes with 2-Benzoylpyridine-Derived Hydrazones: Cytotoxic Activity and Interaction with Biomolecules.

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OmicsDI is part of the ELIXIR infrastructure

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[Ag(L)NO₃] Complexes with 2-Benzoylpyridine-Derived Hydrazones: Cytotoxic Activity and Interaction with Biomolecules.