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Cytotoxic gallium complexes containing thiosemicarbazones derived from 9-anthraldehyde: Molecular docking with biomolecules.

ABSTRACT: We have synthesized a trio of gallium complexes bearing 9-anthraldehyde thiosemicarbazones. The complexes were assessed for their anticancer activity and their biophysical reactivity was also investigated. The three complexes displayed good cytotoxic profiles against two human colon cancer cell lines, HCT-116 and Caco-2. The IC50 ranged from 4.7 - 44.1 ?M with the complex having an unsubstituted amino group on the thiosemicarbazone being the most active. This particular complex also showed a high therapeutic index. All three complexes bind strongly to DNA via intercalation with binding constants ranging from 7.46 × 104 M-1 to 3.25 × 105 M-1. The strength of the binding cannot be directly related to the level of anticancer activity. The complexes also bind strongly to human serum albumin with binding constants on the order of 104 - 105 M-1 as well. The complexes act as chemical nucleases as evidenced by their ability to cleave pBR322 plasmid DNA. The binding constants along with the cleavage results may suggest that the extent of DNA interaction is not directly correlated with anticancer activity. The results of docking studies with DNA, ribonucleotide reductase and human serum albumin, however showed that the complex with the best biological activity had the largest binding constant to DNA.

SUBMITTER: Beckford FA

PROVIDER: S-EPMC5152947 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Cytotoxic gallium complexes containing thiosemicarbazones derived from 9-anthraldehyde: Molecular docking with biomolecules.

Beckford Floyd A FA Brock Alyssa A Gonzalez-Sarrías Antonio A Seeram Navindra P NP

Journal of molecular structure 20160524

We have synthesized a trio of gallium complexes bearing 9-anthraldehyde thiosemicarbazones. The complexes were assessed for their anticancer activity and their biophysical reactivity was also investigated. The three complexes displayed good cytotoxic profiles against two human colon cancer cell lines, HCT-116 and Caco-2. The IC<sub>50</sub> ranged from 4.7 - 44.1 μM with the complex having an unsubstituted amino group on the thiosemicarbazone being the most active. This particular complex also s ...[more]

PMID: 27980346

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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.

Dataset Information

Cytotoxic gallium complexes containing thiosemicarbazones derived from 9-anthraldehyde: Molecular docking with biomolecules.

Publications

Cytotoxic gallium complexes containing thiosemicarbazones derived from 9-anthraldehyde: Molecular docking with biomolecules.

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