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Triethylphosphinegold(I) Complexes with Secnidazole-Derived Thiosemicarbazones: Cytotoxic Activity against HCT-116 Colorectal Cancer Cells under Hypoxia Conditions.
ACS Omega ( IF 4.1 ) Pub Date : 2020-02-06 , DOI: 10.1021/acsomega.9b03778 Ana P A Oliveira 1 , Jennifer T J Freitas 1 , Renata Diniz 1 , Claudia Pessoa 2 , Sarah S Maranhão 2 , Juliana M Ribeiro 3 , Elaine M Souza-Fagundes 3 , Heloisa Beraldo 1
ACS Omega ( IF 4.1 ) Pub Date : 2020-02-06 , DOI: 10.1021/acsomega.9b03778 Ana P A Oliveira 1 , Jennifer T J Freitas 1 , Renata Diniz 1 , Claudia Pessoa 2 , Sarah S Maranhão 2 , Juliana M Ribeiro 3 , Elaine M Souza-Fagundes 3 , Heloisa Beraldo 1
Affiliation
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.
中文翻译:
三乙基膦金(I)与塞尼达唑衍生的硫代咪唑酮的复合物:低氧条件下对HCT-116结直肠癌细胞的细胞毒活性。
三乙基膦金(I)络合物[Au(HL1)P(CH2CH3)3] PF6(1),[Au(HL2)P(CH2CH3)3] PF6(2)和[Au(HL3)P(CH2CH3)3] PF6 (3)用(E)-2-(1-(2-甲基-5-硝基-1H-咪唑-1-基)丙烷-2-亚丙基)肼甲硫酰胺(HL1),(E)-N-甲基-2-(1-(2-(5-甲基-5-硝基-1H-咪唑-1-基)丙-2-亚烷基)肼基碳硫磺酰胺(HL2)和(E)-2-(1-(2-甲基-5 -硝基-1H-咪唑-1-基)丙-2-亚烷基)-N-苯基肼甲硫基酰胺(HL3)。测定了所有化合物在常氧和低氧条件下对HCT-116结肠直肠癌细胞和在常氧条件下对非恶性HEK-293人胚胎肾细胞的细胞毒活性。缺氧条件下,硫半脲酮配体HL1-HL3对HCT-116细胞无活性,而HL3无活性,在常氧条件下,HL1和HL2被证明对两种细胞系均具有细胞毒性。复合物(1-3)和三乙基膦(I)前体被证明对常氧和低氧中的两种细胞谱系都有活性。虽然1和3显示出对HEK-293和HCT-116细胞有活性,但在常氧下对HCT-116细胞的活性与缺氧下的活性大致相同,但是复合物(2)被证明比缺氧下对HCT-116细胞的活性更高。在常氧条件下,对HCT-116细胞的活性高于对非恶性HEK-293细胞的活性,其选择性指数计算为SI = IC50HEK-293 / IC50HCT-116低氧,等于3.7,与对照获得的值相似药物替拉帕明(tirapazamine(TPZ),SI = 4)。尽管这些化合物显示出独特的细胞毒活性,HL1-HL3的电化学行为与配合物(1-3)的行为非常相似。配合物(2)值得特别关注,因为它在低氧条件下的活性明显高于在常氧条件下的活性。因此,在这种情况下,可能会在低氧压环境中选择性还原硝基,导致有毒的活性氧(ROS)以及对DNA或其他生物分子的破坏,而对于其余化合物,可能会有其他作用方式发生。
更新日期:2020-02-18
中文翻译:
三乙基膦金(I)与塞尼达唑衍生的硫代咪唑酮的复合物:低氧条件下对HCT-116结直肠癌细胞的细胞毒活性。
三乙基膦金(I)络合物[Au(HL1)P(CH2CH3)3] PF6(1),[Au(HL2)P(CH2CH3)3] PF6(2)和[Au(HL3)P(CH2CH3)3] PF6 (3)用(E)-2-(1-(2-甲基-5-硝基-1H-咪唑-1-基)丙烷-2-亚丙基)肼甲硫酰胺(HL1),(E)-N-甲基-2-(1-(2-(5-甲基-5-硝基-1H-咪唑-1-基)丙-2-亚烷基)肼基碳硫磺酰胺(HL2)和(E)-2-(1-(2-甲基-5 -硝基-1H-咪唑-1-基)丙-2-亚烷基)-N-苯基肼甲硫基酰胺(HL3)。测定了所有化合物在常氧和低氧条件下对HCT-116结肠直肠癌细胞和在常氧条件下对非恶性HEK-293人胚胎肾细胞的细胞毒活性。缺氧条件下,硫半脲酮配体HL1-HL3对HCT-116细胞无活性,而HL3无活性,在常氧条件下,HL1和HL2被证明对两种细胞系均具有细胞毒性。复合物(1-3)和三乙基膦(I)前体被证明对常氧和低氧中的两种细胞谱系都有活性。虽然1和3显示出对HEK-293和HCT-116细胞有活性,但在常氧下对HCT-116细胞的活性与缺氧下的活性大致相同,但是复合物(2)被证明比缺氧下对HCT-116细胞的活性更高。在常氧条件下,对HCT-116细胞的活性高于对非恶性HEK-293细胞的活性,其选择性指数计算为SI = IC50HEK-293 / IC50HCT-116低氧,等于3.7,与对照获得的值相似药物替拉帕明(tirapazamine(TPZ),SI = 4)。尽管这些化合物显示出独特的细胞毒活性,HL1-HL3的电化学行为与配合物(1-3)的行为非常相似。配合物(2)值得特别关注,因为它在低氧条件下的活性明显高于在常氧条件下的活性。因此,在这种情况下,可能会在低氧压环境中选择性还原硝基,导致有毒的活性氧(ROS)以及对DNA或其他生物分子的破坏,而对于其余化合物,可能会有其他作用方式发生。