Synthesis, characterization and deepening in the comprehension of the biological action mechanisms of a new nickel complex with anti proliferative activity
Synthesis, characterization and deepening in the comprehension of the biological action mechanisms of a new nickel complex with anti proliferative activity
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DOI：
10.1016/j.jinorgbio.2008.12.016
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发表时间：
2009-05-01
影响因子：
3.9
通讯作者：
Tarasconi, Pieralberto
中科院分区：
文献类型：
--
作者：
Buschini, Annamaria;Pinelli, Silvana;Tarasconi, Pieralberto
缩氨基硫脲是一种用途广泛的有机化合物，由于具有广泛的性质而具有相当大的药用价值。本实验室以天然醛为原料，合成了一些具有特殊生物活性的缩氨基硫脲金属配合物。特别是镍配合物[Ni(S-TCITR)(2)](S-TCITR=S-香茅醛缩氨基硫代氨基甲酸酯)在低浓度下(IC_(50)=14.4mM)对人组织细胞淋巴瘤细胞株U937有抑制增殖作用。因此，我们决定研究该分子与各种细胞成分的相互作用，并研究其诱导细胞凋亡的途径。结果表明，[Ni(S-TCITR)(2)]可通过下调Bcl2、改变线粒体膜电位和Caspase3活性而导致细胞程序性死亡，而与P53功能无关。该金属络合物对G(0)细胞(即新鲜白细胞)不起作用，但对受刺激的淋巴细胞和U937细胞能诱导细胞周期紊乱，出现G(2)/M期阻滞。它到达细胞核，在那里它诱导低浓度(2.5-5.0微米)的DNA损伤，这可能部分归因于氧化应激。[Ni(S-TCITR)(2)]还能显著降低端粒酶活性。尽管该金属络合物的生物靶标尚不清楚，但已有报道表明，[Ni(S-柠檬酸)(2)]可能是合成具有特定生物活性的新金属缩氨基硫脲的良好模型。(C)2009 Elsevier Inc.保留所有权利。
Thiosemicarbazones are versatile organic compounds that present considerable pharmaceutical interest because of a wide range of properties. In our laboratory we synthesised some new metal-complexes with thiosemicarbazones derived from natural aldehydes which showed peculiar biological activities. In particular, a nickel complex [Ni(S-tcitr)(2)] (S-tcitr = S-citronellalthiosemicarbazonate) was observed to induce an anti proliferative effect on U937, a human histiocytic lymphoma cell line, at low concentrations (IC50 = 14.4 mu M). Therefore, we decided to study the interactions of this molecule with various cellular components and to characterise the induced apoptotic pathway. Results showed that [Ni(S-tcitr)(2)] causes programmed cell death via down-regulation of Bcl-2, alteration of mitochondrial membrane potential and caspase-3 activity, regardless of p53 function. The metal complex is not active on G(0) cells (i.e. fresh leukocytes) but is able to induce perturbation of the cell cycle on stimulated lymphocytes and U937 cells, in which a G(2)/M block was detected. It reaches the nucleus where it induces, at low concentrations (2.5-5.0 mu M), DNA damage, which could be partially ascribed to oxidative stress. [Ni(S-tcitr)(2)] is moreover able to strongly reduce the telomerase activity. Although the biological target of this metal complex is still unknown, the reported data suggest that [Ni(S-tcitr)(2)] could be a good model for the synthesis of new metal thiosemicarbazones with specific biological activity. (C) 2009 Elsevier Inc. All rights reserved.