Synthesis, Characterization, and in Vitro Antitumor Properties of Tris(hydroxymethyl)phosphine Copper(I) Complexes Containing the New Bis(1,2,4-triazol-1-yl)acetate Ligand
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- 作者：Cristina Marzano ; Maura Pellei ; Davide Colavito ; Simone Alidori ; Giancarlo Gioia Lobbia ; Valentina Gandin ; Francesco Tisato ; Carlo Santini
- 刊名：Journal of Medicinal Chemistry
- 出版年：2006
- 出版时间：December 14, 2006
- 年：2006
- 卷：49
- 期：25
- 页码：7317 - 7324
- 全文大小：162K
- 年卷期：v.49,no.25(December 14, 2006)
- ISSN：1520-4804
文摘
The new sodium bis(1,2,4-triazol-1-yl)acetate ligand, Na[HC(CO2)(tz)2], has been prepared in methanolsolution by using 1,2,4-triazole, dibromoacetic acid, and NaOH. Treatment of the [Cu(CH3CN)4][PF6] acceptorwith Na[HC(CO2)(tz)2] or Na[HC(CO2)[(pzMe2)2], in the presence of the tris(hydroxymethyl)phosphinecoligand in methanol/acetonitrile solutions produced unprecedented mononuclear copper(I) complexes ofthe type [Ln]Cu[P(CH2OH)3]2 (L1, 2; L2, 3) and [(CH3CN)2Cu(P(CH2OH)3)2]PF6, 4. These compounds havebeen characterized by elemental analyses, FTIR, ESI-MS, and multinuclear (1H and 31P) NMR spectraldata. The new copper(I) complexes were tested for their cytotoxic properties against a panel of severalhuman tumor cell lines. The results reported here indicate that all the complexes showed in vitro antitumoractivity similar or better than that of cisplatin, the most used metal-based antitumor drug. In particular,[HC(CO2)(pzMe2)2]Cu[P(CH2OH)3]2, 3 showed IC50 values markedly lower than the reference compoundagainst all tumor cell lines. Chemosensitivity tests performed on cisplatin sensitive and resistant cell lineshave demonstrated that all these Cu(I) complexes were able to overcome cisplatin resistance, supporting thehypothesis of a different mechanism of action compared to that exhibited by the reference drug. Flowcytometric analysis on 2008 human ovarian carcinoma cells revealed that complex 3, chosen as the bestcandidate, induced a marked enlargement of both cell size and granularity, and a significant increase in thefraction of G2/M cells that, differently from cisplatin, was not accompanied by the appearance of a relevantsub-G1 fraction. Besides, no evidence of caspase-3 activation was detected in cells treated with complex 3.We hypothesize that the cytotoxic activity of the new copper(I) complex may be correlated to its ability totrigger paraptosis, a nonapoptotic mechanism of cell death.