Osmium(III) Analogues of KP1019: Electrochemical and Chemical Synthesis, Spectroscopic Characterization, X-ray Crystallography, Hydrolytic Stability, and Antiproliferative Activity

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• 作者：Paul-Steffen Kuhn ; Gabriel E. B眉chel ; Katarina K. Jovanovi膰 ; Lana Filipovi膰 ; Sini拧a Radulovi膰 ; Peter Rapta ; Vladimir B. Arion
• 刊名：Inorganic Chemistry
• 出版年：2014
• 出版时间：October 20, 2014
• 年：2014
• 卷：53
• 期：20
• 页码：11130-11139
• 全文大小：499K
• ISSN：1520-510X

文摘

A one-electron reduction of osmium(IV) complexes trans-[Os^IVClb>4b>(Hazole)b>2b>], where Hazole = 1H-pyrazole ([<b>1b>]⁰), 2H-indazole ([<b>2b>]⁰), 1H-imidazole ([<b>3b>]⁰), and 1H-benzimidazole ([<b>4b>]⁰), afforded a series of eight new complexes as osmium analogues of KP1019, a lead anticancer drug in clinical trials, with the general formula (cation)[trans-Os^IIIClb>4b>(Hazole)b>2b>], where cation = Hb>2b>pz⁺ (Hb>2b>pz[<b>1b>]), Hb>2b>ind⁺ (Hb>2b>ind[<b>2b>]), Hb>2b>im⁺ (Hb>2b>im[<b>3b>]), Phb>4b>P⁺ (Phb>4b>P[<b>3b>]), nBub>4b>N⁺ (nBub>4b>N[<b>3b>]), Hb>2b>bzim⁺ (Hb>2b>bzim[<b>4b>]), Phb>4b>P⁺ (Phb>4b>P[<b>4b>]), and nBub>4b>N⁺ (nBub>4b>N[<b>4b>]). All complexes were characterized by elemental analysis, ¹H NMR spectroscopy, electrospray ionization mass spectrometry, UV鈥搗is spectroscopy, cyclic voltammetry, while Hb>2b>pz[<b>1b>], Hb>2b>ind[<b>2b>], and nBub>4b>[<b>3b>], in addition, by X-ray diffraction. The reduced species [<b>1b>]^{鈭?/sup> and [<b>4b>]鈭?/sup> are stable in aqueous media in the absence of air oxygen and do not react with small biomolecules such as amino acids and the nucleotide 5鈥?dGMP. Cell culture experiments in five different human cancer cell lines (HeLa, A549, FemX, MDA-MB-453, and LS-174) and one noncancerous cell line (MRC-5) were performed, and the results were discussed and compared to those for KP1019 and cisplatin. Benzannulation in complexes with similar structure enhances antitumor activity by several orders of magnitude, implicating different mechanisms of action of the tested compounds. In particular, complexes Hb>2b>ind[<b>2b>] and Hb>2b>bzim[<b>4b>] exhibited significant antiproliferative activity in vitro when compared to Hb>2b>pz[<b>1b>] and Hb>2b>im[<b>3b>].}