Effect of the Piperazine Unit and Metal-Binding Site Position on the Solubility and Anti-Proliferative Activity of Ruthenium(II)- and Osmium(II)- Arene Complexes of Isomeric Indolo[3,2-c]quinol

详细信息    查看全文

• 作者：Lukas K. Filak ; Danuta S. Kalinowski ; Theresa J. Bauer ; Des R. Richardson ; Vladimir B. Arion
• 刊名：Inorganic Chemistry
• 出版年：2014
• 出版时间：July 7, 2014
• 年：2014
• 卷：53
• 期：13
• 页码：6934-6943
• 全文大小：448K
• ISSN：1520-510X

文摘

In this study, the indoloquinoline backbone and piperazine were combined to prepare indoloquinoline鈥損iperazine hybrids and their ruthenium- and osmium-arene complexes in an effort to generate novel antitumor agents with improved aqueous solubility. In addition, the position of the metal-binding unit was varied, and the effect of these structural alterations on the aqueous solubility and antiproliferative activity of their ruthenium- and osmium-arene complexes was studied. The indoloquinoline鈥損iperazine hybrids L^1鈥? were prepared in situ and isolated as six ruthenium and osmium complexes [(畏⁶-p-cymene)M(L^1鈥?)Cl]Cl, where L¹ = 6-(4-methylpiperazin-1-yl)-N-(pyridin-2-yl-methylene)-11H-indolo[3,2-c]quinolin-2-N-amine, M = Ru ([1a]Cl), Os ([1b]Cl), L² = 6-(4-methylpiperazin-1-yl)-N-(pyridin-2-yl-methylene)-11H-indolo[3,2-c]quinolin-4-N-amine, M = Ru ([2a]Cl), Os ([2b]Cl), L³ = 6-(4-methylpiperazin-1-yl)-N-(pyridin-2-yl-methylene)-11H-indolo[3,2-c]quinolin-8-N-amine, M = Ru ([3a]Cl), Os ([3b]Cl). The compounds were characterized by elemental analysis, one- and two-dimensional NMR spectroscopy, ESI mass spectrometry, IR and UV鈥搗is spectroscopy, and single-crystal X-ray diffraction. The antiproliferative activity of the isomeric ruthenium and osmium complexes [1a,b]Cl鈥揫3a,b]Cl was examined in vitro and showed the importance of the position of the metal-binding site for their cytotoxicity. Those complexes containing the metal-binding site located at the position 4 of the indoloquinoline scaffold ([2a]Cl and [2b]Cl) demonstrated the most potent antiproliferative activity. The results provide important insight into the structure鈥揳ctivity relationships of ruthenium- and osmium-arene complexes with indoloquinoline鈥損iperazine hybrid ligands. These studies can be further utilized for the design and development of more potent chemotherapeutic agents.