Development of Ruthenium Antitumor Drugs that Overcome Multidrug Resistance Mechanisms

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• 作者：Carsten A. Vock ; Wee Han Ang ; Claudine Scolaro ; Andrew D. Phillips ; Lucienne Lagopoulos ; Lucienne Juillerat-Jeanneret ; Gianni Sava ; Rosario Scopelliti ; Paul J. Dyson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：May 3, 2007
• 年：2007
• 卷：50
• 期：9
• 页码：2166 - 2175
• 全文大小：289K
• 年卷期：v.50,no.9(May 3, 2007)
• ISSN：1520-4804

文摘

Organometallic ruthenium(II) complexes of the general formula [Ru(mages/gifchars/eta.gif" BORDER=0 >⁶-p-cymene)Cl₂(L)] and [Ru(mages/gifchars/eta.gif" BORDER=0 >⁶-p-cymene)Cl(L)₂][BPh₄] with modified phenoxazine- and anthracene-based multidrug resistance (MDR)modulator ligands (L) have been synthesized, spectroscopically characterized, and evaluated in vitro fortheir cytotoxic and MDR reverting properties in comparison with the free ligands. For an anthracene-basedligand, coordination to a ruthenium(II) arene fragment led to significant improvement of cytotoxicity aswell as Pgp inhibition activity. A similar, but weaker effect was also observed when using a benzimidazole-phenoxazine derivative as Pgp inhibitor. The most active compound in terms of both Pgp inhibition andcytotoxicity is [Ru(mages/gifchars/eta.gif" BORDER=0 >⁶-p-cymene)Cl₂(L)], where L is an anthracene-based ligand. Studies show that it inducescell death via inhibition of DNA synthesis. Moreover, because the complex is fluorescent, its uptake incells was studied, and relative to the free anthracene-based ligand, uptake of the complex is accelerated andaccumulation of the complex in the cell nucleus is observed.