Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 55, Issue 7, Pages 3398-3413Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm3000906
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Funding
- FFG (Austrian Research Promotion Agency) [811591 FA526003]
- Austrian Council for Research and Technology Development
- COST (European Cooperation in the Field of Scientific and Technical Research)
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A series of ruthenium(II) arene complexes with 3-(1H-berairnidazol-2-yl)-1H-quinoxalin-2-one, bearing pharmacophoric groups of known protein kinase inhibitors, and related benzoxazole and benzothiazole derivatives have been synthesized. In addition, the corresponding osmium complexes of the unsubstituted ligands have also been prepared. The compounds have been characterized by NMR, UV-vis, and IR spectroscopy, ESI mass spectrometry, elemental analysis, and by X-ray crystallography. Antiproliferative activity in three human cancer cell lines (AS49, CH1, SW480) was determined by MTT assays, yielding IC50 values of 6-60 mu M for three unsubstituted metal-free ligands, whereas values for the metal complexes vary in a broad range from 0.3 to 140 mu M. Complexation with osmium of quinoxalinone derivatives with benzimidazole or benzothiazole results in a more consistent increase in cytotoxicity than complexation with ruthenium. For selected compounds, the capacity to induce apoptosis was confirmed by fluorescence microscopy and flow-cytometric analysis, whereas cell cycle effects are only moderate.
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