Oxazole-bridged
combretastatin A-4 analogues bind to
tubulin and exert anti-vascular and anti-angiogenic effects. When linked to Ru(η(6)-arene) complex fragments, conjugates with additional cytotoxic activity result which can ruthenate bionucleophiles such as
DNA and
proteins. For instance, the Ru(II)(p-cymene)(isonicotinate)Cl(2) complex 6a of the known 4-(3,4,5-trimethoxyphenyl)-5-(3-hydroxy-4-methoxyphenyl)-oxazole 4a was far more active than the latter against cells of the p53-competent wild-type form of HCT-116 colon
carcinoma at low 0.01 μM concentrations. A fast reaction of 6a with nucleophilic
N-acetyl-L-cysteine was observed in NMR studies. The Ru(arene) complexes 6a-c were also more efficacious against
combretastatin-refractory p53(+) cells of human HT-29 colon
carcinoma when compared to their parent 4-(3,4-dimethoxy-5-methoxy/halo-phenyl)-5-(3-hydroxy-4-methoxyphenyl)-
oxazoles 4a-c. These cells are rich in
ABC-transporters which are responsible for their multi-drug resistance and for which conjugates 6 are less good substrates than the
phenols 4. Unlike 4a, its complex 6a also diminished the motility of human 518A2
melanoma cells in a wound-healing assay which is indicative of anti-metastatic activity in solid
tumors. Overall, the Ru(arene) complex conjugates 6 broaden the anti-tumoral spectrum of the
combretastatin A-4 analogues 4 considerably.