A methyltitanocene complex of schisandrol A with high efficacy against multi‐drug resistant cervix and breast carcinoma cells

Abstract

AbstractThe objective of this work was to combine the ABC‐transporter inhibition characteristic of esters of the Schisandra sphenantera metabolite schisandrol A with the growth inhibitory and anti‐migratory effects typical of titanium complexes. To this end dimethyltitanocene, (h5‐C5H5)2Ti(CH3)2, was reacted with the vicinal diol schisandrol A to afford the schisandroxy(methyl)titanocene (1) as a stable water‐soluble solid. In MTT assays against seven tumor cell lines it proved distinctly more cytotoxic than schisandrol A or dimethyltitanocene or combinations of these. It reached single‐digit micromolar IC50(72 h) values against cells of leukemia HL‐60, melanoma 518A2 and also resistant cervix carcinoma KB‐V1/vbl and resistant breast carcinoma MCF‐7/topo. Non‐malignant fibroblasts were virtually insensitive to it [IC50 (72 h) > 50 µM]. In addition, the new complex inhibited the p‐gp drug transporters of KB‐V1/vbl cells and prevented a regrowth and closure of scratch wounds in cancer cell cultures (‘wound‐healing’ assay) when applied in concentrations < 1 µM, which is an indication of a potential anti‐migratory and anti‐invasive activity in solid tumors. Copyright © 2010 John Wiley & Sons, Ltd.