Tamoxifen-based compounds in the breast cancer therapy

Abstract

Tamoxifen (Scheme 1, 1) is historically well known for its successful application in the therapy of the oestrogen receptor positive (ERα+) breast cancer.1 In this study, we combine a tamoxifenbased ligand2 (Scheme 1, 3) with transition metal complex moieties of platinum(II), palladium(II), copper(II), and nickel(II)3 containing chlorides (Scheme 1, 4-6) or a bulky, hydrophobic and stable nido-dicarborate ligand (Scheme 1, 7-9). We investigated the anticancer activity of the compounds 2-9 in in vitro cell assays. The incorporation of a 2,2’-bipyridine unit into a tamoxifen-inspired structure 3 increases the cytotoxic activity compared to compound 2 against several cell lines including ERα+ human glioblastoma (U251), breast adenocarcinoma (MCF-7, MDA-MB-361) and triple negative (ERα−) MDA-MB-231. The formation of PtII and PdII chloride complexes (4 and 5) insignificantly improve the activity compared to ligand 3. The ability of the CuII chloride moiety for ligand exchange in solution explains the significant rise of the cytotoxicity of 6 compared to 4 and 5. However, the incorporation of a nido-carborate dianion into Pt and Ni complexes (7 and 9) neutralised on average their toxicity towards all studied cell lines, except compound 8 which was active against U251 and MDA-MB-231. The observed cytotoxicity data of compounds 3-6 and 8 against MDAMB-231 (ERα−) suggest other off-target mechanisms rather than only ERα inhibition which is usual for metallodrugs.