Metallodrugs against Breast Cancer: Combining the Tamoxifen Vector with Platinum(II) and Palladium(II) Complexes

The luminal A-subtype of breast cancer, where the oestrogen receptor alpha (ER alpha) is overexpressed, is the most frequent one. The prodrug tamoxifen (1) is the clinically used agent, inhibiting the ER alpha activity via the formation of several active metabolites, such as 4-hydroxytamoxifen (2) or 4,4 '-dihydroxytamoxifen (3). In this study, we present the tamoxifen derivative 4-[1,1-bis(4-methoxyphenyl)but-1-en-2-yl]-2,2 '-bipyridine (4), which was combined with platinum or palladium dichloride, the former a well-known scaffold in anticancer treatment, to give [PtCl2(4-kappa N-2,N ')] (5) or [PdCl2(4-kappa N-2,N '] (6). To prevent fast exchange of weakly coordinating chlorido ligands in aqueous solution, a bulky, highly stable and hydrophobic nido-carborate(-2) ([C2B9H11](2-)) was incorporated. The resulting complexes [3-(4-kappa N-2,N ')-3,1,2-PtC2B9H11] (7) and [3-(4-kappa N-2,N ')-3,1,2-PdC2B9H11] (8) exhibit a dramatic change in electronic and biological properties compared to 5 and 6. Thus, 8 is highly selective for triple-negative MDA-MB-231 cells (IC50 = 3.7 mu M, MTT test), while 7 is completely inactive against this cell line. The observed cytotoxicity of compounds 4-6 and 8 against this triple-negative cell line suggests off-target mechanisms rather than only ER alpha inhibition, for which these compounds were originally designed. Spectroscopic properties and electronic structures of the metal complexes were investigated for possible explanations of the biological activities.

Automated summary

A new complex with potential anti-cancer properties was studied in this research. The complex showed high selectivity towards triple-negative breast cancer cells and no significant effect on other cells. This finding may provide new insights for the treatment of breast cancer.