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

Abstract

The luminal A-subtype of breast cancer, where the oestrogen receptor α (ERα) is overexpressed, is the most frequent one. The prodrug tamoxifen (1) is the clinically used agent, inhibiting the ERα 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-κ2N,N′)] (5) or [PdCl2(4-κ2N,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-κ2N,N′)-3,1,2-PtC2B9H11] (7) and [3-(4-κ2N,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 μM, 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 ERα 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.

Exploring the Anticancer Activity of Tamoxifen-Based Metal Complexes Targeting Mitochondria

“…It is worth mentioning that recently reported Pt(II)-and Pd(II)-TAML analogues showed antitumor activity in the same cancer cell lines, which were attributed to off-target mechanisms rather than only ERα inhibition, for which these compounds were originally designed. 38 Molecular Dynamics Studies of the Metal Complexes' Adducts with ERα. Since the target of tamoxifen is ERα, we examined the binding mode of the new tamoxifen derivatives to this receptor and compared it to that of the active metabolite of tamoxifen, i.e., 4-hydroxytamoxifen (OHT).…”

“…Concerning AuTAML, its intracellular reduction by biological nucleophiles, leading to TAML ligand release, cannot be excluded, in line with the observed similar antiproliferative activities. It is worth mentioning that recently reported Pt­(II)- and Pd­(II)-TAML analogues showed antitumor activity in the same cancer cell lines, which were attributed to off-target mechanisms rather than only ERα inhibition, for which these compounds were originally designed …”

“…37 Recently, the same group reported on Pt(II) and Pd(II) derivatives with the same tamoxifen-related ligand. 38 Inspired by these promising results and to enhance the multitargeting activities of tamoxifen-based metallodrugs, we have synthesized two coordination complexes of Au(III) (AuTAML) and Cu(II) (CuTAML) with the ligand 4-[1,1bis(4-methoxyphenyl)but-1-en-2-yl]-2,2′-bipyridine (TAML) 37 (Scheme 1), a derivative of tamoxifen incorporating a 2,2′-bipyridine moiety as a metal binding bidentate N^N domain. The choice of including gold into the compound's scaffold stems from the already well-established anticancer activity of Au(III) complexes in vitro and in vivo, 39−41 often related to the metallodrug activation either by reduction or ligand substitution mechanisms, 41,42 and attributable to the targeting of several metabolic pathways and a number of metabolites in tumor cells.…”

“…These complexes were found to have diverse biological effects compared to Fc-diOH, including induction of senescence and autophagy . Recently, the same group reported on Pt­(II) and Pd­(II) derivatives with the same tamoxifen-related ligand …”

Exploring the potential of tamoxifen-based copper(ii) dichloride in breast cancer therapy

“…This allows for the modular assembly of ligand L and transition metals to exploit their properties for specific needs in the treatment of (different) cancers regarding the cytotoxicity, selectivity and mechanism of action. 14 The transition metal copper is widely used as active centre in metallodrugs for breast cancer therapy. Like the majority of platinum-based drugs, Cu I and Cu II are able to interact with DNA, causing damage.…”