Efficient new constructs against triple negative breast cancer cells: synthesis and preliminary biological study of ferrocifen–SAHA hybrids and related species

Abstract

Chemotherapeutic agents combining several active groups within a single molecule can modulate multiple cellular pathways and, thus, exhibit higher efficacy than single-target drugs. In this study, six new hybrid compounds combining tamoxifen (TAM) or ferrocifen (FcTAM) structural motifs with suberoylanilide hydroxamic acid (SAHA) were synthesised and evaluated. Antiproliferative activity was first explored in cancer cell lines. Combining FcTAM and SAHA structural motifs to form the unprecedented FcTAM–SAHA hybrid molecule led to an increased cytotoxicity (IC50 = 0.7 μM) in triple-negative MDA-MB-231 breast cancer cells when compared to FcTAM or SAHA alone (IC50 = 2.6 μM and 3.6 μM, respectively), while the organic hybrid analogue TAM–SAHA was far less cytotoxic (IC50 = 8.6 μM). In hormone-dependent MCF-7 breast cancer cells, FcTAM–SAHA was more active (IC50 = 2.0 μM) than FcTAM (IC50 = 4.4 μM) and TAM–SAHA (IC50 > 10 μM), but less toxic than SAHA (IC50 = 1.0 μM). Surprisingly, FcTAM–PSA, an N1-phenylsuberamide derivative, also possessed strong antiproliferative activity (IC50 = 0.5 μM and 1.8 μM in MDA-MB-231 and MCF-7 cells, respectively). Subsequent biochemical studies indicate that estrogen receptor alpha (ERα) and histone deacetylases (HDAC) are not the main targets of the hybrid compounds for their antiproliferative effect. Interestingly, both organometallic compounds were able to induce p21waf1/cip1 gene expression in MCF-7 breast cancer cells in accordance with their antiproliferative activity.

Ferrocifen type anti cancer drugs

“…IC 50 values (µM) of organic and ferrocenyl hybrids of SAHA and PSA on MDA-MB-231 cancer cells after 72h 47. IC 50 value of 0.7 µM versus 3.6 µM for SAHA and 2.6 µM for Fc-Tam).…”

Synthesis and biological evaluation of novel quinolone derivatives dual targeting histone deacetylase and tubulin polymerization as antiproliferative agents

“…So far, a few examples of bifunctional HDACi-derived conjugates have been obtained. [21][22][23][24][25][26] Expansion of the diversity of such bifunctional conjugates could lead to broad acting, therapeutically viable anticancer drugs.…”

Anticancer RuII and RhIII Piano‐Stool Complexes that are Histone Deacetylase Inhibitors

“…In terms of selectivity,a lthough the enzymatic cavity is relatively comparable between HDACs, there is clear variability in the protein structure towards the entrance of the cavity.T he phenylh eadgroup of enzyme-bound SAHA sits in this region and offers scope for modification toward the developmento f HDAC-selective agentso rm ore potent drugs through greater chemicala ffinity.I nr ecent years, HDAC inhibitors have been developed in which the phenylh eadgroupi sr eplacedo rf unctionalised withametalc omplex. Examples include ferrocene-, [17] platinum-, [18] rhenium- [19] and ferrocifen-based [20] inhibitors. In each case the pharmacological effects are retained and, in some cases, improved cytotoxicity relative to SAHA was observed.…”