Synthesis and antiproliferative evaluation of novel hydroxypropyl-ferrociphenol derivatives, resulting from the modification of hydroxyl groups

Abstract

As previously reported, the ferrocenyl derivative HO(CH2)3C(Fc)=C(C6H4OH)2 (2) shows an excellent cytotoxic effect against MDA-MB-231 (TNBC) cancer cell lines. Building on an analysis of this molecular framework, a series of novel hydroxypropyl-ferrociphenol derivatives with modified terminal hydroxyl groups were synthesized, and their antiproliferative activities against MDA-MB-231 cell lines were evaluated. Biological results showed that compound 8, whose terminal hydroxyl was protected by acetylation, exhibited the greatest cytotoxic effect among this series of hydroxypropyl derivatives. Furthermore, the impact of acetyl as a protecting group on the cytotoxicity of hydroxypropyl-ferrociphenol compounds by incorporating it to alkyl or phenyl hydroxyl positions of the core structure has been studied. Several of compounds presented in this study revealed lipophilicity more suitable for formulation in lipid nanocapsules (LNCs) for subsequent in vivo studies. They also inhibit the cancer cell growth of MDA-MB-231 at a submicromolar IC50 value, providing an interesting potential for further development as innovative anticancer agents.

Ferrocene-Based Compounds with Antimalaria/Anticancer Activity

“…They have rich diverse modes of action which are caused by their capability to produce a redox pattern (ferrocenyl-ene-phenol) in the cancer cell [56]. Their target is the mitochondrial system or redox proteins in the cancer cells [62,63,64,65]. Pigeon et al prepared ferrociphenol derivatives 56a and 56b (Figure 18).…”

“…The introduction of benzylated substituents at the terminal hydroxyl position of compound 60 resulted in significant cytotoxic effects against the MDA-MB-231 cells, resulting in a high lipophilic nature of the compound. Compound 59 and 60 exhibited significant cytotoxic effect against the cancer cell lines suggesting that the presence of an ester linker makes the compounds prone to hydrolysis, resulting in the generation of the parent drug, 58 [63] .…”

Enantioselective Synthesis of Planar Chiral Ferrocifens that Show Chiral Discrimination in Antiproliferative Activity on Breast Cancer Cells

“…[21] Ferrociphenols operate not only as the result of reversible redox of the ferrocenyl moiety (Fe 2 + ⇄Fe 3 + ) which leads to the generation of reactive oxygen species (ROS), in particular hydroxyl radicals, but also by the formation of quinone methides (QMs) as primary metabolites. [2,[22][23][24] These QMs are highly electrophilic and react with overexpressed nucleophilic peptides or proteins in the cell, such as those bearing thiols or selenols (Scheme 2), and can lead to cell death by interference with oxidative stress or inactivation of enzymes. [25] Treatment of ferrociphenols or ferrocifens, either chemically with Ag 2 O, or enzymatically by incubation with horseradish peroxidase (HRP) or rat liver microsomes and NADPH, provides a convenient laboratory route to the corresponding QMs.…”

“…[25] Treatment of ferrociphenols or ferrocifens, either chemically with Ag 2 O, or enzymatically by incubation with horseradish peroxidase (HRP) or rat liver microsomes and NADPH, provides a convenient laboratory route to the corresponding QMs. [22][23][24] A wide range of ferrocifens and ferrociphenols (> 300) has been prepared, and their bioactivity has been evaluated. In the early phase of these studies, the molecules all possessed an ethyl substituent, as in hydroxytamoxifen -the current first line adjuvant therapy for hormone-dependent breast cancers -on which they were originally modelled.…”

“…In the early phase of these studies, the molecules all possessed an ethyl substituent, as in hydroxytamoxifen -the current first line adjuvant therapy for hormone-dependent breast cancers -on which they were originally modelled. [1] Subsequent work revealed that incorporation of hydroxyalkyl [22][23][24] (or, even better, imidoalkyl [26,27] ) substituents dramatically lowered IC 50 values into the low nanomolar range, and also greatly extended their spectrum of activity to include lung, prostate, renal, colon, ovarian and CNS tumours, as well as leukaemia and melanomas. [24] However, in all cases, except for those in which the ferrocenyl moiety possessed a polymethylene chain, as in 5, [28] and also the ansa systems, 6, [29][30][31][32] the ferrocenyl unit remained constant.…”