A New Series of Succinimido-ferrociphenols and Related Heterocyclic Species Induce Strong Antiproliferative Effects, Especially against Ovarian Cancer Cells Resistant to Cisplatin

Abstract

Ferrociphenols are known to display anticancer properties by original mechanisms dependent on redox properties and generation of active metabolites such as quinone methides. Recent studies have highlighted the positive impact of oxidative stress on chemosensitivity and prognosis of ovarian cancer patients. Ovarian adenocarcinomas are shown to be an excellent model for defining the impact of selected ferrociphenols as new therapeutic drugs for such cancers. This work describes the syntheses and preliminary mechanistic research of unprecedented multitargeting heterocyclic ferrociphenols bearing either a succinimidyl or phthalimidyl group that show exceptional antiproliferative behavior against epithelial ovarian cancer cells resistant to cisplatin. Owing to the failure of the present pharmaceutical options, such as carboplatin a metallodrug based on Pt coordination chemistry, these species may help to overcome the problem of lethal resistance. Currently, ferrociphenolic entities generally operate via apoptotic and senescence pathways. We present here our first results in this new cyclic-imide series.

Atypical Lone Pair–π Interaction with Quinone Methides in a Series of Imido‐Ferrociphenol Anticancer Drug Candidates

“…Functionalization of the alkyl chain of 1 by attaching a terminal hydroxy substituent or a heterocyclic group, as in 3 or 4 , resulted in extremely low IC 50 values (0.035 μ m ) on TNBC MDA‐MB‐231 cells; moreover, for the epithelial ovarian cancer cell line A2780 and the cisplatin‐resistant species A2780 cis R, the IC 50 values were 0.035 and 0.049 μ m , respectively. The first metabolite obtained either in the chemical (Ag + ) or enzymatic oxidation of 1 in cancer cells is the quinone methide 1‐QM (Figure a), which can react in a 1,8‐Michael addition with selective nucleophiles in the cancer cells .…”

“…[2] Antitumor agents based on iron, an abundant and inexpensive metal, occupy ap rivileged position, and mostly feature ferrocene,acompact, stable,n ontoxic metallocene showing reversible redox properties. [3a] Functionalization of the alkyl chain of 1 by attaching aterminal hydroxy substituent [4] or aheterocyclic group, [5] as in 3 or 4,resulted in extremely low IC 50 values (0.035 mm)on TNBC MDA-MB-231 cells;m oreover,f or the epithelial ovarian cancer cell line A2780 and the cisplatin-resistant species A2780cisR, the IC 50 values were 0.035 and 0.049 mm, respectively.T he first metabolite obtained either in the chemical (Ag + )o re nzymatic oxidation of 1 in cancer cells is the quinone methide 1-QM (Figure 1a), which can react in a1 ,8-Michael addition with selective nucleophiles in the cancer cells. [3a] Functionalization of the alkyl chain of 1 by attaching aterminal hydroxy substituent [4] or aheterocyclic group, [5] as in 3 or 4,resulted in extremely low IC 50 values (0.035 mm)on TNBC MDA-MB-231 cells;m oreover,f or the epithelial ovarian cancer cell line A2780 and the cisplatin-resistant species A2780cisR, the IC 50 values were 0.035 and 0.049 mm, respectively.T he first metabolite obtained either in the chemical (Ag + )o re nzymatic oxidation of 1 in cancer cells is the quinone methide 1-QM (Figure 1a), which can react in a1 ,8-Michael addition with selective nucleophiles in the cancer cells.…”

“…[3] We have investigated the possible use of ferrocenes in oncology in the so-called ferrocifen family (Figure 1a), such as compounds 1 and 2,w hose IC 50 values against triple-negative breast cancer (TNBC) cell lines (MDA-MB-231) are 0.6 and 0.5 mm,r espectively.T hese singular entities possess ar edox motif of the ferrocenyl-ene-phenol type,g iving rise to reactive oxygen species (ROS) in cancer cells.T he initial reversible oxidation of the ferrocenyl antenna permits electronic delocalization, leading selectively to electrophilic quinone methides (QMs,see below), which induce senescence and/or apoptosis,d epending on the particular parameters. [3a] Functionalization of the alkyl chain of 1 by attaching aterminal hydroxy substituent [4] or aheterocyclic group, [5] as in 3 or 4,resulted in extremely low IC 50 values (0.035 mm)on TNBC MDA-MB-231 cells;m oreover,f or the epithelial ovarian cancer cell line A2780 and the cisplatin-resistant species A2780cisR, the IC 50 values were 0.035 and 0.049 mm, respectively.T he first metabolite obtained either in the chemical (Ag + )o re nzymatic oxidation of 1 in cancer cells is the quinone methide 1-QM (Figure 1a), which can react in a1 ,8-Michael addition with selective nucleophiles in the cancer cells. [6] Them echanism of action of 4 may follow asimilar pathway to that of 1.…”

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).…”

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

“…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.…”