Keywords: breast cancer, ferrocifen, indene metabolites, P450-dependent oxidation, quinone methides Ferrociphenols have been found to have high antiproliferative activity against estrogenindependent breast cancer cells. The rat and human liver microsome-mediated metabolism of three compounds of the ferrocifen (FC) family, 1,1-bis(4-hydroxy-phenyl)-2-ferrocenylbut-1-ene (FC1), 1-(4-hydroxyphenyl)-1-(phenyl)-2-ferrocenyl-but-1-ene (FC2), and 1-[4-(3-dimethylaminopropoxy)phenyl]-1-(4-hydroxyphenyl)-2-ferrocenyl-but-1-ene (FC3), was studied.Three main metabolite classes were identified: quinone methides (QMs) deriving from twoelectron oxidation of FCs, cyclic indene products (CPs) deriving from acid-catalyzed cyclization of QMs, and allylic alcohols (AAs) deriving from hydroxylation of FCs. These metabolites are generated by cytochromes P450 (P450s), as shown by experiments with either N-benzylimidazole as a P450 inhibitor or recombinant human P450s. Such P450-dependent oxidation of the phenol function and hydroxylation of the allylic CH 2 group of FCs leads to the formation of QM and AA metabolites, respectively. Some of the new ferrociphenols obtained in this study were found to exhibit remarkable antiproliferative effects toward MDA-MB-231 hormone-independent breast cancer cells.
Keywords: Drug design / Antitumor agents / Osmium / Ruthenium / Metallocenes / Ferrocifen Three osmium analogues 3a-3c of hydroxytamoxifen were prepared. The antiproliferative effects of these complexes were measured against two breast cancer cell lines (MCF-7 and MDA-MB-231) and compared with those of their homologues of ferrocene (1a-1c) and ruthenocene (2a-2c). The tamoxifen-like complexes 2c and 3c derived from osmium and ruthenium show good cytotoxicities against the two cell lines (IC 50 values between 2 and 3 μM), albeit lower than those of ferrocifen 1c (IC 50 between 0.5 and 0.8 μM). These complexes induce senescence of the cells at low concentration (0.5 μM). The mono-and diphenol complexes of osmium and ruthenium show little cytotoxicity against the two cell lines (2a, 2b, 3a, 3b; IC 50 ≈ 30 μM), whereas the iron analogues show
Tamoxifen-like metallocifens (TLMs) of the group-8 metals (Fe, Ru, and Os) show strong anti-proliferative activity on cancer cell lines resistant to apoptosis, owing to their unique redox properties. In contrast, the thioredoxin system, which is involved in cellular redox balance, is often overexpressed in cancer cells, especially in tumour types resistant to standard chemotherapies. Therefore, we investigated the effect of these three TLMs on the thioredoxin system and evaluated the input of the metallocene unit in comparison with structurally related organic tamoxifens. In vitro, all three TLMs became strong inhibitors of the cytosolic (TrxR1) and mitochondrial (TrxR2) isoforms of thioredoxin reductase after enzymatic oxidation with HRP/HO while none of the organic analogues was effective. In Jurkat cells, TLMs inhibited mainly TrxR2, resulting in the accumulation of oxidized thioredoxin 2 and cell redox imbalance. Overproduction of ROS resulted in a strong decrease in the mitochondrial membrane potential, translocation of cytochrome c to the cytosol and activation of caspase 3, thus leading to apoptosis. None of these events occurred with organic tamoxifens. The mitochondrial fraction of cells exposed to TLMs contained a high amount of the corresponding metal, as quantified by ICP-OES. The lipophilic and cationic character associated with the singular redox properties of the TLMs could explain why they alter the mitochondrial function. These results provide new insights into the mechanism of action of tamoxifen-like metallocifens, underlying their prodrug behaviour and the pivotal role played by the metallocenic entity in their cytotoxic activity associated with the induction of apoptosis.
The complete oxidation sequence of ruthenociphenol (1), an organometallic ruthenocenebased analogue of ferrocifens, a promising anticancer drug series, has been investigated by cyclic voltammetry. As for the unsubstituted ruthenocene, the oxidation of 1 produced the corresponding species 1 + , which engaged in a reversible dimerization reaction. The highest reversibility occurred in dichloromethane (DCM), a low-donor solvent, with the weakly coordinating supporting electrolyte anion B(C 6 F 5 ) 4 . Under these conditions, the addition of pyridine triggered a chemical sequence through which the hydroxyl group of electrogenerated 1 + was ultimately converted into the phenoxy radical 2. Unlike analogue ferrocifen derivatives, 2 did not undergo a further electrochemical oxidation but engaged in coupling with 1 + . The slow deprotonation of the resulting species appeared to be the key step leading to the quinone methide 3 after sluggish electron transfer. Again, in contrast with the ferrocifen series, 3 was not the final and stable complex of this oxidation sequence. It was indeed shown that the quinone methide spontaneously underwent a further oxidative evolution under our conditions. This led to a five-membered-ring closure and regeneration of the phenolic species 4, which could be further oxidized irreversibly, leading presumably to the new quinone methide 6. Such distinct behavior in comparison to ferrocene analogues may explain the different cytotoxic activities observed against hormone-independent breast cancer cells for ruthenocifens and ferrocifens.
ABSTRACT:To complete our study of the iron, ruthenium and osmium metallocene triad derived from hydroxytamoxifen, we report here the synthesis and study of the biological effects of two ferrocifen analogs in the osmium series, namely the monophenolic complex 1, the tamoxifen- within the cell and that inhibition of thioredoxin reductase is a key factor in rationalizing the cytotoxicity of these complexes on Jurkat cells.
A structure-activity relationship (SAR) study of the triosmium carbonyl cluster Os3 (CO)10 (NCCH3 )2 was carried out with a series of clusters of the general formula Os3 (CO)12-n Ln , cationic osmium clusters and a hemi-labile maltolato-Os cluster. The SAR results showed that good solubility in DMSO and at least one vacant site are required for cytotoxicity. In vitro evaluation of these new compounds showed that some are selectively active against estrogen receptor (ER)-independent MDA-MB-231 breast cancer cell lines relative to ER-dependent MCF-7 breast cancer cells, suggesting that the compounds have a different biological target specific to MDA-MB-231 cells. In particular, the maltolato cluster exhibits strong antiproliferative activity, with an IC50 value of 3 μM after only 24 h incubation. Additionally, biochemical assays conducted with the cationic cluster show that it induces apoptosis, although a biological target has not yet been identified. Further research to establish the molecular targets of these compounds and to develop improved organometallic clusters as potential breast cancer therapeutics is underway.
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