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The First Organometallic Selective Estrogen Receptor Modulators (SERMs) and Their Relevance to Breast Cancer

In the overall scheme of the future development of new drugs for the treatment of breast cancer, specially tamoxifen resistant tumours, we have explored the unprecedented use of organometallic SERMs. The initial idea is to enhance the efficacy of the current standard, i.e. tamoxifen, by modifying the structure through judicious incorporation of an organometallic moiety possessing novel properties. Results have been varied, justifying a systematic approach that has proved to be full of surprised. The following differing situations were observed (a) the anti-proliferative effect is due to the vector and the organometallic moiety does not improve the effects of the SERM, no matter what concentration is used. In particular, this is the case for the hydroxytamoxifen derivative bearing a CpRe(CO)3 group, which behaves almost identically to hydroxytamoxifen. These stable species have future promise for use with radionucleides of Re and Tc (b) the effect of the organometallic moiety counteracts the anti-estrogenic behaviour of the vector and leads to species with proliferative activity; this is the case with Cp2TiCl2 entity, which when attached to tamoxifen behaves as a powerful estrogen, probably due to in situ release of Ti(IV) (c) a synergy exists between the cytotoxic organometallic moiety and its organic vector, leading to unique anti-proliferative effects on breast cancer cells classed ER+ and ER-. This result opens a new window on organometallic oncology. It is also clear that the range of possibilities is broad, varied and currently unpredictable. A systematic study combining organometallic chemistry and biology is the only option in the search for new SERMs with novel properties.

Studies on organometallic selective estrogen receptor modulators. (SERMs) Dual activity in the hydroxy-ferrocifen series

Abstract Synthesis of 7 , a ferrocene derivative of the antiestrogenic drug hydroxytamoxifen bearing a basic chain-O(CH 2 ) n N(CH 3 ) 2 with n =4 is presented, together with both studies of its antiproliferative effect on the hormone-dependent MCF7 cell line (estrogen receptor positive cells) and of its genotoxicity. This molecule is easily prepared via a McMurry coupling reaction. The antiproliferative effect found for 7 at an incubation molarity of 1 μM was very close to that found for the usual reference molecule, namely OH-tamoxifen. In addition to its structural antiestrogenic effect, 7 showed cytotoxic activity probably due to the vectored ferrocene. This genotoxic component was confirmed by a 3D (damaged DNA detection) test, that permits identification and quantification of lesions induced on DNA. Some key interactions of 7 docked into the alpha-estrogen receptor binding site were also shown.

Ferrocenyl hydroxytamoxifen: a prototype for a new range of oestradiol receptor site-directed cytotoxics

The synthesis of ferrocenyl hydroxytamoxifen 1, a prototype for a new range hof oestradiol receptor site-directed cytotoxic compounds, and some preliminary biochemical tests are reported.

Ferrocenyl Quinone Methides as Strong Antiproliferative Agents: Formation by Metabolic and Chemical Oxidation of Ferrocenyl Phenols†

The modification of the biological effects of some biologically active molecules by ferrocene is an active field of study. The addition of a ferrocenyl moiety to selected polyaromatic phenols, amines, and amides can potentiate their antiproliferative effects against breast and prostate cancer cells. For example, hydroxytamoxifen, the active metabolite of the breast cancer drug tamoxifen, shows limited toxicity against hormone-refractory breast cancer cells (IC50 for MDA-MB231: 29 mm). However, when a phenyl group is replaced by a ferrocene moiety, the resulting “hydroxyferrocifen” displays a dramatic improvement in toxicity (IC50 = 0.5 mm). [6] In 2006, we proposed in this journal a novel mechanism of activation of ferrocene phenols: their ferrocene-mediated oxidation to quinone methide (QM) metabolites. This work was subsequently featured as part of a Highlight article. Quinone metabolites are potentially cytotoxic species, and, when ferrocene is present, QM formation takes place at comparatively mild (i.e. biologically relevant) oxidation potentials. Furthermore, the observation that some cancer cells are under heightened oxidative stress suggests that this class of redox-activated compounds may show an interesting selectivity profile. The formation of ferrocenyl QMs has been supported only by electrochemical experiments until now. We herein show that QMs do form upon metabolism of 1–4 by rat liver

Facile route to ferrocifen, 1-[4-(2-dimethylaminoethoxy)]-1-(phenyl-2-ferrocenyl-but-1-ene), first organometallic analogue of tamoxifen, by the McMurry reaction

Abstract As part of the search for tamoxifen substitutes that could be useful in the treatment of breast cancer, the use of organometallic complexes has been investigated. For this purpose a synthesis has been developed for ferrocifen, the prototype of this new series of complexes. Low valent titanium-mediated (TiCl4/Zn) cross-coupling of 4-MeO-C6H4COPh with ferrocenyl ethyl ketone affords the corresponding but-l-ene in high yield (66%), from which ferrocifen, 3, is rapidly prepared in an overall yield of 41%.

Metal complex SERMs (selective oestrogen receptor modulators). The influence of different metal units on breast cancer cell antiproliferative effects.

The selective oestrogen receptor modulator tamoxifen is a leading agent in the adjuvant treatment of breast cancer. Several organometallic moieties have been vectorised with tamoxifen, in order to improve on the latters antiproliferative properties by the addition of a potentially cytotoxic moiety, and have been evaluated versus both oestrogen receptor positive (MCF7) and oestrogen receptor negative (MDA-MB231) breast cancer cells. For tamoxifen analogues with ((R,R)-trans-1,2-diaminocyclohexane)platinum(II), cyclopentadienyl rhenium tricarbonyl, and ruthenocene tethers, there was no enhancement of the antiproliferative effect on oestrogen receptor positive cells, nor any cytotoxic effect on oestrogen receptor negative cells, while those containing cyclopentadienyl titanium dichloride showed an oestrogenic effect. However, compounds where ferrocene replaces tamoxifens phenyl ring were strongly cytotoxic against both cell lines. The synthesis and biological results of these compounds is reviewed and placed in the historic context of inorganic compounds in therapy.

New paradigms for synthetic pathways inspired by bioorganometallic chemistry

Abstract Two series of particular examples of reactions used in bioorganometallic chemistry are described. One based on a decomplexation-complexation reaction, indicates how, starting from a cymantrenyl derivative, a range of organometallic complexes bearing various metals can be prepared. The second one refers to the easy synthesis in water of the very versatile Albertos reagent, which leads to new organometallic radiopharmaceuticals of Tc and Re.

Synthesis and structure-activity relationships of the first ferrocenyl-aryl-hydantoin derivatives of the nonsteroidal antiandrogen nilutamide.

We present here the first synthesis of organometallic complexes derived from the nonsteroidal antiandrogen nilutamide, bearing a ferrocenyl substituent at position N(1) or at C(5) of the hydantoin ring; for comparison, we also describe the C(5) p-anisyl organic analogue. All of these complexes retain a modest affinity for the androgen receptor. The N-substituted complexes show a weak or moderate antiproliferative effect (IC 50 around 68 microM) on hormone-dependent and -independent prostate cancer cells, while the C(5)-substituted compounds exhibit toxicity levels 10 times higher (IC 50 around 5.4 microM). This strong antiproliferative effect is probably due to a structural effect linked to the aromatic character of the ferrocene rather than to its organometallic feature. In addition, it seems connected to a cytotoxic effect rather than an antihormonal one. These results open the way toward a new family of molecules that are active against both hormone-dependent and hormone-independent prostate cancer cells.

Deciphering the Activation Sequence of Ferrociphenol Anticancer Drug Candidates

The complete oxidation sequence of a model for ferrociphenols, a new class of anticancer drug candidate, is reported. Cyclic voltammetry was used to monitor the formation of oxidation intermediates on different timescales, thereby allowing the electrochemical characterization of both the short-lived and stable species obtained from the successive electron-transfer and deprotonation steps. The electrochemical preparation of the ferrocenium intermediate enabled a stepwise voltammetric determination of the stable oxidation compounds obtained upon addition of a base as well as the electron stoichiometry observed for the overall oxidation process. A mechanism has been established from the electrochemical data, which involves a base-promoted intramolecular electron transfer between the phenol and the ferrocenium cation. The resulting species is further oxidized then deprotonated to yield a stable quinone methide. To further characterize the transient species successively formed during the two-electron oxidation of the ferrociphenol to its quinone methide, EPR was used to monitor the fate of the paramagnetic species generated upon addition of imidazole to the electrogenerated ferrocenium. The study revealed the passage from an iron-centered to a carbon-centered radical, which is then oxidized to yield the quinone methide, namely, the species that interacts with proteins and so forth under biological conditions.

Evidence for Targeting Thioredoxin Reductases with Ferrocenyl Quinone Methides. A Possible Molecular Basis for the Antiproliferative Effect of Hydroxyferrocifens on Cancer Cells

Many anticancer compounds are strong inhibitors of thioredoxin reductases (TrxRs), selenoenzymes involved in cellular redox regulation. This study examined the effect of two hydroxyferrocifens (1, FcOH; 2, FcOHTAM) and of their corresponding quinone methides (QMs), 1-QM, and 2-QM, on these enzymes. In vitro, both QMs were more potent TrxR inhibitors (IC50 ≈ 2.5 μM) than the hydroxyferrocifens (IC50 ≈ 15 μM). This inhibition was due to a Michael addition of the penultimate selenocysteine residue of TrxRs to the QMs. In Jurkat cancer cells, both 2 and 2-QM inhibited TrxRs in the same proportion, leading to accumulation of oxidized forms of thioredoxin, while 1 and 1-QM were scarcely effective. This difference of behavior was ascribed to the competitive conversion of 1-QM to an inactive indene in protic medium. This set of experiments confirms for the first time the role played by ferrocenyl quinone methides on several biological targets and gives a molecular basis for these effects. It also highlights differences in the mechanisms of action of 1 and 2 in cancer cells.