Gérard Jaouen

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%.

A [3]Ferrocenophane Polyphenol Showing a Remarkable Antiproliferative Activity on Breast and Prostate Cancer Cell Lines

We have previously shown that modification of polyphenols with a ferrocenyl group can dramatically enhance their cytotoxicity. We now present two new [3]ferrocenophane compounds, one of which has an antiproliferative effect seven times stronger than the corresponding noncyclic species, with IC50 values of 90 and 94 nM on hormone-independent MDA-MB-231 breast and PC-3 prostate cancer cell lines, respectively. Solubility studies in water using methylated beta-cyclodextrin and electron transfer studies are also presented.

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.

Lipid nanocapsules loaded with an organometallic tamoxifen derivative as a novel drug-carrier system for experimental malignant gliomas

Ferrocenyl diphenol tamoxifen derivative (Fc-diOH) is one of the most active molecules of a new class of organometallic drugs, showing in vitro antiproliferative effects on both hormone-dependent and independent breast cancer cells. For the first time, Fc-diOH was tested on a 9L glioma model according to two encapsulation strategies: lipid nanocapsules (LNC) and swollen micelles. LNC showed a higher drug loading capacity because of a larger oily core in their structure and were able to be up taken by glioma cells. The large amount of PEG present at the micellar interface prevented interaction with cytoplasm membrane which led to a low level of micelle cell uptake and no biological activity. On the contrary, Fc-diOH cytostatic activity was conserved after its encapsulation in LNC and was very effective on 9L-glioma cells as the IC(50) was about 0.6 microM. Interestingly, Fc-diOH-loaded LNC showed low toxicity levels when in contact with healthy cells, conferring a functional specificity of this compound on tumour cells. Finally, Fc-diOH LNC treatment was able to lower significantly both tumour mass and volume evolution after 9L-cell implantation into rats which evidenced for the first time the in vivo efficacy of this new kind of organometallic compound.

A series of unconjugated ferrocenyl phenols: prospects as anticancer agents.

We recently reported that a ferrocenyl diphenol butene derivative showed a very strong cytotoxic effect on both hormone‐dependent and ‐independent breast cancer cell lines. In order to obtain more information about the structure–activity relationship in the cytotoxicity of small ferrocene compounds, we have prepared a series of simple unconjugated ferrocenyl diphenol complexes (ortho,para; meta,para; para,para). These compounds retain a reasonable to good affinity for both estrogen receptor types, with higher values for the β form, and superior binding for the para,para diphenol complex (RBA=28 %). In vitro these complexes exhibit significant cytotoxic effects on hormone‐independent prostate (PC3) and breast cancer cell lines (MDA‐MB231), with IC50 values between 2.5 and 4.1 μM. This effect is more marked with PC3, the ortho,para diphenol complex proving the most effective. On the hormone‐dependent MCF7 breast cancer cell line, the observed effect seems to be the result of two components, one cytotoxic (antiproliferative), the other estrogenic (proliferative). Electrochemical studies show that the cytotoxic effect of the complexes correlates with the ease of oxidation of the ferrocene group. All these complexes are much less cytotoxic than the ferrocenyl diphenol butene derivative.

Ferrocene Functionalized Endocrine Modulators as Anticancer Agents

We present here some of our studies on the synthesis and behaviour of ferrocenyl selective endocrine receptor modulators against cancer cells, particularly breast and prostate cancers. The proliferative/anti-proliferative effects of compounds based on steroidal and non-steroidal endocrine modulators have been extensively explored in vitro. Structure–activity relationship studies of such molecules, particularly the hydroxyferrocifens and ferrocene phenols, have shown the effect of (1) the presence and the length of the N,N-dimethylamino side chain, (2) the presence and position of the phenol group, (3) the role of the ferrocenyl moiety, (4) that of conjugation, (5) phenyl functionalisation and (6) the placement of the phenyl group. Compounds possessing a ferrocene moiety linked to a p-phenol by a conjugated π-system are among the most potent of the series, with IC50 values ranging from 0.090 to 0.6µM on hormone independent breast cancer cells. Based on the SAR data and electrochemical studies, we have proposed an original mechanism to explain the unusual behaviour of these bioorganometallic species and coin the term “kronatropic” to qualify this effect, involving ROS production and bio-oxidation. In addition, the importance of formulation is underlined. We also discuss the behaviour of ferrocenyl androgens and anti-androgens for possible use against prostate cancers. In sum, ferrocene has proven to be a fascinating substituent due to its vast potential for oncology.