The X-ray structure of 17a-ferrocenylestradiol la shows that the ferrocenyl group is at the Q pos... more The X-ray structure of 17a-ferrocenylestradiol la shows that the ferrocenyl group is at the Q position of the steroid, below the plane of the D ring. From acidic medium it is possible to obtain and isolate the derivative with a carbenium ion in 17-(u position. This ion is transformed by various nucleophiles into the corresponding olefin 3 with -C=C-at the C16-Cl7 position. With NaBH, in acidic medium the reduction leads to a mixture of 17a-and 17/3-ferrocenyl C,,H,,O 4a, 4b with a predominance of the /3 product, owing to a more favourable entrance of hydride in the LY position. The oxidized derivative 17a-ferriciniumylestradiol tetrafluoroborate 5 was prepared and its are properties described.
We present here some of our studies on the synthesis and behaviour of ferrocenyl selective endocr... more 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 p-system are among the most potent of the series, with IC 50 values ranging from 0.090 to 0.6 mM 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.
We present here some of our studies on the synthesis and behaviour of ferrocenyl selective endocr... more 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 p-system are among the most potent of the series, with IC 50 values ranging from 0.090 to 0.6 mM 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 substitu-ent due to its vast potential for oncology. Keywords Anti-androgen Á Anti-oestrogen/Anti-oestrogenic Á Breast cancer Á
A first example of the solid-phase immunoassay of a high-weight antigen bovine serum albumin (BSA... more A first example of the solid-phase immunoassay of a high-weight antigen bovine serum albumin (BSA) using an (η 5 -cyclopentadienyl)tricarbonylmanganese (cymantrene) redox probe is presented. The electrochemical detection is based on the impedance measurements of a one-electron reversible reduction of the organometallic probe. The microbeadbased immunoassay is discussed for two types of microbeads with different diameters (2.5 and 90 µm) and capabilities to bind the immunoglobulins (2.4 and 10 µg/mg of beads). The use of larger agarose microbeads allows the formation of an antigen-antibody complex at the surface of microbeads directly dispersed in the analyzed solution. No additional separation step is necessary for the electrochemical competitive immunoassay analysis of BSA. The presence of agarose beads in the analyzed solution has no effect on the electrochemical signal from labeled BSA released from the antigen-antibody complex.
The use of a non-polar medium at room temperature is an efficient, cheap and easy way to improve ... more The use of a non-polar medium at room temperature is an efficient, cheap and easy way to improve the low reactivity of six hindered ketones towards phenyllithium.
The use of a non-polar medium at room temperature is an efficient, cheap and easy way to improve ... more The use of a non-polar medium at room temperature is an efficient, cheap and easy way to improve the low reactivity of six hindered ketones towards phenyllithium.
Ferrociphenols (FCs) and their oxidized, electrophilic quinone methide metabolites (FC-QMs) are o... more Ferrociphenols (FCs) and their oxidized, electrophilic quinone methide metabolites (FC-QMs) are organometallic compounds related to tamoxifen that exhibit strong antiproliferative properties. To evaluate the reactivity of FC-QMs towards cellular nucleophiles, we studied their reaction with selected thiols. A series of new compounds resulting from the addition of these nucleophiles, the FCSR adducts, were thus synthesized and completely characterized. Such conjugates are formed upon metabolism of FCs by liver microsomes in the presence of NADPH and thiols. Some of them exhibit antiproliferative properties comparable to those of their FC precursors. Under oxidizing conditions they either lead to their FC-QM precursors or to new quinone methides containing the SR moiety, FC-SRQM. These results not only provide interesting data about the reactivity and mechanism of antiproliferative effects of FCs, but also open the way towards new series of organometallic anti-tumor compounds.
We describe here the conjugation of polyclonal goat anti-rabbit antibody to generation 4 polyamid... more We describe here the conjugation of polyclonal goat anti-rabbit antibody to generation 4 polyamidoamine (G4-PAMAM) dendrimers carrying (i) (g 5 -cyclopentadienyl) iron dicarbonyl succinimidato complexes as infrared (IR) probes, (ii) nitroaniline entities as nuclear magnetic resonance (NMR) probes, (iii) acetamide groups for surface neutralization, and (iv) hydrazide-terminated spacer arms for the reaction with aldehyde. To preserve a high binding affinity, the conjugation was performed on the carbohydrate moieties located on the Fc fragment. The resulting conjugates were characterized by Fourier transform-IR, ultraviolet (UV), and high-mass matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. On the basis of relative concentration ratios of IR probes and antibody, an average labeling of 30 IR probes per antibody was reached (i.e., more than twice the value obtained with our previous strategy that generated no spacer arm). Immunoassays revealed that the antibodydendrimer conjugates retained 55.1% of immunoreactivity on average with respect to underivatized antibody. Finally, the conjugates were used to quantify their antigen by solid-phase carbonyl metallo immunoassay (CMIA). Results showed a significant enhancement of the IR signal, demonstrating the efficiency of the new conjugation strategy and the potential of the new antibody-dendrimer conjugates as universal immunoanalytical reagents.
Molecular recognition between avidin covalently immobilized at the surface of acrylic resin beads... more Molecular recognition between avidin covalently immobilized at the surface of acrylic resin beads and a transition metallocarbonyl tracer of the biotin ligand was detected using diffuse reflectance infrared Fourier transform spectroscopy. Copyright 2004 John Wiley & Sons, Ltd.
Transition metallo-carbonyl complexes are useful bioprobes to study molecular recognition process... more Transition metallo-carbonyl complexes are useful bioprobes to study molecular recognition processes such as ligand-receptor interactions, owing to their intense absorption bands in the mid-IR spectral range, which enable their detection at the picomole level with FT-IR ...
A new non-radioisotopic immunoassay procedure, which we have termed carbonylmetalloimmunoassay (C... more A new non-radioisotopic immunoassay procedure, which we have termed carbonylmetalloimmunoassay (CMIA), is described. The tracers used in this approach are organometallic carbonyl complexes that can be detected at femtomole levels (300-700 fmol) by Fourier transform infrared (FT-IR) spectroscopy. The validity of the technique has been tested in a phenobarbital assay using as the marker a cyclopentadienyimanganese (I) tricarbonyl (cymantrene) moiety, ethyl acetate extraction to separate the free and bound organometallic fractions, and FT-IR spectroscopy to detect the CO stretching modes of the organometallic label. Typical dilution and standard curves obtained with this CMIA procedure are presented. The method was of comparable sensitivity to a [~4C] radioimmunoassay (RIA) for the detection of phenobarbital. A comparison of the results for phenobarbital assays by both CMIA and RIA showed that higher titres were obtained using the CMIA method. The standard curves suggest that CMIA is a reliable and reproducible immunoassay procedure for phenobarbital.
... IAN S..BUTLER,* A.NNE VESSIERES, MICHELE SALMAIN, PIERRE BROSSIER, and GERARD JAOUEN Departme... more ... IAN S..BUTLER,* A.NNE VESSIERES, MICHELE SALMAIN, PIERRE BROSSIER, and GERARD JAOUEN Department o[ Chemistry, MeGill University, 801 ... are ex-acerbated when one is examining the extremely small amounts of material encountered with biological sam-ples. ...
The complexation of estrogens by transitional metal units e.g. (alkyne)Co2(CO)6 and (alkyne)Mo2Cp... more The complexation of estrogens by transitional metal units e.g. (alkyne)Co2(CO)6 and (alkyne)Mo2Cp2(CO)4, at the 17 alpha-position brings about a dramatic change in the chemical behavior of these compounds with respect to that of the free ligands. The 17 beta-OH function becomes particularly labile, even in weakly acidic medium, giving rise to carbenium ion-like species, from which, depending on the metal and the nucleophile, substitution, elimination and rearrangement take place. This situation provides the basis for a new type of active site directed-reagent for estradiol receptor. The hypothesis of vicinal space positioning of an acidic and a nucleophilic group in the estradiol receptor cavity is examined in the light of the amino-acid composition of the steroid binding domain. The requirement of the sulfhydryl group of a cysteine residue is suspected in the first step of the receptor inactivation process.
Site-specific labelling of the cysteine-containing peptide glutathione with a ferrocene group was... more Site-specific labelling of the cysteine-containing peptide glutathione with a ferrocene group was achieved by reaction with ferrocenylmethanol in aqueous acidic medium. The resulting peptide was shown to be a potent competitive inhibitor of the biologically important enzyme glutathione-(S)-transferase. This approach may prove general for the labelling of proteins with ferrocene. Published by Elsevier Ltd.
Triple-negative breast cancers (TNBC) represent the most aggressive form of breast cancers and th... more Triple-negative breast cancers (TNBC) represent the most aggressive form of breast cancers and their treatment are challenging due to the tumor heterogeneity. The high death rate and the limited systemic treatment options for TNBC necessitate the search for alternative chemotherapeutics. We previously found that FcOHTAM, an organometallic derivative of hydroxytamoxifen, showed in vitro a strong antiproliferative effect on various breast cancer cell lines, including MDA-MB-231 cells, the archetype of TNBC. In this study, we developed stealth FcOHTAM loaded lipid nanocapsules (LNCs) to further evaluate this novel drug on a TNBC xenografted model. Cell cycle analysis of MDA-MB-231 cells confirmed the preservation of the drug activity through LNCs causing a cycle arrest in phase S after 48 h exposure at the IC 50 concentration (2 mM). Two intraperitoneal injections of FcOHTAM loaded LNCs (20 mg/kg) administered to luciferase-transfected MDA-MB-231 tumors bearing mice led to a marked delay in tumor growth. As a consequence, a significantly lower tumor volume was obtained at the end of the experiment with a difference of 36% at day 38 compared to the untreated group. These results represent the first evidence of an in vivo effect of FcOHTAM and ferrocenyl derivatives in general on xenografted breast tumors.
The synthesis and chemical oxidation profile of an ew generation of ferrocifen derivatives with s... more The synthesis and chemical oxidation profile of an ew generation of ferrocifen derivatives with strong antiproliferative behavior in vitro is reported. In particular,t he hydroxypropyl derivative HO(CH 2 ) 3 C(Fc) = C(C 6 H 4 OH) 2 (3b)e xhibited exceptional antiproliferative activity against the cancer cell lines HepG2 and MDA-MB-231 TNBC,w ith IC 50 values of 0.07 and 0.11 mm,r espectively.C hemical oxidation of 3b yielded an unprecedented tetrahydrofuransubstituted quinone methide (QM) via internal cyclization of the hydroxyalkyl chain, whereas the corresponding alkyl analogue CH 3 CH 2 -C(Fc) = C(C 6 H 4 OH) 2 merely formed av inyl QM. The ferrocenyl group in 3b playsakey role,n ot only as an intramolecular reversible redox "antenna", but also as astabilized carbenium ion "modulator". The presence of the oxygen heterocycle in 3b-QM enhances its stability and leads to au nique chemical oxidation profile,t hus revealing crucial clues for deciphering its mechanism of action in vivo.
The synthesis and chemical oxidation profile of an ew generation of ferrocifen derivatives with s... more The synthesis and chemical oxidation profile of an ew generation of ferrocifen derivatives with strong antiproliferative behavior in vitro is reported. In particular,t he hydroxypropyl derivative HO(CH 2 ) 3 C(Fc) = C(C 6 H 4 OH) 2 (3b)e xhibited exceptional antiproliferative activity against the cancer cell lines HepG2 and MDA-MB-231 TNBC,w ith IC 50 values of 0.07 and 0.11 mm,r espectively.C hemical oxidation of 3b yielded an unprecedented tetrahydrofuransubstituted quinone methide (QM) via internal cyclization of the hydroxyalkyl chain, whereas the corresponding alkyl analogue CH 3 CH 2 -C(Fc) = C(C 6 H 4 OH) 2 merely formed av inyl QM. The ferrocenyl group in 3b playsakey role,n ot only as an intramolecular reversible redox "antenna", but also as astabilized carbenium ion "modulator". The presence of the oxygen heterocycle in 3b-QM enhances its stability and leads to au nique chemical oxidation profile,t hus revealing crucial clues for deciphering its mechanism of action in vivo.
Covalent embedding of a (eta(6)-arene) ruthenium(II) complex into the protein papain gives rise t... more Covalent embedding of a (eta(6)-arene) ruthenium(II) complex into the protein papain gives rise to a metalloenzyme displaying a catalytic efficiency for a Lewis acid-mediated catalysed Diels-Alder reaction enhanced by two orders of magnitude in water.
The X-ray structure of 17a-ferrocenylestradiol la shows that the ferrocenyl group is at the Q pos... more The X-ray structure of 17a-ferrocenylestradiol la shows that the ferrocenyl group is at the Q position of the steroid, below the plane of the D ring. From acidic medium it is possible to obtain and isolate the derivative with a carbenium ion in 17-(u position. This ion is transformed by various nucleophiles into the corresponding olefin 3 with -C=C-at the C16-Cl7 position. With NaBH, in acidic medium the reduction leads to a mixture of 17a-and 17/3-ferrocenyl C,,H,,O 4a, 4b with a predominance of the /3 product, owing to a more favourable entrance of hydride in the LY position. The oxidized derivative 17a-ferriciniumylestradiol tetrafluoroborate 5 was prepared and its are properties described.
We present here some of our studies on the synthesis and behaviour of ferrocenyl selective endocr... more 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 p-system are among the most potent of the series, with IC 50 values ranging from 0.090 to 0.6 mM 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.
We present here some of our studies on the synthesis and behaviour of ferrocenyl selective endocr... more 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 p-system are among the most potent of the series, with IC 50 values ranging from 0.090 to 0.6 mM 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 substitu-ent due to its vast potential for oncology. Keywords Anti-androgen Á Anti-oestrogen/Anti-oestrogenic Á Breast cancer Á
A first example of the solid-phase immunoassay of a high-weight antigen bovine serum albumin (BSA... more A first example of the solid-phase immunoassay of a high-weight antigen bovine serum albumin (BSA) using an (η 5 -cyclopentadienyl)tricarbonylmanganese (cymantrene) redox probe is presented. The electrochemical detection is based on the impedance measurements of a one-electron reversible reduction of the organometallic probe. The microbeadbased immunoassay is discussed for two types of microbeads with different diameters (2.5 and 90 µm) and capabilities to bind the immunoglobulins (2.4 and 10 µg/mg of beads). The use of larger agarose microbeads allows the formation of an antigen-antibody complex at the surface of microbeads directly dispersed in the analyzed solution. No additional separation step is necessary for the electrochemical competitive immunoassay analysis of BSA. The presence of agarose beads in the analyzed solution has no effect on the electrochemical signal from labeled BSA released from the antigen-antibody complex.
The use of a non-polar medium at room temperature is an efficient, cheap and easy way to improve ... more The use of a non-polar medium at room temperature is an efficient, cheap and easy way to improve the low reactivity of six hindered ketones towards phenyllithium.
The use of a non-polar medium at room temperature is an efficient, cheap and easy way to improve ... more The use of a non-polar medium at room temperature is an efficient, cheap and easy way to improve the low reactivity of six hindered ketones towards phenyllithium.
Ferrociphenols (FCs) and their oxidized, electrophilic quinone methide metabolites (FC-QMs) are o... more Ferrociphenols (FCs) and their oxidized, electrophilic quinone methide metabolites (FC-QMs) are organometallic compounds related to tamoxifen that exhibit strong antiproliferative properties. To evaluate the reactivity of FC-QMs towards cellular nucleophiles, we studied their reaction with selected thiols. A series of new compounds resulting from the addition of these nucleophiles, the FCSR adducts, were thus synthesized and completely characterized. Such conjugates are formed upon metabolism of FCs by liver microsomes in the presence of NADPH and thiols. Some of them exhibit antiproliferative properties comparable to those of their FC precursors. Under oxidizing conditions they either lead to their FC-QM precursors or to new quinone methides containing the SR moiety, FC-SRQM. These results not only provide interesting data about the reactivity and mechanism of antiproliferative effects of FCs, but also open the way towards new series of organometallic anti-tumor compounds.
We describe here the conjugation of polyclonal goat anti-rabbit antibody to generation 4 polyamid... more We describe here the conjugation of polyclonal goat anti-rabbit antibody to generation 4 polyamidoamine (G4-PAMAM) dendrimers carrying (i) (g 5 -cyclopentadienyl) iron dicarbonyl succinimidato complexes as infrared (IR) probes, (ii) nitroaniline entities as nuclear magnetic resonance (NMR) probes, (iii) acetamide groups for surface neutralization, and (iv) hydrazide-terminated spacer arms for the reaction with aldehyde. To preserve a high binding affinity, the conjugation was performed on the carbohydrate moieties located on the Fc fragment. The resulting conjugates were characterized by Fourier transform-IR, ultraviolet (UV), and high-mass matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. On the basis of relative concentration ratios of IR probes and antibody, an average labeling of 30 IR probes per antibody was reached (i.e., more than twice the value obtained with our previous strategy that generated no spacer arm). Immunoassays revealed that the antibodydendrimer conjugates retained 55.1% of immunoreactivity on average with respect to underivatized antibody. Finally, the conjugates were used to quantify their antigen by solid-phase carbonyl metallo immunoassay (CMIA). Results showed a significant enhancement of the IR signal, demonstrating the efficiency of the new conjugation strategy and the potential of the new antibody-dendrimer conjugates as universal immunoanalytical reagents.
Molecular recognition between avidin covalently immobilized at the surface of acrylic resin beads... more Molecular recognition between avidin covalently immobilized at the surface of acrylic resin beads and a transition metallocarbonyl tracer of the biotin ligand was detected using diffuse reflectance infrared Fourier transform spectroscopy. Copyright 2004 John Wiley & Sons, Ltd.
Transition metallo-carbonyl complexes are useful bioprobes to study molecular recognition process... more Transition metallo-carbonyl complexes are useful bioprobes to study molecular recognition processes such as ligand-receptor interactions, owing to their intense absorption bands in the mid-IR spectral range, which enable their detection at the picomole level with FT-IR ...
A new non-radioisotopic immunoassay procedure, which we have termed carbonylmetalloimmunoassay (C... more A new non-radioisotopic immunoassay procedure, which we have termed carbonylmetalloimmunoassay (CMIA), is described. The tracers used in this approach are organometallic carbonyl complexes that can be detected at femtomole levels (300-700 fmol) by Fourier transform infrared (FT-IR) spectroscopy. The validity of the technique has been tested in a phenobarbital assay using as the marker a cyclopentadienyimanganese (I) tricarbonyl (cymantrene) moiety, ethyl acetate extraction to separate the free and bound organometallic fractions, and FT-IR spectroscopy to detect the CO stretching modes of the organometallic label. Typical dilution and standard curves obtained with this CMIA procedure are presented. The method was of comparable sensitivity to a [~4C] radioimmunoassay (RIA) for the detection of phenobarbital. A comparison of the results for phenobarbital assays by both CMIA and RIA showed that higher titres were obtained using the CMIA method. The standard curves suggest that CMIA is a reliable and reproducible immunoassay procedure for phenobarbital.
... IAN S..BUTLER,* A.NNE VESSIERES, MICHELE SALMAIN, PIERRE BROSSIER, and GERARD JAOUEN Departme... more ... IAN S..BUTLER,* A.NNE VESSIERES, MICHELE SALMAIN, PIERRE BROSSIER, and GERARD JAOUEN Department o[ Chemistry, MeGill University, 801 ... are ex-acerbated when one is examining the extremely small amounts of material encountered with biological sam-ples. ...
The complexation of estrogens by transitional metal units e.g. (alkyne)Co2(CO)6 and (alkyne)Mo2Cp... more The complexation of estrogens by transitional metal units e.g. (alkyne)Co2(CO)6 and (alkyne)Mo2Cp2(CO)4, at the 17 alpha-position brings about a dramatic change in the chemical behavior of these compounds with respect to that of the free ligands. The 17 beta-OH function becomes particularly labile, even in weakly acidic medium, giving rise to carbenium ion-like species, from which, depending on the metal and the nucleophile, substitution, elimination and rearrangement take place. This situation provides the basis for a new type of active site directed-reagent for estradiol receptor. The hypothesis of vicinal space positioning of an acidic and a nucleophilic group in the estradiol receptor cavity is examined in the light of the amino-acid composition of the steroid binding domain. The requirement of the sulfhydryl group of a cysteine residue is suspected in the first step of the receptor inactivation process.
Site-specific labelling of the cysteine-containing peptide glutathione with a ferrocene group was... more Site-specific labelling of the cysteine-containing peptide glutathione with a ferrocene group was achieved by reaction with ferrocenylmethanol in aqueous acidic medium. The resulting peptide was shown to be a potent competitive inhibitor of the biologically important enzyme glutathione-(S)-transferase. This approach may prove general for the labelling of proteins with ferrocene. Published by Elsevier Ltd.
Triple-negative breast cancers (TNBC) represent the most aggressive form of breast cancers and th... more Triple-negative breast cancers (TNBC) represent the most aggressive form of breast cancers and their treatment are challenging due to the tumor heterogeneity. The high death rate and the limited systemic treatment options for TNBC necessitate the search for alternative chemotherapeutics. We previously found that FcOHTAM, an organometallic derivative of hydroxytamoxifen, showed in vitro a strong antiproliferative effect on various breast cancer cell lines, including MDA-MB-231 cells, the archetype of TNBC. In this study, we developed stealth FcOHTAM loaded lipid nanocapsules (LNCs) to further evaluate this novel drug on a TNBC xenografted model. Cell cycle analysis of MDA-MB-231 cells confirmed the preservation of the drug activity through LNCs causing a cycle arrest in phase S after 48 h exposure at the IC 50 concentration (2 mM). Two intraperitoneal injections of FcOHTAM loaded LNCs (20 mg/kg) administered to luciferase-transfected MDA-MB-231 tumors bearing mice led to a marked delay in tumor growth. As a consequence, a significantly lower tumor volume was obtained at the end of the experiment with a difference of 36% at day 38 compared to the untreated group. These results represent the first evidence of an in vivo effect of FcOHTAM and ferrocenyl derivatives in general on xenografted breast tumors.
The synthesis and chemical oxidation profile of an ew generation of ferrocifen derivatives with s... more The synthesis and chemical oxidation profile of an ew generation of ferrocifen derivatives with strong antiproliferative behavior in vitro is reported. In particular,t he hydroxypropyl derivative HO(CH 2 ) 3 C(Fc) = C(C 6 H 4 OH) 2 (3b)e xhibited exceptional antiproliferative activity against the cancer cell lines HepG2 and MDA-MB-231 TNBC,w ith IC 50 values of 0.07 and 0.11 mm,r espectively.C hemical oxidation of 3b yielded an unprecedented tetrahydrofuransubstituted quinone methide (QM) via internal cyclization of the hydroxyalkyl chain, whereas the corresponding alkyl analogue CH 3 CH 2 -C(Fc) = C(C 6 H 4 OH) 2 merely formed av inyl QM. The ferrocenyl group in 3b playsakey role,n ot only as an intramolecular reversible redox "antenna", but also as astabilized carbenium ion "modulator". The presence of the oxygen heterocycle in 3b-QM enhances its stability and leads to au nique chemical oxidation profile,t hus revealing crucial clues for deciphering its mechanism of action in vivo.
The synthesis and chemical oxidation profile of an ew generation of ferrocifen derivatives with s... more The synthesis and chemical oxidation profile of an ew generation of ferrocifen derivatives with strong antiproliferative behavior in vitro is reported. In particular,t he hydroxypropyl derivative HO(CH 2 ) 3 C(Fc) = C(C 6 H 4 OH) 2 (3b)e xhibited exceptional antiproliferative activity against the cancer cell lines HepG2 and MDA-MB-231 TNBC,w ith IC 50 values of 0.07 and 0.11 mm,r espectively.C hemical oxidation of 3b yielded an unprecedented tetrahydrofuransubstituted quinone methide (QM) via internal cyclization of the hydroxyalkyl chain, whereas the corresponding alkyl analogue CH 3 CH 2 -C(Fc) = C(C 6 H 4 OH) 2 merely formed av inyl QM. The ferrocenyl group in 3b playsakey role,n ot only as an intramolecular reversible redox "antenna", but also as astabilized carbenium ion "modulator". The presence of the oxygen heterocycle in 3b-QM enhances its stability and leads to au nique chemical oxidation profile,t hus revealing crucial clues for deciphering its mechanism of action in vivo.
Covalent embedding of a (eta(6)-arene) ruthenium(II) complex into the protein papain gives rise t... more Covalent embedding of a (eta(6)-arene) ruthenium(II) complex into the protein papain gives rise to a metalloenzyme displaying a catalytic efficiency for a Lewis acid-mediated catalysed Diels-Alder reaction enhanced by two orders of magnitude in water.
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Papers by Gérard Jaouen