Direct Synthesis of Tricarbonyl(cyclopentadienyl)rhenium and Tricarbonyl(cyclopentadienyl)technetium Units from Ferrocenyl Moieties − Preparation of 17α‐Ethynylestradiol Derivatives Bearing a Tricarbonyl(cyclopentadienyl)technetium Group

Masi, Stéphane; Top, Siden; Boubekeur, Leïla; Jaouen, Gérard; Mundwiler, Stefan; Spingler, Bernhard; Alberto, Roger

doi:10.1002/ejic.200300731

Cited by 62 publications

(61 citation statements)

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“…[44] 4-Halogenoalkoxyphenyl-4'-hydroxyphenyl ketones 4 a: Potassium hydride (5.70 g of 35 % dispersion in oil, 50 mmol) was introduced into a Schlenk tube filled with argon. The mixture was washed three times with petroleum ether, and then the rest of the petroleum ether was evaporated under reduced pressure for 10 min.…”

Section: Resultsmentioning

confidence: 99%

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Selective Estrogen‐Receptor Modulators (SERMs) in the Cyclopentadienylrhenium Tricarbonyl Series: Synthesis and Biological Behaviour

et al. 2004

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A series of organometallic antiestrogens based on the OH-tamoxifen (OH-Tam) skeleton and bearing the (eta(5)-C(5)H(4))Re(I)(CO)(3) unit has been prepared by using McMurry coupling for the purpose of studying their biological behaviour. The cyclopentadienylrhenium tricarbonyl moiety is indeed stable in biological media, compact, lipophilic and easy to handle. Furthermore, this study allowed us to select the best candidates for subsequent use as radiopharmaceuticals either for imaging or therapy by using appropriate radionucleides, namely (99m)Tc and (188)Re. In these molecules the beta-phenyl group of OH-Tam has been replaced by the (eta(5)-C(5)H(4))Re(CO)(3) moiety, and the length of the dimethylamino side chain --O(CH(2))(n)N(CH(3))(2) was varied (n=2, 3, 4, 5 and 8). The compounds 7 a-7 e were obtained as mixtures of their Z and E isomers, which could be separated by semipreparative HPLC. Unlike their ferrocene homologues, the compounds do not isomerise in solution. Structural identification was carried out with NMR spectroscopy by using the HMBC and NOE techniques and was confirmed by the X-ray structural determination of (E)-7 a (n=2). These molecules were more lipophilic than OH-Tam (log P(o/w)=4.5-6.3) and they were all reasonably well recognized by the two forms of the estrogen receptor (ERalpha and ERbeta). For example, (Z)-7 b (n=3) has high relative binding affinity (RBA) values of 31 % for ERalpha and 16.8 % for ERbeta. The antiproliferative effects of two pairs of isomers, (Z)- and (E)-7 b (n=3) and (Z)- and (E)-7 d (n=5), were studied at a molarity of 1 microM on two breast-cancer cell lines, MCF7 (ERalpha positive) and MDA-MB231 (ERalpha negative). These molecules had an antiproliferative effect on MCF7 cells slightly higher than that of OH-Tam and no effect on MDA-MB231 cells. Thus, the antiproliferative effect observed on the MCF7 cells seemed essentially to be linked to an antiestrogenic effect. Molecular modelling studies have allowed us to rationalise these effects and select the best compounds for future development of a radioactive series.

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Section: Resultsmentioning

confidence: 99%

“…The reaction gives high yields of > 90 % at 95 8C in a H 2 O/dimethyl sulfoxide (DMSO) mixture in 3.5 h (Scheme 2). [44] Experimental Section General: Starting materials were synthesized by using standard Schlenk techniques under an argon atmosphere. Anhydrous THF and diethyl ether were distilled from sodium/benzophenone.…”

Section: Resultsmentioning

confidence: 99%

Selective Estrogen‐Receptor Modulators (SERMs) in the Cyclopentadienylrhenium Tricarbonyl Series: Synthesis and Biological Behaviour

et al. 2004

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“…[37,38] In designing this compound, we chose to functionalize the ferrocenyl group with a ketone, which has been shown to pro-mote double metal-ligand exchange reactions to yield other organometallic compounds, such as those containing 188 Re, 186 Re, or 99m Tc. [39,40] Molecular modeling experiments showed that the interaction of 5 with the crystal structure of the antiestrogenic conformation of ERa is highly thermodynamically favored, particularly due to the interaction with the ketone and the LBD residue Asp351, [38] and this was subsequently reflected in a high relative binding affinity (RBA) value for ERa of 14 %. This good receptor recognition, and the lability of the CpFe moiety, suggests that this compound could be a useful precursor in the development of ER-targeted radiopharmaceuticals or imaging agents.…”

Section: Cenyl (àOa C H T U N G T R E N N U N G (Ch 2 ) 2 C(o)a C H Tmentioning

confidence: 99%

Synthesis and Structure–Activity Relationships of Ferrocenyl Tamoxifen Derivatives with Modified Side Chains

Nguyen

Top

Pigeon

et al. 2008

Chemistry A European J

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We report here the synthesis and cell-proliferation properties of derivatives of the breast cancer drug tamoxifen, in which the -O(CH(2))(2)N(CH(3))(2) side chain, responsible for the drug's antiestrogenic properties, has been modified by a ferrocenyl moiety. We recently reported the diphenol compound 5, in which this amino chain had been replaced with an acyl-ferrocenyl (-O(CH(2))(2)C(O)[(eta(5)-C(5)H(4))FeCp]) group, and which showed antiproliferative effects against both the hormone-dependent MCF-7 and -independent MDA-MB-231 breast cancer cell lines. We now report the results of a structure-activity relationship (SAR) study, in which the lateral chain length has been varied, the ketone group has been omitted, and the number of phenol groups has been varied. Compounds 1-4, with a side chain lacking the carbonyl function (-O(CH(2))(n)[(eta(5)-C(5)H(4))FeCp], n = 1-4) and which show a decreasing affinity for ERalpha (ER = estrogen receptor) with increasing chain length, act as estrogens on MCF-7 cells, and mild cytotoxics on PC-3 prostate cancer cells, with IC(50) values around 10 microM. The two monophenolic derivatives of 2, 2 a and 2 b, which show a reduced affinity for ERalpha compared to 2, are also estrogenic, but are only slightly cytotoxic. Finally, we have reexamined compound 5 and discovered that its antiproliferative effect against the MCF-7 cell line does not arise from antiestrogenicity as we had originally suspected, but by means of a cytotoxic pathway. This compound is also sensitive to the number of phenol groups as cell death is diminished when one of the hydroxyl groups is omitted (5 a and 5 b). Molecular modeling studies of the ligand-ERalpha binding stability are broadly consistent with the experimental binding affinity results for compounds 2, 2 a, 2 b, 5, 5 a, and 5 b. Electrochemical experiments show that 1-4, 2 a, and 2 b are stable to oxidation on the electrochemical timescale, unlike 5, 5 a, and 5 b, and that cytotoxicity is related to less positive phenol oxidation potentials. The SAR study shows that the presence of a ketone group and two phenol groups is necessary for strong receptor binding and cytotoxic effects, and that all compounds are estrogenic, despite the presence of a bulky side chain.

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“…The estradiol derivative 55b had been synthesized previously by a four-step procedure via the lithiation of MOM-protected ethynylestradiol, followed by coupling with the Weinreb-amide derivative of ferrocene, and deprotection of the OH groups. 20 It is worth noting that the carbonylative Sonogashira reaction tolerates the tertiary alcohol functionality, and therefore protection of 17-OH groups is not necessary. Slow decomposition of ferrocenyl alkynyl ketones 54b and 55b was observed in solution.…”

Section: Page 206mentioning

confidence: 99%

Copper-catalyzed steroid reactions

Ibrahim‐Ouali¹,

Dumur²

2017

Arkivoc

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Direct Synthesis of Tricarbonyl(cyclopentadienyl)rhenium and Tricarbonyl(cyclopentadienyl)technetium Units from Ferrocenyl Moieties − Preparation of 17α‐Ethynylestradiol Derivatives Bearing a Tricarbonyl(cyclopentadienyl)technetium Group

Cited by 62 publications

References 20 publications

Selective Estrogen‐Receptor Modulators (SERMs) in the Cyclopentadienylrhenium Tricarbonyl Series: Synthesis and Biological Behaviour

Selective Estrogen‐Receptor Modulators (SERMs) in the Cyclopentadienylrhenium Tricarbonyl Series: Synthesis and Biological Behaviour

Synthesis and Structure–Activity Relationships of Ferrocenyl Tamoxifen Derivatives with Modified Side Chains

Copper-catalyzed steroid reactions

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