Identification of new triarylethylene oxyalkanoic acid analogues as bone selective estrogen mimetics

Rubin, Valeria Norma; Ruenitz, Peter C.; Boudinot, F. Douglas; Boyd, Jason

doi:10.1016/s0968-0896(01)00038-4

Cited by 23 publications

(15 citation statements)

References 43 publications

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“…Piperidine-substituted amides 14e and 14g proved to be the most active, together with 14h (IC 50 = 0.48, 1.05, and 0.70 μM, respectively). Oxyacetic analogues of 2a had been reported to act as estrogen antagonists in MCF-7 cells. , In series III, compounds 19a and 19b , containing a 4-oxyacetic acid substituent in place of the acrylic acid in 11b and 11c , along with compound 22 , did not have antiproliferative activity at concentrations up to 20 μM (as was observed for the oxyacetic analogue of 2a ).…”

Section: X-ray Crystallographymentioning

confidence: 82%

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Lead Optimization of Benzoxepin-Type Selective Estrogen Receptor (ER) Modulators and Downregulators with Subtype-Specific ERα and ERβ Activity

et al. 2017

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Estrogen receptor ERis an important target for the design of drugs such as tamoxifen (2a) and fulvestrant (5). Three series of ER-ligands based on the benzoxepin scaffold structure were 2 synthesised -series I containing an acrylic acid, series II with an acrylamide and series III with a saturated carboxylic acid substituent. These compounds were shown to be high affinity ligands for the ER with nanomolar IC50 binding values. Series I acrylic acid ligands were generally ER selective. In particular, compound 13e featuring a phenylpenta-2,4-dienoic acid substituent was shown to be antiproliferative and downregulated ERand ER expression in MCF-7 breast cancer cells. Interestingly, from series III, the phenoxybutyric acid derivative compound 22 was not antiproliferative and selectively downregulated ER. A docking study of the benzoxepin ligands was undertaken. Compound 13e is a promising lead for development as a clinically relevant SERD, whilst compound 22 will be a useful experimental probe for helping to elucidate the role of ERβ in cancer cells.

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Section: X-ray Crystallographymentioning

confidence: 82%

“…Triarylethylene oxyalkanoic acid modifications of 2a have been reported as bone selective estrogen mimetics . Of our compounds in Series III, 19a and 19b had high IC 50 binding values indicative of poor affinity for both ERα and ERβ, perhaps explaining their poor antiproliferative activity.…”

Section: X-ray Crystallographymentioning

confidence: 82%

Lead Optimization of Benzoxepin-Type Selective Estrogen Receptor (ER) Modulators and Downregulators with Subtype-Specific ERα and ERβ Activity

et al. 2017

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“…[12][13][14] The substitution of the amino side chain by carboxylic acids, such as in GW5638 and GW7604, has been the only important functional modification of the OH À Tam side chain yielding strong antiestrogenic activity in the breast to date. [15][16][17][18][19] The covalent tethering of ferrocene to the OH À Tam backbone has given rise to the "hydroxyferrocifens" and some active ferrocenyl phenols. [20][21][22][23][24][25][26] The former, created by the replacement of the b phenyl group of OHÀTam with ferrocene, were designed to combine the antiestrogenicity of the OHÀTam scaffold with the cytotoxicity of a ferrocenyl group, [27,28] resulting in compounds efficacious both on hormone-dependent and -independent breast cancer cells in vitro.…”

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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“…Higher yields are obtained from the mixed coupling reaction when one of the reactants is a diaryl ketone, because the latter undergoes a rapid twoelectron reduction and the resulting dianion then nucleophilically attacks the other ketone before it can be reduced; thus, 62 was isolated in 77% yield [80]. Such a reaction constitutes a classical route to the antitumor agent tamoxifen 63 [81] and many of its derivatives [82][83][84][85][86][87][88][89], including 64 and 65, and organometallic analogues such as 66 and 67 [90][91][92][93] (Figure 6.13).…”

Section: Intermolecular Cross-coupling Reactionsmentioning

confidence: 99%

The McMurry Coupling and Related Reactions

Ephritikhine

Villiers

2003

Modern Carbonyl Olefination

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Identification of new triarylethylene oxyalkanoic acid analogues as bone selective estrogen mimetics

Cited by 23 publications

References 43 publications

Lead Optimization of Benzoxepin-Type Selective Estrogen Receptor (ER) Modulators and Downregulators with Subtype-Specific ERα and ERβ Activity

Lead Optimization of Benzoxepin-Type Selective Estrogen Receptor (ER) Modulators and Downregulators with Subtype-Specific ERα and ERβ Activity

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

The McMurry Coupling and Related Reactions

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