- Estrogenic activity of bis(4-hydroxyphenyl)methanes with cyclic hydrophobic structure
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Monoalkylated bis(4-hydroxyphenyl)methanes (e.g., 1) are reported to show weak binding affinity for estrogen receptor (ER). We hypothesized that introduction of appropriately located hydrophobic substituents in these compounds would increase the binding affinity. Indeed, we found that bis(4-hydroxyphenyl)methane bearing a 3,3-dimethylcyclohexyl group (7) shows potent ERα binding affinity, comparable to that of estradiol. Bulkier substituents could be introduced at the 3,3-position without decreasing the affinity. However, the position of the substituents was critical: the 4,4-dimethylcyclohexyl derivative (2) showed very weak binding affinity. The compounds with high ER-binding affinity showed predominantly agonistic activity, together with weak antagonistic activity at high concentration, in cell proliferation assay with human breast cancer cell line MCF-7. Further structure-function studies of these compounds and their derivatives might lead to the development of more selective and potent estrogen receptor modulators.
- Kojima, Tomohiro,Ogawa, Takumi,Kitao, Souichiro,Sato, Manabu,Oda, Akifumi,Ohta, Kiminori,Endo, Yasuyuki
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p. 6900 - 6911
(2015/11/11)
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- Cytotoxicity and antiestrogenicity of a novel series of basic diphenylethylenes
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On the premise that it is necessary to develop antiestrogens with a higher cytotoxic component in order to reduce the risks of the development of heterogeneous malignant cell populations in breast cancer, we studied a novel series of basic diphenylethylenes, for the most part devoid of estrogenic activity, with low antiestrogenicity but much enhanced cytotoxicity compared to the reference drug tamoxifen. The main structural features associated with cytotoxicity were E isomery, substituents of five to eight carbons on the ethylene bond, and dibasicity.
- Gilbert, Jacques,Fuentes, Maryse,Ojasoo, Tiiu,Doré, Jean-Christophe,Pons, Michel
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p. 1104 - 1111
(2007/10/03)
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- Gem-dichlorocyclopropanes as antitumor agents
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Gem-Dichlorocyclopropanes (Analog II derivatives) which demonstrate antiproliferative activity toward MCF-7 cells, in vitro and are generally not reversed by estradiol or having intrinsic estrogenicity (except the hydroxyphenyl derivative Compound 30). In general the cyclopropane compounds have the formula: STR1 or any pharmaceutically acceptable salt thereof. X is selected from a group consisting of hydrogen and halogen atoms. The group R1 may be a hydrogen atom, an alkyl group, an acyl group, or an arylalkyl group. The group R2 may be a hydrogen atom, an unsubstituted aryl group or a substituted aryl group. The group R3 may be a hydrogen atom, an alkyl group, a cycloalkyl group, a substituted aryl group or an unsubstituted aryl group. The group R4 may be a hydrogen atom, an unsubstituted aryl group or a substituted aryl group. The R4 is absent when R3 is a cycloalkyl group having a first position carbon and a terminal position carbon bonded to the same carbon of the cyclopropane. Further, no more than any two of R2, R3 and R4 has an aryl group.
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