| Item type: | Article | ||||||||||||||||||||||
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| Journal or Publication Title: | Archiv der Pharmazie | ||||||||||||||||||||||
| Volume: | 334 | ||||||||||||||||||||||
| Number of Issue or Book Chapter: | 4 | ||||||||||||||||||||||
| Page Range: | pp. 125-137 | ||||||||||||||||||||||
| Date: | 2001 | ||||||||||||||||||||||
| Institutions: | Chemistry and Pharmacy > Institute of Pharmacy > Alumni or Retired Professors > Prof. Schönenberger Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) | ||||||||||||||||||||||
| Projects (Historical): | SFB 234 | ||||||||||||||||||||||
| Identification Number: |
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| Classification: |
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| Keywords: | 1-(2,6-Dichloro-4-hydroxyphenyl)-2-phenylethanes; biological response modifiers; synthesis; estrogen receptor affinity; estrogenic/antiestrogenic activity | ||||||||||||||||||||||
| Dewey Decimal Classification: | 500 Science > 570 Life sciences 500 Science > 540 Chemistry & allied sciences | ||||||||||||||||||||||
| Status: | Published | ||||||||||||||||||||||
| Refereed: | Yes, this version has been refereed | ||||||||||||||||||||||
| Created at the University of Regensburg: | Yes | ||||||||||||||||||||||
| Item ID: | 4837 |
Abstract
[meso-1,2-Bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]platinum(II) complexes (meso-1-PtLL'; L,L' = Cl or L = H2O and L' = OSO3) are highly effective towards hormone-sensitive, rodent breast cancers due to their significant estrogenic potencies. Their antitumor activities are caused by modification of the immune response. The pharmacophor of these compounds, the ...
Abstract
[meso-1,2-Bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]platinum(II) complexes (meso-1-PtLL'; L,L' = Cl or L = H2O and L' = OSO3) are highly effective towards hormone-sensitive, rodent breast cancers due to their significant estrogenic potencies. Their antitumor activities are caused by modification of the immune response. The pharmacophor of these compounds, the 1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethane (23H), was used as the lead structure in a structure-activity study with the goal of finding new biological response modifiers for the therapy of breast cancer. As intermediates for the synthesis of the 23H derivatives, the CH3O-substituted stilbenes 12E/12Z-16E/16Z were prepared by reaction of the related benzyltriphenylphosphonium halides with 2,6-dichloro-4-methoxybenzaldehyde by the method of Wittig/Campbell and Donald, respectively. Separation of the E/Z-mixtures was performed by fractional crystallization and/or column chromatography. The E-1,2-bis(2,6-dichloro-4-methoxyphenyl)ethene (17E) was obtained by reductive coupling of 2,6-dichloro-4-methoxybenzaldehyde with TiCl4/Zn according to the method of Mukaiyama. Illumination of the solution of 17E in benzene with UV light resulted in an E/Z-isomerization. Compound 17Z could be isolated from this mixture. The CH3O-substituted stilbenes were transformed into their 1,2-diphenylethanes (12H-17H) by catalytic hydrogenation of the C1=C2 double bond. Ether cleavage of the compounds was performed with BBr3. In the estrogen receptor binding assay all OH-substituted 1,2-diphenylethanes showed affinity to the estrogen receptor, which was about two orders of magnitude lower than that of 17 beta-estradiol. In the uterus weight test on the immature mouse 1,2-diphenylethanes with 4-substituted OH groups proved to be "true" estrogens (19H: 2-F/4-OH; 20H: 2-Cl/4-OH; 23H: 2,6-Cl2/4-OH), while those with a 3-substituted OH group in the 2-phenyl ring showed the properties of a "partial" estrogen (18H: 3-OH) or of an "impeded" estrogen (21H: 2-Cl/3-OH; 22H: 2-Cl/5-OH). The latter also showed significant additional antiestrogenic activity. The related E-stilbenes mostly exhibit similar hormonal activities. As a rule, the replacement of the OH groups by the CH3O groups and the change from the E- to the Z-configuration led to a reduction of the estrogenic potencies. Several of the 1-(2,6-dichloro-4-methoxyphenyl)-2-phenylethenes (12E: 3-OCH3; 12Z: 3-OCH3; 15E: 2-Cl/3-OCH3; 15Z: 2-Cl/3-OCH3; 16E: 2-Cl/5-OCH3) produced antiestrogenic effects in the uterus weight test. It is supposed that those new 1-(2,6-dichloro-4-hydroxyphenyl)-2-phenylethanes endowed with marked estrogenic properties are also active as biological response modifiers in animals bearing hormone-sensitive breast cancer. The antiestrogenic derivatives presumably inhibit the breast cancer development by competing with tumor growth stimulating endogenous estrogens for the binding to the receptor. This is to be confirmed in a further study.
Metadata last modified: 29 Sep 2021 07:28
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