Abstract
Tamoxifen (TAM) is widely used in the treatment of hormone dependent breast cancer. TAM itself acts as prodrug, which is activated by hydroxylation of the 4-position of the A-ring. The resulting 4-hydroxytamoxifen (4-OHT) possesses an 8 times higher binding affinity to the estrogen receptor (ER) and acts as pure anti-estrogen in hormone dependent tumor cells. The dimethylaminoethoxy side chain in 4-position of the B-ring seems to be crucial for the anti-estrogenic activity.
As it could be previously shown a series of O-acyl triarylalkene derivatives possessed weak but significant antagonistic effects, without bearing a basic side chain. Therefore in this work the necessicity of a basic side chain for the antagonistic effects of triarylalkenes was examined on molecular level.
According to this 1,1-Bis(4-hydroxyphenyl)-2-phenylalkenes (BisOHR), 1,1,2-Tris(4-hydroxyphenyl)alkenes (TrisOHR), 1-(3-Fluor-4-hydroxyphenyl)-1,2-bis(4-hydroxyphenyl)alkenes (FTrisOHR) and the corresponding O-methylethers with different C2-alkyl side chains were synthesized. Additionally BisOHPr and TrisOHPr derivatives with different functional groups at the alkyl side chain were synthesized. Receptor binding affinity, agonistic and antagonistic properties on the MCF-7-2a hormone dependent breast cancer cell line and the cytotoxic properties were examined. Receptor binding affinity and antagonistic properties were influenced by the length and the functional groups at the end of the side chain at C2. The most active compounds BisOHEt, TrisOHEt and FTrisOHBu possessed similar antagonistic properties on molecular level as 4-OHT.
These strong antagonistic effects cannot be mediated by the mode of action that is known for 4-OHT, as the examined compounds do not bear a basic side chain. It might rather be assumed that the antagonistic properties are exerted by a mode of action termed &rdquo passive &rdquo antagonism which was proposed recently for a tetrahydrochrysene derivative.
The cytotoxic properties could not be correlated with the length of the C2-alkyl side chain. The most active compounds were the O-methylated amines BisOMePrNH2 and TrisOMePrNH2 which showed even cytocidal effects on MCF-7 cells.
Furthermore investigations on the fluorescence labelling of ER-ligands were carried out. To achieve this goal conjugation of a triarylalkene with a fluorescent probe seemed the most suitable method. Two positions of the triarylalkene scaffold were chosen for conjugation by overlay with E2. Regarding an application of the conjugates in fluorescence correlation spectroscopy the triarylalkenes were connected with rhodamine b by means of a hexyl spacer. The resulting compounds 27 and 33Z still require optimisation according to ER-affinity and fluorescence characteristics in view of their future application. |
