Background: Tamoxifen (TAM), a non-steroidal antiestrogen, constitutes the endocrine treatment of choice
against breast cancer. Since its inauguration, substantial effort has been devoted towards the design and synthesis of TAM’s
analogues aiming to improve its bioactivity and reveal their structure-activity relationship.
Objective: One of the most studied synthetic features of TAM’s structure is the ether side chain, which is strongly related to
its positioning into the active site of the Estrogen Receptors (ERα and ERβ). Herein, we present the application of a straightforward route for the efficient synthesis of selected novel carbamoyloxy analogues of TAM and the evaluation of their respective binding affinities to the Estrogen Receptors α and β.
Method: A one-pot reaction was applied for the construction of TAM’s triarylethylene core moiety, which subsequently was
derivatized to provide efficiently the target carbamoyloxy analogues of TAM. The Z and E isomers of the latter were separated using RP-HPLC-UV and their binding affinities to ERα and ERβ were measured.
Results and Discussion: Among all compounds synthesized, the dimethyl derivative was determined as the most potent for
both receptors, displaying binding affinity values comparable to TAM, though the Z-diethyl analogue maintained substantial
affinity to both ERs. The aforementioned results were further studied by theoretical calculations and molecular modelling to
delineate a concordance among calculations and biological activity.
Conclusion: Approach applied herein permitted the extraction of a useful structure-activity relationship correlation pattern
highlighting the importance of a chemically stabilized tamoxifen side chain.