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.
Methods: 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: 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 Zdiethyl
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.