Flexible estrogen receptor modulators: synthesis, biochemistry and molecular modeling studies for...

Selective estrogen receptor modulators (SERMs) such as tamoxifen and toremifene are clinically useful drugs in the endocrine treatment of estrogen receptor positive breast cancer while raloxifene is an effective intervention for osteoporosis. In an ongoing SERM discovery programme we now report the synthesis of a series of 3-benzyl-4,6-diarylhex-3-enes and 3,4,6-triarylhex-3-enes containing an extended flexible core structure. In these novel structures, the ethylene group acts as a flexible spacing group linking the aryl Ring A or Ring B with the core alkene group. In the benzyl-4,6-diarylhex-3-ene series an additional methylene group is inserted as a spacing group between the aryl ring C and the ethylene core group. These products demonstrated antiproliferative activity against the MCF-7 human breast cancer cell line. The alkene compounds were also shown to have binding affinity for the estrogen receptor alpha (IC50 values for the most active compounds in the range 0.110-0.293 microM) together with selectivity for ER alpha/beta. The compounds demonstrated antiestrogenic activity in Ishikawa cells with low estrogenic stimulation. The structure-activity relationships for the active ligands were further explored in a computational study where docked structures of the active compounds were compared with the X-ray crystal structures for the complexes of ER alpha with 4-hydroxytamoxifen and ER beta with raloxifene. The alignment of the aromatic rings B and C of the compounds within the ligand binding domain could then be correlated with their observed ER alpha/beta selectivity.