Design and Synthesis of Norendoxifen Analogues with Dual Aromatase Inhibitory and Estrogen Receptor Modulatory Activities

Both
selective estrogen receptor modulators and aromatase inhibitors
are widely used for the treatment of breast cancer. Compounds with
both aromatase inhibitory and estrogen receptor modulatory activities
could have special advantages for treatment of breast cancer. Our
previous efforts led to the discovery of norendoxifen as the first
compound with dual aromatase inhibitory and estrogen receptor binding
activities. To optimize its efficacy and aromatase selectivity versus
other cytochrome P450 enzymes, a series of structurally related norendoxifen
analogues were designed and synthesized. The most potent compound,
4′-hydroxynorendoxifen (10), displayed elevated
inhibitory potency against aromatase and enhanced affinity for estrogen
receptors when compared to norendoxifen. The selectivity of 10 for aromatase versus other cytochrome P450 enzymes was
also superior to norendoxifen. 4′-Hydroxynorendoxifen is therefore
an interesting lead for further development to obtain new anticancer
agents of potential value for the treatment of breast cancer.