The New Non-steroidal Aromatase Inhibitor Design, Synthesis And Activity Assay

Breast cancer, as the most frequent cancer among women worldwide, is a seriously life-threatening disease in women. Estrogens play a critical role in the development and growth of breast tumors, thus, estrogen deprivation is a key therapeutic approach for breast cancer. Aromatase, otherwise called CYP19, is a rate-limiting enzyme in the biosynthesis of estrogens. Inhibition of aromatase and deprivation of estrogens can inhibit the growth of breast cancer cells and extend the patients’lifespan. Nowadays, Aromatase inhibitors(AIs) have become the first-line drugs for hormonally-responsive breast cancer in postmenopausal women. However, with the wide application of AIs in clinical practice, some problems are gradually shown up such as non-response in many patients, resistance to AI treatment and inhibition of some CYP450enzymes. Hence, there is a need to discover and develop the new generation of AIs to overcome these defects.In this study, with the help of molecular docking we designed and synthesized a novel series of non-steroidal AIs based on a2-phenylindole scaffold. Aromatase inhibitory activities of all compounds were evaluated by ELISA and several compounds are more powerful than the positive control(letrozole) that is one of the most potent AIs. AIs based on a2-phenylindole scaffold have never been reported by now. The discovery of new highly potent compounds based on a novel scaffold will help to discover the next generation of AIs.