Journal : Bioorg Med Chem
Title : Drug repurposing and rediscovery: Design, synthesis and preliminary biological evaluation of 1-arylamino-3-aryloxypropan-2-ols as anti-melanoma agents.
Year : 2020
Volume : 28
Issue : 9
First Page : 115404
Last Page : 115404
Authors : Chang Q, Long J, Hu L, Chen Z, Li Q, Hu G.
Abstract : Malignant melanoma (MM) presents as the highest morbidity and mortality type in skin cancer. Herein, inspired by the previously reported anti-melanoma effect of propranolol, a widely applied β adrenergic receptor antagonist as cardiovascular drug, we set out to exploit its potential as anti-melanoma therapy based on the drug repurposing strategy. Structural optimization of propranolol yielded 5m, which exhibits dramatically improved potency on human melanoma cell growth (1.98-3.70 μM), compared to propranolol (59.5-75.8 μM). Further investigation demonstrated that 5m could inhibit colony formation of melanoma cell line (completely abolished at 2 μM for 5m, partially inhibited at 50 μM for propranolol), induce cell apoptosis and cell cycle arrest in the G<sub>2</sub>/M phase (both observed at 1 μM). Preliminary mechanism study indicated that 5m could disrupt the cellular microtubule network, which suggested tubulin as a potential target. Docking study provided a structural insight into the interaction between 5m and tubulin. In summary, our study presents a drug repurposing case that redirects a cardiovascular agent to an anti-melanoma agent.
