Synthesis and evaluation of 7-(3-aminopropyloxy)-substituted flavone analogue as a topoisomerase IIα catalytic inhibitor and its sensitizing effect to enzalutamide in castration-resistant prostate cancer cells

Abstract

Prostate cancer patients primarily receive androgen receptor (AR)-targeted drugs as a primary treatment option because prostate cancer is associated with highly activated AR signaling. AR amplification made prostate cancer cells viable under treatment of AR-targeted therapy, leading to castration resistance. AR amplification was more common in enzalutamide-resistant patients. As a strategy to overcome castration resistance and to improve the efficacy of enzalutamide, second-generation nonsteroidal antiandrogen drugs for castration-resistant prostate cancer (CRPC) including topoisomerase II (topo II) poisons such as etoposide and mitoxantrone, have been administered in combination with enzalutamide. In the present study, it was confirmed that amplification of topo IIα, but not I and IIβ, was directly and proportionally associated with poor clinical outcome of Prostate cancer. Among a novel series of newly designed and synthesized 7-(3-aminopropyloxy)-substituted flavone analogues, compound 6, the most potent derivative, was further characterized and identified as a topo IIα catalytic inhibitor that intercalates into DNA and binds to the DNA minor groove with better efficacy and less genotoxicity than etoposide, a topo II poison. Compound 6 showed remarkable efficacy in inhibiting AR-negative CRPC cell growth and sensitizing activity to enzalutamide in AR-positive CRPC cells, thus confirming the potential of topo IIα catalytic inhibitor to overcome resistance to androgen deprivation therapy.