Bicyclic Chalcones as Mitotic Inhibitors for Overcoming Androgen Receptor-Independent and Multidrug-Resistant Prostate Cancer

• Published in: ACS omega 2021-02, Vol.6 (7), p.4842-4849
• Main Authors: Saito, Yohei, Mizokami, Atsushi, Maeda, Sayaka, Takahashi, Kyoko, Izumi, Kouji, Goto, Masuo, Nakagawa-Goto, Kyoko
• Format: Article
• Language: English
• ISSN: 2470-1343; 2470-1343
• DOI: 10.1021/acsomega.0c05822

To improve the biological effects of the lead compound 5′-chloro-2,2′-dihydroxychalcone (Cl-DHC), bicyclic aromatic chalcones were designed, synthesized, and evaluated against androgen-independent prostate cancer (PCa) DU145 and PC-3 cell proliferation. Newly synthesized bi-naphthyl derivatives 2 and 3 suppressed the proliferation of these two cell lines and also taxane-resistant prostate cancer cell lines at a submicromolar level. The two compounds were 4–18 times more potent than the parent molecule Cl-DHC. A structure–activity relationship analysis revealed that the orientation of the 10π-electron ring-A naphthalene had a significant effect on the activity. Mode-of-action studies in KB-VIN cells demonstrated that 2 and 3 arrested cells in mitosis at prometaphase and metaphase followed by induction of sub-G1 accumulation. Thus, 2 and 3 have good potential as leads for continued development of treatments for cancers especially for not only androgen-independent PCa but also multidrug-resistant tumors.