Saito Yohei, Mizokami Atsushi, Maeda Sayaka, Takahashi Kyoko, Izumi Kouji, Goto Masuo, Nakagawa-Goto Kyoko
School of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Science, Kanazawa University, Kanazawa 920-1192, Japan.
Department of Integrative Cancer Therapy and Urology, School of Medical Sciences, Kanazawa University, Kanazawa 920-8641, Japan.
ACS Omega. 2021 Feb 9;6(7):4842-4849. doi: 10.1021/acsomega.0c05822. eCollection 2021 Feb 23.
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 and 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 and arrested cells in mitosis at prometaphase and metaphase followed by induction of sub-G1 accumulation. Thus, and have good potential as leads for continued development of treatments for cancers especially for not only androgen-independent PCa but also multidrug-resistant tumors.
为提高先导化合物5'-氯-2,2'-二羟基查耳酮（Cl-DHC）的生物学效应，设计、合成了双环芳族查耳酮，并评估其对雄激素非依赖性前列腺癌（PCa）DU145和PC-3细胞增殖的影响。新合成的双萘基衍生物 和 在亚微摩尔水平上抑制了这两种细胞系以及紫杉烷耐药前列腺癌细胞系的增殖。这两种化合物的活性比母体分子Cl-DHC强4-18倍。构效关系分析表明，10π电子环A萘的取向对活性有显著影响。在KB-VIN细胞中的作用机制研究表明， 和 使细胞在有丝分裂的前中期和中期停滞，随后诱导亚G1期积累。因此， 和 作为癌症治疗尤其是雄激素非依赖性PCa以及多药耐药肿瘤治疗持续开发的先导物具有良好的潜力。
