Zhang Xiaojie, Guo Shanchun, Chen Chengsheng, Perez German Ruiz, Zhang Changde, Patanapongpibul Manee, Subrahmanyam Nithya, Wang Rubing, Keith Joshua, Chen Guanglin, Dong Yan, Zhang Qiang, Zhong Qiu, Zheng Shilong, Wang Guangdi, Chen Qiao-Hong
Department of Chemistry, California State University, Fresno, 2555 E. San Ramon Avenue, M/S SB70, Fresno, CA 93740, USA.
Department of Chemistry, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA; RCMI Cancer Research Center, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA.
Eur J Med Chem. 2017 Sep 8;137:263-279. doi: 10.1016/j.ejmech.2017.05.062. Epub 2017 Jun 3.
To further engineer dienones with optimal combinations of potency and bioavailability, thirty-four asymmetric 1,5-diarylpenta-1,4-dien-3-ones (25-58) have been designed and synthesized for the evaluation of their in vitro anti-proliferative activity in three human prostate cancer cell lines and one non-neoplastic prostate epithelial cell line. All these asymmetric dienones are sufficiently more potent than curcumin and their corresponding symmetric counterparts. The optimal dienone 58, with IC values in the range of 0.03-0.12 μM, is 636-, 219-, and 454-fold more potent than curcumin in three prostate cancer cell models. Dienones 28 and 49 emerged as the most promising asymmetric dienones that warrant further preclinical studies. The two lead compounds demonstrated substantially improved potency in cell models and superior bioavailability in rats, while exhibiting no acute toxicity in the animals at the dose of 10 mg/kg. Dienones 28 and 46 can induce PC-3 cell cycle regulation at the G/G phase. However, dienone 28 induces PC-3 cell death in a different way from 46 even though they share the same scaffold, indicating that terminal heteroaromatic rings are critical to the action of mechanism for each specific dienone.
为了进一步构建具有最佳效力和生物利用度组合的二烯酮，设计并合成了34种不对称的1,5 - 二芳基戊 - 1,4 - 二烯 - 3 - 酮（25 - 58），以评估它们在三种人前列腺癌细胞系和一种非肿瘤性前列腺上皮细胞系中的体外抗增殖活性。所有这些不对称二烯酮的效力均比姜黄素及其相应的对称类似物强得多。最佳二烯酮58的IC值在0.03 - 0.12 μM范围内，在三种前列腺癌细胞模型中比姜黄素的效力分别高636倍、219倍和454倍。二烯酮28和49成为最有前景的不对称二烯酮，值得进一步进行临床前研究。这两种先导化合物在细胞模型中表现出显著提高的效力，在大鼠中具有优异的生物利用度，同时在10 mg/kg剂量下对动物无急性毒性。二烯酮28和46可在G/G期诱导PC - 3细胞周期调控。然而，尽管二烯酮28和46具有相同的骨架，但它们诱导PC - 3细胞死亡的方式不同，这表明末端杂芳环对于每种特定二烯酮的作用机制至关重要。
