Design, synthesis and activity of BBI608 derivatives targeting on stem cells

作者：Zhou, Qifan; Peng, Chen; Du, Fangyu; Zhou, Linbo; Shi, Yajie; Du, Yang; Liu, Dongdong; Sun, Wenjiao; Zhang, Meixia^*; Chen, Guoliang^*

来源：European Journal of Medicinal Chemistry, 2018, 151: 39-50.

DOI：10.1016/j.ejmech.2018.03.054

• BBI608 derivatives
• STAT3 inhibitors
• Tumor stem cells
• Antitumor activity

STAT3 plays a vital role in maintaining the self-renewal of tumor stem cells. BBI608, a small molecule identified by its ability to inhibit gene transcription driven by STAT3 and cancer stemness properties, can inhibit stemness gene expression and kill stemness-high cancer cells isolated from a variety of cancer types. In order to improve the pharmacokinetic properties of BBI608 and the antitumor activity, a series of BBI608 derivatives were designed and synthesized here. Most of these compounds were more potent than BBI608 on HepG2 cells, compound LD-8 had the most potent inhibitory activity among them and was 5.4-fold more potent than BBI608 (IC50 = 11.2 mu M), but had considerable activity on normal liver cells L-02. Compounds LD-17 (IC50 = 3.5 mu M) and LD-19 (10(50) = 2.9 mu M) were found to possess significant inhibitory activities and good selectivity. The results showed that compound LD-19 was worthy to investigate further as a lead compound according to its potent inhibitory activity, ideal ClogP value and better water solubility.

• 出版日期2018-5-10
• 单位沈阳药科大学; 中国医科大学