Chen Xiang, Gan Yong Jun, Yu Yu, Zhang Yuan
Research Laboratory of Pharmaceutical Chemistry School of Pharmacy, Chongqing Medical University Chongqing People's Republic of China 400016
Experimental Teaching Center, Chongqing Medical University Chongqing People's Republic of China 401331
RSC Adv. 2018 Jul 24;8(47):26528-26537. doi: 10.1039/c8ra04152k.
The current optimization of tetrazanbigen (TNBG) on the C-ring provided a series of new sterol derivatives 2a-2n. All new synthesized compounds were screened for their anti-proliferation activities against five human cancer cell lines (HepG2, QGY-7701, SMMC-7721, A-431 and NCI-H23 cell lines) . Among them, 2a, 2b, 2c, 2m and 2n exhibited high anti-proliferation activities on SMMC-7721, and their IC values approach that of the positive control drug cisplatin. Compound 2a not only showed strong anti-proliferation activities against QGY-7701 and HepG2 cell lines, with IC values (IC: 6.81 ± 0.24 μM, 7.69 ± 0.87 μM) better than that of cisplatin (IC: 8.75 μM, 18.89 ± 2.01 μM), but also exhibited good aqueous solubility (0.15-15 mg mL at pH 7.4 and 2.0). On the most sensitive QGY-7701 cell line, Oil red O staining and western blot analysis were performed. The results suggested that 2a can inhibit the growth of cancer cells possibly by interfering with the lipid metabolism balance of tumor cells, resulting in lipid accumulation and cell apoptosis (lipotoxicity). Moreover, after being treated with 2a, lipid accumulation of QGY-7701 cell was increased in a time and dose dependent manner. Based on these promising results, 2a was selected for drug formulation and further pre-clinical development.
目前对四嗪苯醌（TNBG）C环的优化得到了一系列新的甾醇衍生物2a - 2n。对所有新合成的化合物针对五种人类癌细胞系（HepG2、QGY - 7701、SMMC - 7721、A - 431和NCI - H23细胞系）进行了抗增殖活性筛选。其中，2a、2b、2c、2m和2n对SMMC - 7721表现出高抗增殖活性，其IC值接近阳性对照药物顺铂。化合物2a不仅对QGY - 7701和HepG2细胞系表现出强抗增殖活性，IC值（IC：6.81±0.24 μM，7.69±0.87 μM）优于顺铂（IC：8.75 μM，18.89±2.01 μM），而且还表现出良好的水溶性（在pH 7.4和2.0时为0.15 - 15 mg/mL）。在最敏感的QGY - 7701细胞系上进行了油红O染色和蛋白质印迹分析。结果表明，2a可能通过干扰肿瘤细胞的脂质代谢平衡来抑制癌细胞生长，导致脂质积累和细胞凋亡（脂毒性）。此外，用2a处理后，QGY - 7701细胞的脂质积累呈时间和剂量依赖性增加。基于这些有前景的结果，选择2a进行药物制剂开发和进一步的临床前研究。
