CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
University of Chinese Academy of Sciences , Beijing 100049, China.
J Med Chem. 2018 Feb 8;61(3):760-776. doi: 10.1021/acs.jmedchem.7b01259. Epub 2018 Jan 19.
The clinical development of natural product tanshinone I (1) for cancer therapy is hampered by its weak potency and poor drug-like properties. Herein, a more broad and systemic structural modification on 1 was conducted to generate four series of new tanshinone derivatives. Among them, the lactam derivative 22h demonstrated the most potent antiproliferative activity against KB and drug-resistant KB/VCR cancer cells, which are approximately 13- to 49-fold more potent than 1. Compound 22h possesses significantly improved drug-like properties including aqueous solubility (15.7 mg/mL), metabolic stability of liver microsomes, and PK characters (T = 2.58 h; F = 21%) when compared to 1. Preliminary mechanism studies showed that 22h significantly induced apoptosis of HCT116 cells, at least partially, through activation of caspase-3/-7. More importantly, administration of 22h at 10 mg/kg significantly suppressed the tumor growth of HCT116 xenograft in vivo without significant loss of body weight of the tested nude mice.
天然产物丹参酮 I（1）在癌症治疗中的临床应用受到其效力弱和药物样性质差的限制。在此，对 1 进行了更广泛和系统的结构修饰，生成了四个系列的新型丹参酮衍生物。其中，内酰胺衍生物 22h 对 KB 和耐药 KB/VCR 癌细胞的增殖表现出最强的抑制活性，其效力约比 1 强 13 至 49 倍。与 1 相比，化合物 22h 具有明显改善的药物样性质，包括水溶解度（15.7mg/mL）、肝微粒体的代谢稳定性和 PK 特征（T = 2.58h；F = 21%）。初步的机制研究表明，22h 通过激活 caspase-3/-7，显著诱导 HCT116 细胞凋亡，至少部分是这样。更重要的是，以 10mg/kg 的剂量给予 22h 可显著抑制 HCT116 异种移植瘤在体内的生长，而接受测试的裸鼠体重没有明显减轻。
