Structural Modification of Natural Product Tanshinone I Leading to Discovery of Novel Nitrogen-Enriched Derivatives with Enhanced Anticancer Profile and Improved Drug-like Properties,Journal of Medicinal Chemistry

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Structural Modification of Natural Product Tanshinone I Leading to Discovery of Novel Nitrogen-Enriched Derivatives with Enhanced Anticancer Profile and Improved Drug-like Properties
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-01-19 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01259
Chunyong Ding _{1,

2} , Qianting Tian _{2,

3} , Jie Li _{1,

4} , Mingkun Jiao ₁ , Shanshan Song ₃ , Yingqing Wang _{2,

3} , Zehong Miao _{2,

3} , Ao Zhang _{1,

2,

3,

4}

Affiliation

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_1/2 = 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.

中文翻译：

天然产物丹参酮I的结构修饰导致发现新型的富含氮的衍生物，具有增强的抗癌特性和改进的类药物特性

天然产物丹参酮I（1）用于癌症治疗的临床开发受到其效力弱和药物样性质差的阻碍。在本文中，对1进行了更广泛和系统的结构修饰，以生成四个系列的新丹参酮衍生物。其中，内酰胺衍生物22h对KB和耐药性KB / VCR癌细胞显示出最有效的抗增殖活性，其效力比1高约13至49倍。化合物22h具有明显改善的类药物特性，包括水溶性（15.7 mg / mL），肝微粒体的代谢稳定性和PK特性（T _1/2 = 2.58 h; F= 21％）相比，1。初步的机理研究表明，22h通过激活caspase-3 / -7至少部分地显着诱导了HCT116细胞的凋亡。更重要的是，以10 mg / kg的剂量给药22h可以显着抑制体内HCT116异种移植物的肿瘤生长，而不会显着降低测试裸鼠的体重。

更新日期：2018-01-19

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