Gao Xiang, Li Jia, Wang Mingying, Xu Shengtao, Liu Weiwei, Zang Linghe, Li Zhanlin, Hua Huiming, Xu Jinyi, Li Dahong
Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China.
Department of Medicinal Chemistry and State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China.
Eur J Med Chem. 2018 Feb 25;146:588-598. doi: 10.1016/j.ejmech.2018.01.069. Epub 2018 Feb 4.
Natural derived enmein-type diterpenoids exert cytotoxicity against a wide range of human cancer cells. Yet their medicinal applications are hindered by insufficient potency for chemotherapy. Hence, a series of novel enmein-type diterpenoid hybrids coupled with nitrogen mustards were designed and synthesized to increase antitumor efficacy while reducing systemic toxicity. Most conjugates exhibited stronger antiproliferative activities than parent diterpenoids and nitrogen mustards, especially for multidrug-resistant tumor cell line Bel-7402/5-FU. Among them, compound E2 showed the most potent inhibitory activities in human leukemia HL-60 cells, human prostate cancer PC-3 cells, human liver cancer Bel-7402 cells and drug-resistant human liver cancer Bel-7402/5-FU cells with IC values of 7.83 μM, 3.97 μM, 0.77 μM and 2.07 μM, respectively. Additionally, high selectivity with selectivity index over 130 was also observed from cytotoxic evaluation between L-02 human normal liver cells and Bel-7402 malignant liver cells. Further studies on mechanism of action indicated that E2 induced both apoptosis and G1 phase cell cycle arrest in Bel-7402 hepatoma cells. Moreover, the dysfunction in mitochondrial pathway was also involved in E2 initiated apoptotic activation, which entailed the loss of mitochondrial membrane potential followed by upregulating the bax/bcl-2 ratio and increasing the expression of cytochrome c, p53, caspase-3 and -9. Overall, E2 has the potential to emerge as a promising drug candidate for cancer therapy.
天然来源的二萜类化合物对多种人类癌细胞具有细胞毒性。然而，它们的药用应用因化疗效力不足而受到阻碍。因此，设计并合成了一系列与氮芥偶联的新型二萜类化合物杂化物，以提高抗肿瘤疗效并降低全身毒性。大多数缀合物表现出比母体二萜类化合物和氮芥更强的抗增殖活性，尤其是对多药耐药肿瘤细胞系Bel-7402/5-FU。其中，化合物E2在人白血病HL-60细胞、人前列腺癌PC-3细胞、人肝癌Bel-7402细胞和耐药人肝癌Bel-7402/5-FU细胞中表现出最有效的抑制活性，IC值分别为7.83 μM、3.97 μM、0.77 μM和2.07 μM。此外，在L-02人正常肝细胞和Bel-7402恶性肝癌细胞的细胞毒性评估中也观察到选择性指数超过130的高选择性。对作用机制的进一步研究表明，E2在Bel-7402肝癌细胞中诱导细胞凋亡和G1期细胞周期阻滞。此外，线粒体途径的功能障碍也参与了E2引发的凋亡激活，这导致线粒体膜电位丧失，随后上调bax/bcl-2比值并增加细胞色素c、p53、caspase-3和-9的表达。总体而言，E2有潜力成为一种有前景的癌症治疗候选药物。
