Lan Junjie, Huang Lan, Lou Huayong, Chen Chao, Liu Tangjingjun, Hu Shengcao, Yao Yao, Song Junrong, Luo Jun, Liu Yazhou, Xia Bin, Xia Lei, Zeng Xueyi, Ben-David Yaacov, Pan Weidong
State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, 3491 Baijin Road, Guiyang 550014, PR China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, 3491 Baijin Road, Guiyang, 550014, PR China.
State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, 3491 Baijin Road, Guiyang 550014, PR China.
Eur J Med Chem. 2018 Jan 1;143:1968-1980. doi: 10.1016/j.ejmech.2017.11.007. Epub 2017 Nov 6.
Tetrandrine is a dibenzyltetrahydroisoquinoline alkaloid, isolated from traditional Chinese medicinal plant Stephania tetrandra, with anti-tumor activity. Our previous study identified several derivatives of tetrandrine showing better activities than parental compound against human hepatocellular carcinoma cells. To increase diversity and cytotoxic activities of the original compound, a series of novel 14-urea-tetrandrine derivatives were synthesized through structural modification of tetrandrine. These derivaties demonstrated a moderate to strong anti-proliferative activities against human cell lines HEL and K562 (Leukemia), prostate (PC3), breast (MDA-MB-231) and melanoma (WM9). Compound 4g showed strongest cytotoxic effect against PC3 cells with IC value of 0.64 μM, which was 12-fold, 31-fold and 26-fold lower than the parental tetrandrine, 5-fluorouracil and cisplatin, respectively. Preliminary structure-activity relationship study indicated that urea subsititution was the key pharmacophore for the enhancement of their antitumor activities. Induction of apoprosis by 4g was associated with the activation of pro-apoptotic protein BAX and inhibition of antiapoptosis proteins survivin as well as Bcl-2. Moreover, activation of caspases led to increase cleavage of PARP, which further accelerates apoptotic cell death. These results reveal that the compound 4g may be used as a potential anticancer drug candidate.
粉防己碱是一种双苄基四氢异喹啉生物碱，从传统中药植物粉防己中分离得到，具有抗肿瘤活性。我们之前的研究鉴定了几种粉防己碱衍生物，它们对人肝癌细胞的活性比母体化合物更好。为了增加原始化合物的多样性和细胞毒性活性，通过对粉防己碱进行结构修饰，合成了一系列新型的14-脲基粉防己碱衍生物。这些衍生物对人细胞系HEL和K562（白血病）、前列腺（PC3）、乳腺（MDA-MB-231）和黑色素瘤（WM9）表现出中度至强的抗增殖活性。化合物4g对PC3细胞显示出最强的细胞毒性作用，IC值为0.64 μM，分别比母体粉防己碱、5-氟尿嘧啶和顺铂低12倍、31倍和26倍。初步的构效关系研究表明，脲取代是增强其抗肿瘤活性的关键药效团。4g诱导凋亡与促凋亡蛋白BAX的激活以及抗凋亡蛋白生存素和Bcl-2的抑制有关。此外，半胱天冬酶的激活导致PARP的切割增加，这进一步加速了凋亡细胞死亡。这些结果表明化合物4g可能作为一种潜在的抗癌药物候选物。
