Design and synthesis of novel C14-urea-tetrandrine derivatives with potent anti-cancer activity
Design and synthesis of novel C14-urea-tetrandrine derivatives with potent anti-cancer activity
复制标题
具有有效抗癌活性的新型C14-脲-粉防己碱衍生物的设计与合成
DOI：
10.1016/j.ejmech.2017.11.007
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发表时间：
2018-01-01
影响因子：
6.7
通讯作者：
Pan, Weidong
中科院分区：
文献类型：
--
作者：
Lan, Junjie;Huang, Lan;Pan, Weidong
粉防己碱是从传统药用植物粉防己中分离得到的一种二苄基四氢异喹啉类生物碱，具有抗肿瘤活性。我们先前的研究发现了几种粉防己碱衍生物对人肝癌细胞的活性比亲本化合物更好。为了增加原化合物的多样性和细胞毒活性，通过对粉防己碱进行结构修饰，合成了一系列新的14-尿素-粉防己碱衍生物。这些衍生物对人类细胞系HEL和K562（白血病）、前列腺（PC3）、乳腺（MDA-MB-231）和黑色素瘤（WM9）具有中等至强的抗增殖活性。化合物4g对PC3细胞的细胞毒作用最强，1050值为0.64 μ M，分别比亲本粉防己碱、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，尿素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的激活和抗凋亡蛋白survivin和Bcl-2的抑制有关。此外，caspase的激活导致PARP的裂解增加，进一步加速凋亡细胞的死亡。这些结果表明，化合物4g可能作为一种潜在的抗癌候选药物。(C) 2017 Elsevier Masson SAS。版权所有。
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 1050 value of 0.64 mu M, 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. (C) 2017 Elsevier Masson SAS. All rights reserved.