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 IC₅₀ 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.

粉防己碱是一种二苄基四氢异喹啉生物碱，从传统中草药Stephania tetrandra中分离出来，具有抗肿瘤活性。我们先前的研究确定了粉防己碱的几种衍生物在对抗人肝癌细胞方面显示出比母体化合物更好的活性。为了增加原始化合物的多样性和细胞毒活性，通过对粉防己碱的结构修饰合成了一系列新颖的14-脲-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）和黑素瘤（WM9）具有中等至强的抗增殖活性。化合物4g对PC3细胞的IC ₅₀表现出最强的细胞毒性作用值分别为0.64μM，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。初步的结构-活性关系研究表明，尿素取代是增强其抗肿瘤活性的关键药效​​团。4g诱导凋亡的发生与促凋亡蛋白BAX的激活和抗凋亡蛋白survivin以及Bcl-2的抑制有关。此外，胱天蛋白酶的激活导致PARP的切割增加，这进一步加速了凋亡细胞的死亡。这些结果表明，化合物4g可用作潜在的抗癌药物候选物。