He Yu, Zhang Si-Si, Wei Meng-Xue
State Key Laboratory of High-efficiency Utilization of Coal and Green Chemical Engineering, Ningxia Research Center for Natural Medicine Engineering and Technology, College of Chemistry and Chemical Engineering, Ningxia University 489 Helanshan West Road Yinchuan 750021 China
RSC Med Chem. 2024 Feb 13;15(3):848-855. doi: 10.1039/d3md00619k. eCollection 2024 Mar 20.
Novel rhein-piperazine-furanone hybrids, 5, were designed and synthesized efficiently from rhein. Cytotoxicity of all hybrids 5a-j against A549 human lung cancer cells was superior to the parent rhein and the reference cytarabine (CAR). Hybrid 5e (IC = 5.74 μM), the most potent compound, was 46- and 35-fold more toxic against A549 cells than rhein (IC = 265.59 μM) and CAR (IC = 202.57 μM), respectively. Moreover, hybrid 5e (IC = 69.28 μM) was less toxic to normal WI-38 human lung fibroblast cells with good selectivity (WI-38/A549, SI ≈ 12), being much higher than rhein (SI ≈ 1) and CAR (SI ≈ 2). Structure-activity relationship (SAR) analysis showed that cytotoxicity and selectivity against A549 lung cancer cells were greatly enhanced when methoxy-containing furanone was introduced to the hybrids (5e and 5h). Further, hybrid 5e showed better cytotoxicity against four types of human lung cancer cells (H460, A549, PC-9, and Calu-1; IC = 4.35-15.39 μM) than six other types of human cancer cells (SK-BR-3, SK-OV-3, 786-O, Huh-7, HCT116, and HeLa; IC = 13.77-60.45 μM), showing specificity. In particular, hybrid 5e showed the highest cytotoxicity (IC = 4.35 μM) and the highest selectivity (WI-38/H460, SI ≈ 16) against H460 human lung cancer cells. Flow cytometric analysis showed that hybrid 5e induced apoptosis in a concentration-dependent manner in H460 cells. The results show that the cytotoxicity and selectivity of rhein can be greatly enhanced by hybridization with furanone. Hybrid 5e is expected to be a leading candidate for anti-lung cancer drugs.
新型大黄酸 - 哌嗪 - 呋喃酮杂合物5由大黄酸高效设计并合成。所有杂合物5a - j对A549人肺癌细胞的细胞毒性均优于母体大黄酸和参比药物阿糖胞苷（CAR）。最具活性的化合物杂合物5e（IC = 5.74 μM）对A549细胞的毒性分别比大黄酸（IC = 265.59 μM）和阿糖胞苷（IC = 202.57 μM）高46倍和35倍。此外，杂合物5e（IC = 69.28 μM）对正常WI - 38人肺成纤维细胞的毒性较小，具有良好的选择性（WI - 38/A549，SI≈12），远高于大黄酸（SI≈1）和阿糖胞苷（SI≈2）。构效关系（SAR）分析表明，当将含甲氧基的呋喃酮引入杂合物（5e和5h）时，对A549肺癌细胞的细胞毒性和选择性大大增强。此外，杂合物5e对四种人肺癌细胞（H460、A549、PC - 9和Calu - 1；IC = 4.35 - 15.39 μM）的细胞毒性优于其他六种人癌细胞（SK - BR - 3、SK - OV - 3、786 - O、Huh - 7、HCT116和HeLa；IC = 13.77 - 60.45 μM），显示出特异性。特别是，杂合物5e对H460人肺癌细胞表现出最高的细胞毒性（IC = 4.35 μM）和最高的选择性（WI - 38/H460，SI≈16）。流式细胞术分析表明，杂合物5e在H460细胞中以浓度依赖性方式诱导凋亡。结果表明，通过与呋喃酮杂交可大大增强大黄酸的细胞毒性和选择性。杂合物5e有望成为抗肺癌药物的先导候选物。
