Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
Bioorg Med Chem Lett. 2012 Oct 1;22(19):6297-300. doi: 10.1016/j.bmcl.2012.06.102. Epub 2012 Jul 7.
In this study, a new series of bis-benzimidazole derivatives were designed and synthesized. Most of these new compounds showed significant anti-tumor activity in vitro compared to Hoechst 33258. Among them, the most potent compound 8 had the IC(50) values of 0.56μM for HL60 (Human promyelocytic leukemia cells) tumor cell line and 0.58μM for U937 (Human leukemic monocyte lymphoma cells) tumor cell line. Subsequent toxicity study on human peripheral blood mononuclear cells (PBMC) showed that compound 8 exhibited less toxicity than 5-FU. We also found that apoptosis and autophagy were simultaneously induced by compound 8 in HL60 cells, and inhibition of autophagy by 3-MA decreased compound 8-induced apoptosis, indicating that they acted in synergy to exert tumor cell death.
在这项研究中，设计并合成了一系列新的双苯并咪唑衍生物。与 Hoechst 33258 相比，这些新化合物中的大多数在体外都显示出显著的抗肿瘤活性。其中，最有效的化合物 8 对 HL60（人早幼粒细胞白血病细胞）肿瘤细胞系和 U937（人白血病单核细胞淋巴瘤细胞）肿瘤细胞系的 IC50 值分别为 0.56μM 和 0.58μM。对人外周血单个核细胞（PBMC）的后续毒性研究表明，化合物 8 的毒性比 5-FU 小。我们还发现化合物 8 可同时诱导 HL60 细胞凋亡和自噬，而 3-MA 抑制自噬可降低化合物 8 诱导的细胞凋亡，表明它们协同作用以发挥肿瘤细胞死亡的作用。
