Abstract：
Hepatocellular carcinoma is the most common type of primary liver cancer. However, multidrug resistance (MDR) is a major obstacle to the effective chemotherapy of cancer cells. This report documents the rational design, synthesis, and biological evaluation of a novel series of triazolotriazines substituted with CH2NH-linked pyridine for use as dual c-Met/MDR inhibitors. Compound 12g with IC50 of 3.06 μM on HepG2 cells showed more potency than crizotinib (IC50 = 5.15 μM) in the MTT assay. In addition, 12g inhibited c-Met kinase at a low micromolar level (IC50 = 0.052 μM). 12g significantly inhibited P-gp and MRP1/2 efflux pumps in both cancerous HepG2 and BxPC3 cells starting from the lower concentrations of 3 and 0.3 µM, respectively. 12g did not inhibit MDR1 and MRP1/2 in noncancerous H69 cholangiocytes up to the concentration of 30 and 60 µM, respectively. Current results highlighted that cancerous cells were more susceptible to the effect of 12g than normal cells, in which the inhibition occurred only at the highest concentrations, suggesting a further interest in 12g as a selective anticancer agent. Overall, 12g, as a dual c-Met and P-gp/MRP inhibitor, is a promising lead compound for developing a new generation of anticancer agents.
摘要：
肝细胞癌是原发性肝癌的最常见类型。然而,多药耐药(MDR)是癌细胞有效化疗的主要障碍。这份报告记录了合理的设计，合成，以及用CH2-NH-连接的吡啶取代的一系列新型三唑三嗪用作双重c-Met/MDR抑制剂的生物学评估。在MTT测定中,对HepG2细胞的IC50为3.06μM的化合物12g比克唑替尼(IC50=5.15μM)显示出更高的效力。此外,12g以低微摩尔水平抑制c-Met激酶(IC50=0.052μM)。12g从较低浓度的3μM和0.3μM开始显着抑制癌性HepG2和BxPC3细胞中的P-gp和MRP1/2外排泵，分别。12g在非癌H69胆管细胞中不抑制MDR1和MRP1/2，浓度高达30和60μM，分别。目前的研究结果表明，癌细胞比正常细胞更容易受到12g的影响，其中抑制仅在最高浓度下发生，表明对12g作为选择性抗癌剂的进一步兴趣。总的来说,12g,作为双重c-Met和P-gp/MRP抑制剂，是开发新一代抗癌剂的有前途的先导化合物。
