Medicinal Chemistry   2016 年 12 卷 7 期

2016.11.01

A novel series of 2,4,6-trisubstituted 1,3,5-triazine derivatives bearing aryl hydrazone moiety were designed and synthesized under the guidance of scaffold hopping and bioisosterism from the autophagy inhibitor VLX600. The target compounds were evaluated for cytotoxicity against HT-29 by MTT assay with VLX600 as positive control. Then, ten potent target compounds (5c-5f, 5i-5r, 5s, 5t) were further evaluated against two cancer cell lines H460 and A549 and one normal cell line WI-38. Most of them exhibited significant cytotoxicity against one or more cell lines. Particularly, a promising compound 5f was identified, which exhibited the most potent cytotoxicity against HT-29, H460 and A549 cancer cell lines with IC50 values of 0.047 ??M, 0.071 ??M and 0.071 ??M, respectively, which was 10-to 62-folds more potent than VLX600 (IC50 = 0.47 ??M, 4.1 ??M, 4.4 ??M). The preliminary structure-activity relationships (SARs) of the compounds were also discussed.