期刊
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
卷 38, 期 1, 页码 166-175出版社
TAYLOR & FRANCIS LTD
DOI: 10.1080/14756366.2022.2136173
关键词
Tubulin; NEDDylation; molecular docking; antiproliferative activity
In this study, a series of potential dual tubulin-NEDDylation inhibitors were synthesized and evaluated. Compound C11 exhibited the strongest antiproliferative activity and showed potent inhibition against tubulin and NEDDylation.
Although various dual-target tubulin inhibitors have been designed and synthesised, no dual tubulin-NEDDylation inhibitors as antiproliferative agents were reported so far. In this work, a series of trimethoxyphenyl analogues as potential dual tubulin-NEDDylation inhibitors were synthesised and evaluated for their antiproliferative activity. Among them, compound C11 exhibited the most potent inhibitory activity with IC50 values of 1.17, 2.48, and 1.47 mu M against HepG2, PC3, and MCF7 cells, respectively. In addition, it displayed the potent inhibitory activity against tubulin with an IC50 value of 2.40 mu M and obviously inhibited tubulin polymerisation in HepG2 cells. Furthermore, C11 inhibited NEDDylation by a ATP-dependent manner. Molecular docking studies revealed that the methoxy group and dithiocarbamate group of C11 could form hydrogen bonds with residues of tubulin and E1 NEDD8-activating enzyme (NAE). These results suggested that compound C11 was a dual tubulin-NEDDylation inhibitor with antiproliferative activity.
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