Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 25, Issue 15, Pages 4088-4099Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2017.05.057
Keywords
Imidazo[1,2-a]pyridines; Tubulin; Synthesis; Cytotoxicity; Molecular modeling
Funding
- National Natural Science Foundation of China [81273357]
- Doctoral Research Foundation of Shenyang Medical College [2014-3057]
- Development Project of Ministry of Education Innovation Team [IRT1073]
Ask authors/readers for more resources
Two series of novel 5,7-diarylimidazo[1,2-alpyridine-8-carbonitrile derivatives (3a-3q and 7a-7n) were designed by modification of CA-4 pharmacophore to develop colchicine targeted antitubulin agents. All compounds were efficiently synthesized and evaluated for their cytotoxicity against five selected cancer cell lines (HT-29, H460, A549, MKN-45 and SMMC-7721) which got an insight in structure and activity relationships (SARs). Several molecules (7e, 7f, 7h-7j and 7m) were disclosed to exhibit promising antiproliferative activity with IC50 values in double-digit nanomolar degree. Optimization toward these compounds led to the discovery of a promising lead 7e, which showed noteworthy potency with IC50 value ranging from 0.01 to 3.2 mu M superior to CA-4 and Crolibulin. Importantly, immunofluorescence staining and colchcine competitive binding assay revealed that microtubule dynamics was disrupted by 7e by binding at the colchicine site of tubulin. Moreover, molecular docking studies suggested the binding of this mimic at colchcine-binding site is similar to Crolibulin, as was in conformity with the observed SARs for these compounds. (C) 2017 Elsevier Ltd. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available