Journal
SCIENTIFIC REPORTS
Volume 7, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41598-017-12912-4
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Funding
- National Natural Science Foundation of China [81430085, 21372206, 81172937, 81273393, 81673322]
- Ministry of Education [20134101130001]
- Outstanding PhD Training Program of Zhengzhou University
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We have synthesized a series of new beta-lactam-azide derivatives as orally active anti-tumor agents by targeting tubulin colchicine binding site and examined their structure activity relationship (SAR). Among them, compound 28 exhibited the most potent antiproliferative activity against MGC-803 cells with an IC50 value of 0.106 mu M by induction of G2/M arrest and apoptosis and inhibition of the epithelial to mesenchymal transition. 28 acted as a novel inhibitor of tubulin polymerization by its binding to the colchicine site. SAR analysis revealed that a hydrogen atom at the C-3 position of the beta-lactam was required for the potent antiproliferative activity of beta-lactam-azide derivatives. Oral administration of compound 28 also effectively inhibited MGC-803 xenograft tumor growth in vivo in nude mice without causing significant loss of body weight. These results suggested that compound 28 is a promising orally active anticancer agent with potential for development of further clinical applications.
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