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Synthesis and biological evaluation of 3-(1,3,4-oxadiazol-2-yl)-1,8-naphthyridin-4(1H)-ones as cisplatin sensitizers

Abstract

A series of novel 3-(1,3,4-oxadiazol-2-yl)-1,8-naphthyridin-4(1H)-one derivatives were synthesized and their anti-cancer as well as cisplatin sensitization activities were evaluated. Among them, compound 6e and 6h exhibited the significantly cisplatin sensitization activity against HCT116. Hoechst staining and annexin V-FITC/PI dual-labeling studies demonstrated that the combination of 6e/6h and cisplatin can induce tumour cells apoptosis. Western blot showed the expression of ATR downstream protein, CHK1, decreased in 6e + cisplatin and 6h + cisplatin groups, compared with that in test compound and cisplatin group. Furthermore, docking of 6e/6h into the ATR structure active site revealed that the N1 and N8 atoms in the naphthyridine ring and the hybrid atom in the oxadiazol ring are involved in hydrogen bonding with Val170, Glu168 and Tyr155. Additionally, the naphthyridine ring is also involved in π-π stack with Trp169. Accordingly, compounds 6e and 6h can be expected to be the potential cisplatin sensitizers to participate in HCT116 cancer therapy.

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Publication details

The article was accepted on 22 Sep 2018 and first published on 25 Sep 2018


Article type: Research Article
DOI: 10.1039/C8MD00464A
Citation: Med. Chem. Commun., 2018, Accepted Manuscript
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    Synthesis and biological evaluation of 3-(1,3,4-oxadiazol-2-yl)-1,8-naphthyridin-4(1H)-ones as cisplatin sensitizers

    X. Hou, H. Luo, M. Zhang, G. Yan, C. Pu, S. Lan and R. Li, Med. Chem. Commun., 2018, Accepted Manuscript , DOI: 10.1039/C8MD00464A

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