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Issue 3, 2019
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Identification and biological evaluation of novel benzothiazole derivatives bearing a pyridine-semicarbazone moiety as apoptosis inducers via activation of procaspase-3 to caspase-3

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Abstract

Three series of compounds were designed, synthesized and evaluated for their in vitro anticancer activity against a procaspase-3 over-expression cancer cell line (U937) and a procaspase-3 no-expression cancer cell line (MCF-7) to rule out off-target effects. Biological evaluation led to the identification of a series of benzothiazole derivatives bearing a pyridine-semicarbazone moiety, 8j and 8k, with promising anticancer activity and remarkable selectivity. Further mechanism studies revealed that compounds 8j and 8k could induce apoptosis of cancer cells by activating procaspase-3 to caspase-3, and compound 8k exhibited the strongest procaspase-3 activation activity. Structure–activity relationships (SARs) revealed that the presence of benzothiazole and an N,N,O-donor set is crucial for the anticancer activity and selectivity, and reducing the electron density of the N,N,O-donor set results in a dramatic decline in the anticancer activity and selectivity. Furthermore, toxicity evaluation (zebrafish) in vivo and metabolic stability studies (human, rat and mouse liver microsomes) were performed to provide reliable guidance for further PK/PD studies in vivo.

Graphical abstract: Identification and biological evaluation of novel benzothiazole derivatives bearing a pyridine-semicarbazone moiety as apoptosis inducers via activation of procaspase-3 to caspase-3

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Publication details

The article was received on 21 Dec 2018, accepted on 19 Feb 2019 and first published on 25 Feb 2019


Article type: Research Article
DOI: 10.1039/C8MD00624E
Med. Chem. Commun., 2019,10, 465-477

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    Identification and biological evaluation of novel benzothiazole derivatives bearing a pyridine-semicarbazone moiety as apoptosis inducers via activation of procaspase-3 to caspase-3

    J. Ma, X. Ni, Y. Gao, K. Huang, J. Liu, Y. Wang, R. Chen and C. Wang, Med. Chem. Commun., 2019, 10, 465
    DOI: 10.1039/C8MD00624E

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