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.
journal_name
Medchemcommjournal_title
MedChemCommauthors
Ma J,Ni X,Gao Y,Huang K,Liu J,Wang Y,Chen R,Wang Cdoi
10.1039/c8md00624esubject
Has Abstractpub_date
2019-02-25 00:00:00pages
465-477issue
3eissn
2040-2503issn
2040-2511pii
c8md00624ejournal_volume
10pub_type
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