Background: A large number of pyrazole derivatives have different biological activities
such as anticancer, antimicrobial, anti-inflammatory, analgesic and antiepileptic activity.
Among them, pyrazole oximes have attracted much attention due to their potential pharmacological
activities, particularly anticancer activities.
Objective: Our goal is to synthesize novel thiazolyl substituted bis-pyrazole oxime derivatives
with potent antitumor activities by selectively inducing apoptosis and reactive oxygen species
(ROS) accumulation in cancer cells.
Methods: Eighteen bis-pyrazole oximes were synthesized by conjugating thiazolyl substituted
pyrazoles with pyrazoxime. The target compounds were characterized by 1HNMR, 13C NMR, and
HRMS, and screened for their antiproliferative activity against four cancer cells in MTT assay.
The most potent compound was examined for its inhibitory effect and ROS accumulation in both
cancer cells HCT116 and normal intestinal epithelial cells CCD841. Finally, the most potent
compound was further evaluated for its apoptotic induction by flow cytometry analysis and immunoblot
analysis of apoptosis-related proteins and DNA damage proteins.
Result: Most compounds displayed potent antiproliferative activity against four cancer cell lines
in vitro, displaying potencies superior to 5-FU. In particular, the most potent compound 13l selectively
inhibited proliferation of colorectal cancer HCT116 cells but not normal colon CCD841
cells. Furthermore, compound 13l also selectively promoted intracellular ROS accumulation in
HCT116 which was involved in 13l inhibiting cancer cell proliferation and induced cell apoptosis.
Finally, compound 13l also dose-dependently induced cancer cell apoptosis by regulating apoptotic
and DNA damage related proteins expressions.
Conclusion: Our synthetic bis-pyrazole oxime derivatives possess potent antitumor activities by
selectively inducing apoptosis and ROS accumulation in cancer cells, which may hold great
promise as therapeutic agents for the treatment of human cancers.