Background:
Fibroblast growth factors (FGFs) and their high affinity receptors (FGFRs)
play a major role in cell proliferation, differentiation, migration, and apoptosis. Aberrant FGFR signaling
pathway might accelerate development in a broad panel of malignant solid tumors. However,
the full application of most existing small molecule FGFR inhibitors has become a challenge due to
the potential target mutation. Hence, it has attracted a great deal of attention from both academic and
industrial fields for hunting for novel FGFR inhibitors with potent inhibitory activities and high selectivity.
Objective:
Novel 5-amino-1H-pyrazole-1-carbonyl derivatives were designed, synthesized, and
evaluated as FGFR inhibitors.
Methods:
A series of 5-amino-1H-pyrazole-1-carbonyl derivatives were established by a condensation
of the suitable formyl acetonitrile derivatives with either hydrazine or hydrazide derivatives in
the presence of anhydrous ethanol or toluene. The inhibitory activities of the target compounds were
screened against the FGFRs and two representative cancer cell lines. Tests were carried out to observe
the inhibition of 8e against FGFR phosphorylation and downstream signal phosphorylation in
human gastric cancer cell lines (SNU-16). The molecular docking of all the compounds were performed
using Molecular Operating Environment in order to evaluate their binding abilities with the
corresponding protein kinase.
Results:
A series of 5-amino-1H-pyrazole-1-carbonyl derivatives have been designed and synthesized,
screened for their inhibitory activities against FGFRs and cancer cell lines. Most of the target
compounds showed moderate to good anti-proliferate activities against the tested enzymes and cell
lines. The most promising compounds 8e suppressed FGFR1-3 with IC50 values of 56.4, 35.2, 95.5 nM,
and potently inhibited the SNU-16 and MCF-7 cancer cells with IC50 values of 0.71 1.26 μM, respectively.
And 8e inhibited the growth of cancer cells containing FGFR activated by multiple mechanisms. In
addition, the binding interactions were quite similar in the molecular models between generated
compounds and Debio-1347 with the FGFR1.
Conclusion:
According to the experimental findings, 5-amino-1H-pyrazole-1-carbonyl might serve
as a promising template of an FGFR inhibitor.
Design, Synthesis and Preliminary Biological Evaluation of Benzylsulfone Coumarin Derivatives as Anti-Cancer Agents
