ChemPlusChem
10.1002/cplu.201900616
FULL PAPER
aggregate form) to green (the monomeric form) when Experimental Section
[
11,12]
mitochondrial membrane potential declines.
As shown in
Figure. 3C, the green fluorescence increased obviously as the
concentration of 4f increased, implying a decline of MMP. Taken
together, these results demonstrated that 4f exhibited the potent
antitumor activity via inducing apoptosis and inhibiting
proliferation in A549, H1299 and H460 cells.
The mixture of N-methoxybenzamides 1 (0.2 mmol, 1.0 equiv), propargyl
cycloalkanols 2 (0.2 mmol, 1.0 equiv), [Cp*RhCl ] (2.5 mol %) and
2 2
NaOAc (0.2 mmol, 1.0 equiv) was dissolved in toluene (2.0 mL) in a
o
sealed tube and stirred for 24 h at 80 C without exclusion of air or
moisture. Afterwards, the solvent was removed with the reduced
pressure and the crude product was purified by preparative TLC to afford
the corresponding products 3 or 4.
Acknowledgements
We thank the NSFC (21877020), Guangdong Natural Science
Funds for Distinguished Young Scholar (2017A030306031) and
Natural Science Foundation of Guangdong Province
(
2018A030313274) for financial support on this study.
Keywords: antitumor agents
•
cell apoptosis
•
C-H
functionalization • isoquinolin-1(2H)-one • rhodium(III) catalysis
[
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Figure 3. Apoptosis in A549, H1299 and H460 cells induced by 4f. (A)
A549, 299 and H460 cells apoptosis was detected by Annexin V-FITC/PI
on flow cytometry after treatment with 4f for 48
h at different
concentrations (0, 3, 6, 12 μM). (B) Western blotting analysis of the
intervention effect on the expression of Bcl-2 and Bax in A549, H1299
and H460 cells after treatment with 4f for 48 h, β-tubulin was used as
control. (C) Cells were cultured with 4f at a concentration of 0, 3, 6, 12
μM for 48 h; mitochondrial membrane potential (MMP) were measured
with JC-1, an indicator of mitochondrial function. Data in A was shown as
mean±SD, n=3. *P<0.05,** P<0.001.
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In conclusion, we have developed an efficient rhodium(III)-
catalyzed
redox-neutral
coupling
reaction
of
N-
methoxybenzamides with propargyl cycloalkanols for the
construction of 3-acyl substituted isoquinolin-1(2H)-one
skeletons via sequential C-H activation/ring-opening of strained
ring/[4+2] annulation cascade. This transformation features mild
conditions, broad substrate compatibility and specific regio- and
chemo-selectivity. In vitro studies of the synthesized
isoquinolinones showed the potent antitumor activities against
diverse human cancer cell lines, among which 4f possessed the
most potent efficacy by inhibiting proliferation and inducing
apoptosis of A549, H1299 and H460 cells. Further investigation
on developing novel synthetic strategy for the rapid access of
bioactive molecules and modifying the structure of 4f as the lead
compound for anti-lung cancer drug discovery are in progress.
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