5728
S. Jiang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5725–5728
Based on the characteristics of broad activity against different
OMe
cancer cell lines and G2/M arrest preceding apoptosis, as well as
the structural similarity between 2a and phenstatin (Chart 2), a
well known potent inhibitor of tubulin polymerization,17 we sus-
pected that 2a and related analogs might be tubulin inhibitors. In
a tubulin polymerization assay,18 the ketone compound 2a as well
as the methylamine compound 4a were found to inhibit tubulin
polymerization with an IC50 value of 500 nM, suggesting inhibition
of tubulin polymerization as the main mechanism of action for
these compounds.
NMe2
OMe
OMe
O
O
OH
NMe2
2a
OMe
Phenstatin
In conclusion, we have identified a series of substituted (naph-
thalen-4-yl)(phenyl)methanones as potent apoptosis inducers.
Compound 2a was found to arrest cancer cells in G2/M and to inhi-
bit tubulin polymerization, which most probably is its main mech-
anism of action for inhibiting cell proliferation and inducing
apoptosis. Through SAR studies, a group of N-methyl-N-phen-
ylnaphthalen-1-amines also was identified as potent apoptosis
inducers. Compound 2a and 2c were highly active in the caspase
activation assay with EC50 values in T47D, HCT116 and SNU398
cells of 37–49 nM and 72–86 nM, respectively. Compound 2a also
was highly active in the growth inhibition assay with a GI50 value
of 34 nM in T47D cells.
Chart 2.
profile of these compounds. Compounds 4a was about 3-fold less
active than 3b, indicating that a methylamino group can replace
the methanol group in 3b. The 3-methoxy analog 4b was about
9-fold less active than the 4-methoxy analog 4a, indicating that
similar to the observed SAR for the ketones, a substituent at the
4-position is important for activity. Interestingly, the 10-nitro ana-
log 4c was about 2-fold more active than 4a. The 10-amino analog
4d was about 20-fold less active than the 10-dimethylamino analog
4a, suggesting a preference for hydrophobic group at the 10-position.
Overall, the apoptosis-inducing activities of these compounds in
human breast cancer T47D cells was similar to that observed in hu-
man colon cancer HCT116 cells and hepatocellular carcinoma can-
cer SNU398 cells (Tables 1 and 2). Compound 2a and 2c, two of the
most active analogs in T47D cells, also were the most active ones in
HCT116 and SNU398 cells, suggesting that compound 2a and re-
lated analogs most probably will be broadly active against many
cancer cell lines.
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