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B. Gong et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1455–1459
Table 4. Inhibition of growth of MCF-7 breast and DU145 prostate carcinoma cells by LPAAT-b inhibitors
Compd
X
R1
R2
LPAAT-b
IC50 (mM)
MCF-7
IC50 (mM)a
DU145
IC50 (mM)a
2
9t
9w
18e
18f
O
O
O
S
Me
Cl
H
CF3
Cl
Et
1.5
0.035
0.05
0.015
0.006
4040
15
20
30–40
>50
OCH2CꢂCH
OCH2Cꢂ CH
OCH2Cꢂ CH
OCH2Cꢂ CH
50
50
20
>50
S
a IC50’s were determined using a fluorescence-based indirect assay of proliferation; CyQuant (Molecular Probes, Eugene, OR).
–NHC(¼O)– at the 50-position. The most potent inhibi-
tors in this series incorporated sp hybridization in the
50-acylamino substituent. Analogues with an alkynyl or
a cyano group in the 50 substituent were particularly
effective inhibitors. Comparing activities for an homo-
logous series of 50-substituted 3-carbon carbamates 9c,
9e, and 9f, inhibition followed a trend with increased pi
bonding: propyl <allyl <propargyl. Noteworthy
exceptions to this enhanced activity with increased sp
hybridization were observed with compounds 8e and 8l
with the alkynyl group in conjugation with the 50-acyl
carbonyl group. These two agents were devoid of
LPAAT-b inhibitory activity.
inhibitors than the compound with R2=H. Within the
group of 2-arylbenzimidazoles with R2=Me, inhibitors
were of comparable potency to 2-arylbenzoxazoles.
Selected LPAAT-b inhibitors were tested for their abil-
ity to inhibit proliferation of MCF-7 breast and DU145
prostate carcinoma cells in vitro (Table 4) but proved to
be only weakly antiproliferative, suggestive of limited
uptake by tumor cells.18 While 9t and 9w display some
increased antiproliferative effect on the mammary
tumor cell line compared to the prostate tumor cell, the
other compounds show a very similar level of anti-
proliferative effect on both lines. Although most of
these agents were antiproliferative to both cell lines
tested, the relatively high concentrations necessary to
reach IC50s (15–50 mM) would suggest that they might
not prove to be particularly efficacious in vivo. How-
ever, with regard to their properties as new molecular
classes that specifically inhibit the beta isoform of
LPAAT these agents may prove useful as tools for the
study of inhibition of cell signaling processes involving
LPA and PA.
Analysis of the assay data for 2-arylbenzothiazoles
(Table 2) indicated a trend toward increased LPAAT-b
inhibition by replacement of the benzoxazole oxygen
with sulfur. In fact, the most potent analogue of 2 tested
was 18f, a benzothiazole with IC50=0.006 mM. How-
ever, SAR differences between benzoxazoles and ben-
zothiazoles were observed that were contrary to this
trend. For example, compounds 9l with 4-methyl sub-
stitution and 9m with 6-methyl substitution in the ben-
zoxazole were effective inhibitors with IC50=0.5 mM
and 0.4 mM, respectively. In contrast, comparable com-
pounds 18a and 18b in the benzothiazole series were
significantly less active with IC50=9 mM and >64 mM,
respectively, indicative of the existence of more rigorous
structural constraints in benzothiazole binding to
LPAAT-b compared to the analogous benzoxazole.
Acknowledgements
We thank Lisa Romero for conducting LPAAT assays.
References and notes
Compound 28 is a member of a series 2-arylbenzothia-
zoles reported to have potent antitumor activity but its
biomolecular target has not been identified.17 Because
of its structural similarity to our LPAAT-b inhibitors,
we tested 28 for LPAAT-b inhibition and found it to be
inactive (IC50>40 mM).
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Gong, Baoqing
