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above. This minimum energy conformation is not readily accessi-
References and notes
ble to the amide, which prefers to adopt a planar conformation
(Fig. 2b), and therefore prevents the CAP group from getting into
the cavity (compound 11a, Fig. 2b). This explains the lower
potency of these analogs. Because of the H-bond interaction be-
tween amide group in CAP and ASP104 in protein, CAP of com-
pound 11c can move close into the cavity mentioned above, but
not deeper than compounds 12a–c, which improves its potency
but still weaker than compounds with scaffold 2.
In conclusion, a series of benzamides including two scaffolds
were designed, synthesized and evaluated for their inhibition of
HDAC. According to the HDAC potency, compounds 12a–b were se-
lected for anticancer activity test. Compound 12a showed moderate
potency against 3 cell lines, while the most potent compound 12b,
which showed a 4-fold increase enzymatic potency to MS-275,
exhibited significant anticancer effect, particularly 50-fold
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This research was supported by the Natural Science Foundation
of Jiangsu Province of China (BK2008514).
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We thank Dr. Huan Ming Chen, Institute of Discovery Chemis-
try, JiangSu Simcere Pharmaceutical R&D Co., Ltd, for his manu-
script reading.