TY - JOUR
T1 - New betulinic acid derivatives as potent proteasome inhibitors
AU - Qian, Keduo
AU - Kim, Sang Yong
AU - Hung, Hsin Yi
AU - Huang, Li
AU - Chen, Chin Ho
AU - Lee, Kuo Hsiung
N1 - Funding Information:
This investigation was supported by Grant GM-084337 from the National Instituted of General Medical Sciences (NIGMS) awarded to C.H.C and AI-077417 from the National Institute of Allergy and Infectious Diseases (NIAID) awarded to K.H.L. This study was also supported in part by Taiwan Department of Health Clinical Trial and Research Center of Excellence (DOH100-TD-B-111-004). Efficient purification of all the synthetic BA analogs was performed with a Grace Reveleris® flash chromatography system equipped with RevealX™ detection allowing for multisignal (UV/ELSD) collection to low mg quantities. Reveleris® Navigator method optimizer and Grace Reveleris® flash silica cartridges were employed for high quality separations.
PY - 2011/10/1
Y1 - 2011/10/1
N2 - In this study, 22 new betulinic acid (BA) derivatives were synthesized and tested for their inhibition of the chymotrypsin-like activity of 20S proteasome. From the SAR study, we concluded that the C-3 and C-30 positions are the pharmacophores for increasing the proteasome inhibition effects, and larger lipophilic or aromatic side chains are favored at these positions. Among the BA derivatives tested, compounds 13, 20, and 21 showed the best proteasome inhibition activity with IC 50 values of 1.42, 1.56, and 1.80 μM, respectively, which are three to fourfold more potent than the proteasome inhibition controls LLM-F and lactacystin.
AB - In this study, 22 new betulinic acid (BA) derivatives were synthesized and tested for their inhibition of the chymotrypsin-like activity of 20S proteasome. From the SAR study, we concluded that the C-3 and C-30 positions are the pharmacophores for increasing the proteasome inhibition effects, and larger lipophilic or aromatic side chains are favored at these positions. Among the BA derivatives tested, compounds 13, 20, and 21 showed the best proteasome inhibition activity with IC 50 values of 1.42, 1.56, and 1.80 μM, respectively, which are three to fourfold more potent than the proteasome inhibition controls LLM-F and lactacystin.
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U2 - 10.1016/j.bmcl.2011.07.072
DO - 10.1016/j.bmcl.2011.07.072
M3 - Article
C2 - 21856154
AN - SCOPUS:80052566948
SN - 0960-894X
VL - 21
SP - 5944
EP - 5947
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 19
ER -