TY - JOUR
T1 - Design, synthesis and biological study of pinacolyl boronate-substituted stilbenes as novel lipogenic inhibitors
AU - Das, Bhaskar C.
AU - Zhao, Xiaoping
AU - Tang, Xiang Ying
AU - Yang, Fajun
N1 - Funding Information:
This work was supported by AECOM start-up funds (to B.F. & F.Y.) and a DRTC pilot & feasibility grant (to B.F. & F.Y.) under P60 DK020541 (to Einstein DRTC). The authors thank Drs. Bhavapriya Vaitheesvaran and Irwin Kurland for measuring biosynthesis of palmitate and cholesterol, and Dr. Jeffrey E. Pessin for his support and advice.
PY - 2011/9/15
Y1 - 2011/9/15
N2 - A pilot library of novel 4,4,5,5-tetramethyl-2-(4-substitutedstyrylphenyl)- 1,3,2 dioxaborolane derivatives has been synthesized. 4-(4,4,5,5-Tetramethyl-1, 3,2-dioxaboratophenyl)-methyl triphenylphosphonium bromide 3 was treated with various aldehydes in the presence of 3 equiv of tBuONa in DMF, and stirred at room temperature for 4-6 h to yield the corresponding boron-containing stilbene derivatives in 71-94% yields. Several of them, including BF102 and BF175, have the lipogenesis inhibitory effect by suppressing lipogenic gene expression in mammalian hepatocytes. Further, BF102 also inhibits cholesterol biosynthesis by suppressing HMG-CoA reductase gene expression in hepatocytes. Interestingly, our preliminary in vivo data suggests that BF102 has no significant toxicity in mice at the highest possible dose we can administered. Thus, BF102 is a potential lead for the next generation of lipid-lowering drugs.
AB - A pilot library of novel 4,4,5,5-tetramethyl-2-(4-substitutedstyrylphenyl)- 1,3,2 dioxaborolane derivatives has been synthesized. 4-(4,4,5,5-Tetramethyl-1, 3,2-dioxaboratophenyl)-methyl triphenylphosphonium bromide 3 was treated with various aldehydes in the presence of 3 equiv of tBuONa in DMF, and stirred at room temperature for 4-6 h to yield the corresponding boron-containing stilbene derivatives in 71-94% yields. Several of them, including BF102 and BF175, have the lipogenesis inhibitory effect by suppressing lipogenic gene expression in mammalian hepatocytes. Further, BF102 also inhibits cholesterol biosynthesis by suppressing HMG-CoA reductase gene expression in hepatocytes. Interestingly, our preliminary in vivo data suggests that BF102 has no significant toxicity in mice at the highest possible dose we can administered. Thus, BF102 is a potential lead for the next generation of lipid-lowering drugs.
KW - Boron-containing stilbene derivatives
KW - Lipid-lowering drugs
KW - Lipogenic inhibitors
KW - Sterol regulatory element binding proteins (SREBPs)
KW - Wittig reaction
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U2 - 10.1016/j.bmcl.2011.05.124
DO - 10.1016/j.bmcl.2011.05.124
M3 - Article
C2 - 21798740
AN - SCOPUS:80051921838
SN - 0960-894X
VL - 21
SP - 5638
EP - 5641
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 18
ER -