title: Design, synthesis and biological study of pinacolyl boronate-substituted stilbenes as novel lipogenic inhibitors.
abstract: 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 (t)BuONa in DMF, and stirred at room temperature for 4-6h 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.
authors.affiliation: Department of Developmental & Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. bdas@aecom.yu.edu
authors.forename: Bhaskar C
authors.initials: BC
authors.lastname: Das
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhao
authors.forename: Xiang-Ying
authors.initials: XY
authors.lastname: Tang
authors.forename: Fajun
authors.initials: F
authors.lastname: Yang
mesh_terms: D000818:Animals; D001897:Boronic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D060326:Chemistry Techniques, Synthetic; D002784:Cholesterol / Q000096:biosynthesis / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D050155:Lipogenesis / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D015394:Molecular Structure; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013267:Stilbenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000591244:BF175 compound; D001897:Boronic Acids; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D054852:Small Molecule Libraries; D013267:Stilbenes; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D064429:Fatty Acid Synthases