148983-67-9Relevant academic research and scientific papers
Gluco-1 H -imidazole: A New Class of Azole-Type β-Glucosidase Inhibitor
Schr?der, Sybrin P.,Wu, Liang,Artola, Marta,Hansen, Thomas,Offen, Wendy A.,Ferraz, Maria J.,Li, Kah-Yee,Aerts, Johannes M. F. G.,Van Der Marel, Gijsbert A.,Codée, Jeroen D. C.,Davies, Gideon J.,Overkleeft, Herman S.
supporting information, p. 5045 - 5048 (2018/04/23)
Gluco-azoles competitively inhibit glucosidases by transition-state mimicry and their ability to interact with catalytic acid residues in glucosidase active sites. We noted that no azole-type inhibitors described, to date, possess a protic nitrogen characteristic for 1H-imidazoles. Here, we present gluco-1H-imidazole, a gluco-azole bearing a 1H-imidazole fused to a glucopyranose-configured cyclitol core, and three close analogues as new glucosidase inhibitors. All compounds inhibit human retaining β-glucosidase, GBA1, with the most potent ones inhibiting this enzyme (deficient in Gaucher disease) on a par with glucoimidazole. None inhibit glucosylceramide synthase, cytosolic β-glucosidase GBA2 or α-glucosidase GAA. Structural, physical and computational studies provide first insights into the binding mode of this conceptually new class of retaining β-glucosidase inhibitors.
3-(Hydroxymethyl)-bearing phosphatidylinositol ether lipid analogues and carbonate surrogates block PI3-K, akt, and cancer cell growth
Hu,Qiao,Wang,Rong,Meuillet,Berggren,Gallegos,Powis,Kozikowski
, p. 3045 - 3051 (2007/10/03)
Phosphatidylinositol 3-kinase (PI3-K) phosphorylates the 3-position of phosphatidylinositol to give rise to three signaling phospholipids. Binding of the pleckstrin homolgy (PH) domain of Akt to membrane PI(3)P's causes the translocation of Akt to the plasma membrane bringing it into contact with membrane-bound Akt kinase (PDK1 and 2), which phosphorylates and activates Akt. Akt inhibits apoptosis by phosphorylating Bad, thus promoting its binding to and blockade of the activity of the cell survival factor Bcl-x. Herein we present the synthesis and biological activity of several novel phosphatidylinositol analogues and demonstrate the ability of the carbonate group to function as a surrogate for the phosphate moiety. Due to a combination of their PI3-K and Akt inhibitory activities, the PI analogues 2, 3, and 5 proved to be good inhibitors of the growth of various cancer cell lines with IC50 values in the 1-10μM range. The enhanced Akt inhibitory activity of the axial hydroxymethyl-bearing analogue 5 compared to its equatorial counterpart 6 is rationalized based upon postulated differences in the H-bonding patterns of these compounds in complex with a homology modeling generated structure of the PH domain of Akt. This work represents the first attempt to examine the effects of 3-modified PI analogues on these two crucial cell signaling proteins, PI3-K and Akt, in an effort to better understand their cell growth inhibitory properties.
Synthesis of (-)-conduritol F, (+)-conduritol B, cyclophellitol from L- quebrachitol
Akiyama,Shima,Ohnari,Okazaki,Ozaki
, p. 3760 - 3767 (2007/10/02)
The methyl ether of cyclitols with vicinal hydroxyl group was cleaved chemoselectively in preference to both cis-and trans-cyclohexylidene moieties by AlCl3-n-Bu4NI to afford parent alcohols in good yields. (-) Conduritol F was prepared from L-quebrachitol, an optically active cyclitol from the serum of rubber trees, in five steps by use of the demethylation reaction. The first chiral synthesis of (+)-conduritol B and the total synthesis of cyclophellitol, a novel β-glucosidase inhibitor, are described.
