N,O-Dialkyl deoxynojirimycin derivatives as CERT START domain ligands

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:30

Article

Castellan, Tessa¹  Santos, Cecile¹  Rodriguez, Frederic¹  Lepage, Mathieu L.²  Liang, Yan²  Bodlenner, Anne²  Compain, Philippe²  Genisson, Yves¹  Dehoux, Cecile¹  Ballereau, Stephanie¹ 

[1] Univ Paul Sabatier Toulouse III, CNRS, UMR5068, SPCMIB, 118 Route Narbonne, F-31062 Toulouse, France

[2] Univ Strasbourg, Univ Haute Alsace, CNRS UMR 7042, Equipe Synthese Organ & Mol Bioact SYBIO,ECPM,LIM, 25 Rue Becquerel, F-67000 Strasbourg, France

关键词: Sphingolipid;    Ceramide;    CERT;    Iminosugar;    Deoxynojirimycin;   

DOI  :  10.1016/j.bmcl.2019.126796

来源: Elsevier

【 摘 要 】

Dysregulation of the ceramide transport protein CERT is associated to diseases such as cancer. In search for new CERT START domain ligands, N-dodecyl-deoxynojirimycin (N-dodecyl-DNJ) iminosugar was found to display, as a ceramide mimic, significant protein recognition. To reinforce the lipophilic interactions and strengthen this protein binding, a docking study was carried out in order to select the optimal position on which to introduce an additional O-alkyl chain on N-dodecyl-DNJ. Analysis of the calculated poses for three different regioisomers indicated an optimal calculated interaction pattern for N,O3-didodecyl-DNJ. The two most promising regioisomers were prepared by a divergent route and their binding to the CERT START domain was evaluated with fluorescence intensity (FLINT) binding assay. N,O3-didodecyl-DNJ was confirmed to be a new binder prototype with level of protein recognition in the FLINT assay comparable to the best known ligands from the alkylated HPA-12 series. This work opens promising perspectives for the development of new inhibitors of CERT-mediated ceramide trafficking.

【 授权许可】

Free