Articles producció científica> Química Analítica i Química Orgànica

Revealing 2-dimethylhydrazino-2-alkyl alkynyl sphingosine derivatives as sphingosine kinase 2 inhibitors: Some hints on the structural basis for selective inhibition

  • Identification data

    Identifier: imarina:9246571
  • Authors:

    Corro-Morón M
    Granell A
    Ivanova V
    Domingo E
    Beltrán-Debón R
    Barril X
    Sanz MJ
    Matheu MI
    Castillón S
    Díaz Y
  • Others:

    Author, as appears in the article.: Corro-Morón M; Granell A; Ivanova V; Domingo E; Beltrán-Debón R; Barril X; Sanz MJ; Matheu MI; Castillón S; Díaz Y
    Department: Química Analítica i Química Orgànica Bioquímica i Biotecnologia
    URV's Author/s: Beltrán Debón, Raúl Alejandro / Castillón Miranda, Sergio / Corro Morón, Macarena / Díaz Giménez, María Yolanda / Granell Fort, Albert / Matheu Malpartida, María Isabel
    Keywords: Synthesis Sphk2 Sphk1 Sphk inhibition activity Sphingosine kinase inhibitors Sphingolipids Enantioselective synthesis Docking Cell viability assay synthesis stereoselective-synthesis sphk2 sphk1 sphk inhibition activity sphingosine-1-phosphate metabolism sphingosine kinase inhibitors expression efficient docking cells cell viability assay cancer aziridination apoptosis 1-phosphate
    Abstract: Sphingosine kinase (SphK), which catalyzes the transfer of phosphate from ATP to sphingosine (Sph) generating sphingosine-1-phosphate (S1P) has emerged as therapeutic target since the discovery of connections of S1P with cancer progress. So far, most effort has focused on the development of inhibitors of SphK1, and selective inhibitors of SphK2 have been much less explored. Here, we describe the syntheses of new sphingosine derivatives bearing a tetrasubstituted carbon atom at C-2, dimethylhydrazino or azo moieties in the polar head, and alkane, alkene or alkyne moieties as linkers between the polar ahead and the fatty tail. In vitro inhibitory assays based on a time resolved fluorescence energy transfer (TR-FRET) have revealed the hydrazino and alkynyl moieties as the best combination for the design of selective SphK2 inhibitors (19a and 19b). Docking studies showed that compounds 19a-b have the optimal binding to SphK2 through the exploitation of polar but also hydrophobic interactions of their head group with the head of the enzyme binding pocket, while also producing full contact of the fatty tail with the hydrophobic pocket of the enzyme. By contrast, this elongation causes loss of contact surface with the shorter hydrophobic toe of the SphK1 isoform, thus accounting for the SphK2-biased selectivity of these compounds. Cell viability assays of the most promising candidates 19a-b have shown that 19a is not cytotoxic to human endothelial cells at 30 μM.
    Thematic Areas: Saúde coletiva Química Organic chemistry Molecular biology Medicina veterinaria Medicina i Farmacia Drug discovery Ciências biológicas iii Ciências biológicas ii Ciências biológicas i Chemistry, organic Biotecnología Biochemistry & molecular biology Biochemistry
    licence for use: https://creativecommons.org/licenses/by/3.0/es/
    Author's mail: albert.granell@estudiants.urv.cat albert.granell@estudiants.urv.cat yolanda.diaz@urv.cat maribel.matheu@urv.cat raul.beltran@urv.cat sergio.castillon@urv.cat
    Author identifier: 0000-0001-5567-8108 0000-0001-5216-9260 0000-0001-9691-1906 0000-0002-0690-7549
    Record's date: 2024-07-20
    Papper version: info:eu-repo/semantics/publishedVersion
    Link to the original source: https://www.sciencedirect.com/science/article/pii/S0045206822000736
    Licence document URL: http://repositori.urv.cat/ca/proteccio-de-dades/
    Papper original source: Bioorganic Chemistry. 121 105668-
    APA: Corro-Morón M; Granell A; Ivanova V; Domingo E; Beltrán-Debón R; Barril X; Sanz MJ; Matheu MI; Castillón S; Díaz Y (2022). Revealing 2-dimethylhydrazino-2-alkyl alkynyl sphingosine derivatives as sphingosine kinase 2 inhibitors: Some hints on the structural basis for selective inhibition. Bioorganic Chemistry, 121(), 105668-. DOI: 10.1016/j.bioorg.2022.105668
    Article's DOI: 10.1016/j.bioorg.2022.105668
    Entity: Universitat Rovira i Virgili
    Journal publication year: 2022
    Publication Type: Journal Publications
  • Keywords:

    Biochemistry,Biochemistry & Molecular Biology,Chemistry, Organic,Drug Discovery,Molecular Biology,Organic Chemistry
    Synthesis
    Sphk2
    Sphk1
    Sphk inhibition activity
    Sphingosine kinase inhibitors
    Sphingolipids
    Enantioselective synthesis
    Docking
    Cell viability assay
    synthesis
    stereoselective-synthesis
    sphk2
    sphk1
    sphk inhibition activity
    sphingosine-1-phosphate metabolism
    sphingosine kinase inhibitors
    expression
    efficient
    docking
    cells
    cell viability assay
    cancer
    aziridination
    apoptosis
    1-phosphate
    Saúde coletiva
    Química
    Organic chemistry
    Molecular biology
    Medicina veterinaria
    Medicina i
    Farmacia
    Drug discovery
    Ciências biológicas iii
    Ciências biológicas ii
    Ciências biológicas i
    Chemistry, organic
    Biotecnología
    Biochemistry & molecular biology
    Biochemistry
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