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Quaternary Indolizidine and Indolizidone Iminosugars as Potential Immunostimulating and Glycosidase Inhibitory Agents: Synthesis, Conformational Analysis, Biological Activity, and Molecular Docking Study.
Pawar, Nitin J; Parihar, Vijay Singh; Khan, Ayesha; Joshi, Rakesh; Dhavale, Dilip D.
Afiliação
  • Pawar NJ; Department of Chemistry, Garware Research Centre, Savitribai Phule Pune University (formerly University of Pune), Pune 411 007, India.
  • Parihar VS; Department of Chemistry, Garware Research Centre, Savitribai Phule Pune University (formerly University of Pune), Pune 411 007, India.
  • Khan A; Department of Chemistry, Savitribai Phule Pune University , Pune 411 007, India.
  • Joshi R; Institute of Bioinformatics and Biotechnology, Savitribai Phule Pune University , Pune 411 007, India.
  • Dhavale DD; Department of Chemistry, Garware Research Centre, Savitribai Phule Pune University (formerly University of Pune), Pune 411 007, India.
J Med Chem ; 58(19): 7820-32, 2015 Oct 08.
Article em En | MEDLINE | ID: mdl-26375725
New quaternary indolizidine iminosugars, with hydroxymethyl group at the ring junction, namely, C-8a-hydroxymethyl-1-deoxycastanospermine congeners 1a, 2a, 3a and their 3-oxo analogs 1b, 2b, and 3b were synthesized by using intramolecular reductive aminocyclization/lactamization of d-mannose/D-glucose derived C5-γ-azido esters as a key step wherein both the rings of the indolizidine skeleton were built up in one pot following the cascade reaction pathway. The conformations ((5)C8 or (8)C5) of 1-3 were assigned on the basis of the (1)H NMR studies. All compounds were found to be potent inhibitors of various glycosidase enzymes with Ki and IC50 values in the micromolar/nanomolar concentration range and further substantiated by molecular docking studies. The effect of synthesized iminosugars 1-3 on the cytokine secretion of IL-4, IL-6, and IFN-γ was evaluated. All compounds were found to be TH1 bias increasing the TH1/TH2 cytokines ratio (IL-6 and IL-4) indicating their potency as immunostimulating agents. Our study suggests that immunomodulatory activity of indolizidine iminosugars can be tuned by minor structural/stereochemical alterations.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Adjuvantes Imunológicos / Imino Açúcares / Glicosídeo Hidrolases Limite: Animals Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2015 Tipo de documento: Article País de afiliação: Índia País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Adjuvantes Imunológicos / Imino Açúcares / Glicosídeo Hidrolases Limite: Animals Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2015 Tipo de documento: Article País de afiliação: Índia País de publicação: Estados Unidos