Exploring the effect of chirality on the therapeutic potential of N-alkyl-deoxyiminosugars: anti-inflammatory response to Pseudomonas aeruginosa infections for application in CF lung disease

Maria De Fenza, Daniele D'Alonzo, Anna Esposito, Silvia Munari, Nicoletta Loberto, Alessandra Santangelo, Ilaria Lampronti, Anna Tamanini, Alice Rossi, Serena Ranucci, Ida De Fino, Alessandra Bragonzi, Massimo Aureli, Rosaria Bassi, Matteo Tironi, Giuseppe Lippi, Roberto Gambari, Giulio Cabrini, Giovanni Palumbo, Maria Cristina DechecchiAnnalisa Guaragna

Research output: Contribution to journalArticle

Abstract

In the frame of a research program aimed to explore the relationship between chirality of iminosugars and their therapeutic potential, herein we report the synthesis of N-akyl L-deoxyiminosugars and the evaluation of the anti-inflammatory properties of selected candidates for the treatment of Pseudomonas aeruginosa infections in Cystic Fibrosis (CF)lung disease. Target glycomimetics were prepared by the shortest and most convenient approach reported to date, relying on the use of the well-known PS-TPP/I2 reagent system to prepare reactive alkoxyalkyl iodides, acting as key intermediates. Iminosugars ent-1-3 demonstrated to efficiently reduce the inflammatory response induced by P. aeruginosa in CuFi cells, either alone or in synergistic combination with their D-enantiomers, by selectively inhibiting NLGase. Surprisingly, the evaluation in murine models of lung disease showed that the amount of ent-1 required to reduce the recruitment of neutrophils was 40-fold lower than that of the corresponding D-enantiomer. The remarkably low dosage of the L-iminosugar, combined with its inability to act as inhibitor for most glycosidases, is expected to limit the onset of undesired effects, which are typically associated with the administration of its D-counterpart. Biological results herein obtained place ent-1 and congeners among the earliest examples of L-iminosugars acting as anti-inflammatory agents for therapeutic applications in Cystic Fibrosis.

Original languageEnglish
Pages (from-to)63-71
Number of pages9
JournalEuropean Journal of Medicinal Chemistry
Volume175
DOIs
Publication statusPublished - Aug 1 2019

    Fingerprint

Keywords

  • AGIWPLUWFDFEJS-UHFFFAOYSA-N
  • ANOOTOPTCJRUPK-UHFFFAOYSA-N
  • Cystic fibrosis
  • FTSCEGKYKXESFF-LXTVHRRPSA-N
  • FTSCEGKYKXESFF-XGUBFFRZSA-N
  • GPDCQWNBEJWTAD-UHFFFAOYSA-N
  • IAEOYUUPFYJXHN-UHFFFAOYSA-N
  • INKBDAIKCKXOSE-UHFFFAOYSA-N
  • KIHGPSMGDUHOIV-UHFFFAOYSA-N
  • L-Deoxyiminosugars
  • L-NBDNJ
  • LXBIFEVIBLOUGU-FSIIMWSLSA-N
  • MDVGOOIANLZFCP-UHFFFAOYSA-N
  • NLGase
  • NUTSEDIYNMVYMT-UHFFFAOYSA-N
  • OGSJMFCWOUHXHN-UHFFFAOYSA-N
  • Polymeric triphenylphosphine
  • RCJYHJGGHWFOTN-UHFFFAOYSA-N
  • RCXJPSZNTHETPE-YVSFHVDLSA-N
  • RCXJPSZNTHETPE-YYIAUSFCSA-N
  • SXPLUAKSZJTQBC-IYWMVGAKSA-N
  • SXPLUAKSZJTQBC-YRPNKDGESA-N
  • UQRORFVVSGFNRO-JXUBOQSCSA-N
  • UQRORFVVSGFNRO-UTINFBMNSA-N
  • WWFJFHUGMYYKEF-UHFFFAOYSA-N
  • XVYLNHVEAOOEGI-FAIWKWDXSA-N
  • XVYLNHVEAOOEGI-LJNKJDIJSA-N
  • ZSIAUFGUXNUGDI-UHFFFAOYSA-N
  • ZWRUINPWMLAQRD-UHFFFAOYSA-N

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

De Fenza, M., D'Alonzo, D., Esposito, A., Munari, S., Loberto, N., Santangelo, A., Lampronti, I., Tamanini, A., Rossi, A., Ranucci, S., De Fino, I., Bragonzi, A., Aureli, M., Bassi, R., Tironi, M., Lippi, G., Gambari, R., Cabrini, G., Palumbo, G., ... Guaragna, A. (2019). Exploring the effect of chirality on the therapeutic potential of N-alkyl-deoxyiminosugars: anti-inflammatory response to Pseudomonas aeruginosa infections for application in CF lung disease. European Journal of Medicinal Chemistry, 175, 63-71. https://doi.org/10.1016/j.ejmech.2019.04.061