Simplified immunosuppressive and neuroprotective agents based on gracilin A

Mikail E Abbasov, Rebeca Alvariño, Christian M Chaheine, Eva Alonso, Jon A Sánchez, Michael L Conner, Amparo Alfonso, Marcel Jaspars, Luis M Botana, Daniel Romo

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

The architecture and bioactivity of natural products frequently serve as embarkation points for the exploration of biologically relevant chemical space. Total synthesis followed by derivative synthesis has historically enabled a deeper understanding of structure-activity relationships. However, synthetic strategies towards a natural product are not always guided by hypotheses regarding the structural features required for bioactivity. Here, we report an approach to natural product total synthesis that we term 'pharmacophore-directed retrosynthesis'. A hypothesized, pharmacophore of a natural product is selected as an early synthetic target and this dictates the retrosynthetic analysis. In an ideal application, sequential increases in the structural complexity of this minimal structure enable development of a structure-activity relationship profile throughout the course of the total synthesis effort. This approach enables the identification of simpler congeners retaining bioactivity at a much earlier stage of a synthetic effort, as demonstrated here for the spongiane diterpenoid, gracilin A, leading to simplified derivatives with potent neuroprotective and immunosuppressive activity.

Original languageEnglish
Pages (from-to)342-350
Number of pages9
JournalNature Chemistry
Volume11
Early online date22 Mar 2019
DOIs
Publication statusPublished - Apr 2019

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Keywords

  • ACYLAMMONIUM SALTS
  • CYCLOPHILIN
  • CYCLOSPORINE-A
  • DISCOVERY
  • DRUG
  • INHIBITORS
  • ISOMERASES
  • NATURAL-PRODUCTS
  • POTENT
  • SECONDARY METABOLITES

ASJC Scopus subject areas

  • Chemical Engineering(all)
  • Chemistry(all)

Cite this

Abbasov, M. E., Alvariño, R., Chaheine, C. M., Alonso, E., Sánchez, J. A., Conner, M. L., ... Romo, D. (2019). Simplified immunosuppressive and neuroprotective agents based on gracilin A. Nature Chemistry, 11, 342-350. https://doi.org/10.1038/s41557-019-0230-0