Total Synthesis of the Endocannabinoid Uptake Inhibitor Guineensine and SAR Studies

ChemMedChem. 2019 Sep 4;14(17):1590-1596. doi: 10.1002/cmdc.201900390. Epub 2019 Aug 23.


Guineensine ((2E,4E,12E)-13-(benzo[d][1,3]dioxol-5-yl)-N-isobutyltrideca-2,4,12-trienamide) is a plant-derived natural product that inhibits reuptake of the endocannabinoid anandamide with sub-micromolar potency. We have established a highly efficient total synthesis of guineensine, which provided the natural product in only five steps from commercially available 3-nonyn-1-ol in 17 % overall yield, relying on the attachment of the benzodioxolyl moiety to the unsaturated fatty acid chain by means of a Suzuki coupling as the key step. Subsequent SAR studies revealed that replacement of the N-isobutyl group in the natural product by various alkyl, arylalkyl, or aryl groups is generally well tolerated, and derivatives could be identified that are slightly more potent anandamide reuptake inhibitors than guineensine itself. In contrast, modifications of the benzodioxolyl moiety led to decreased activity. Intriguingly, a change in the configuration of the C4=C5 double bond from E to Z was found to be very well tolerated, in spite of the associated change in the overall geometry of the molecule.

Keywords: endocannabinoid membrane transport; endocannabinoids; guineensine; natural products; total synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkenes / chemical synthesis
  • Alkenes / chemistry
  • Alkenes / pharmacology*
  • Arachidonic Acids / metabolism*
  • Biological Transport / drug effects
  • Cell Line, Tumor
  • Endocannabinoids / metabolism*
  • Heterocyclic Compounds, 2-Ring / chemical synthesis
  • Heterocyclic Compounds, 2-Ring / chemistry
  • Heterocyclic Compounds, 2-Ring / pharmacology*
  • Humans
  • Molecular Structure
  • Polyunsaturated Alkamides / metabolism*
  • Structure-Activity Relationship


  • Alkenes
  • Arachidonic Acids
  • Endocannabinoids
  • Heterocyclic Compounds, 2-Ring
  • Polyunsaturated Alkamides
  • guineensine
  • anandamide