1. Total Synthesis of the Endocannabinoid Uptake Inhibitor Guineensine and SAR Studies
- Author
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Alice Baumann, Ruben Bartholomäus, Mark Rau, Simon Nicolussi, Karl-Heinz Altmann, Jürg Gertsch, and Ana Catarina Simão
- Subjects
Stereochemistry ,Polyunsaturated Alkamides ,Arachidonic Acids ,Alkenes ,01 natural sciences ,Biochemistry ,Heterocyclic Compounds, 2-Ring ,Reuptake ,chemistry.chemical_compound ,Structure-Activity Relationship ,Cell Line, Tumor ,Drug Discovery ,Moiety ,Humans ,General Pharmacology, Toxicology and Pharmaceutics ,610 Medicine & health ,Unsaturated fatty acid ,Pharmacology ,Natural product ,Molecular Structure ,010405 organic chemistry ,Aryl ,Organic Chemistry ,Total synthesis ,Biological Transport ,Anandamide ,Endocannabinoid system ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,chemistry ,Molecular Medicine ,570 Life sciences ,biology ,Endocannabinoids - Abstract
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.
- Published
- 2019