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Total Synthesis of the Endocannabinoid Uptake Inhibitor Guineensine and SAR Studies
Author(s) -
Bartholomäus Ruben,
Nicolussi Simon,
Baumann Alice,
Rau Mark,
Simão Ana Catarina,
Gertsch Jürg,
Altmann KarlHeinz
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900390
Subject(s) - anandamide , moiety , endocannabinoid system , chemistry , natural product , stereochemistry , total synthesis , alkyl , fatty acid , yield (engineering) , potency , aryl , cannabinoid receptor , biochemistry , in vitro , antagonist , organic chemistry , receptor , materials science , metallurgy
Abstract Guineensine ((2 E ,4 E ,12 E )‐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.