Total Synthesis of the Endocannabinoid Uptake Inhibitor Guineensine and SAR Studies.

Bartholomäus, Ruben; Nicolussi, Simon; Baumann, Alice; Rau, Mark; Simão, Ana Catarina; Gertsch, Jürg; Altmann, Karl-Heinz (2019). Total Synthesis of the Endocannabinoid Uptake Inhibitor Guineensine and SAR Studies. ChemMedChem, 14(17), pp. 1590-1596. Wiley-VCH 10.1002/cmdc.201900390

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Nicolussi, Simon; Rau, Mark and Gertsch, Jürg

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1860-7179

Publisher:

Wiley-VCH

Language:

English

Submitter:

Barbara Järmann-Bangerter

Date Deposited:

26 Sep 2019 13:18

Last Modified:

27 Oct 2019 04:55

Publisher DOI:

10.1002/cmdc.201900390

PubMed ID:

31322825

Uncontrolled Keywords:

endocannabinoid membrane transport endocannabinoids guineensine natural products total synthesis

BORIS DOI:

10.7892/boris.133488

URI:

https://boris.unibe.ch/id/eprint/133488

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