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Chemistry. 2019 Jan 28;25(6):1476-1480. doi: 10.1002/chem.201806029. Epub 2018 Dec 20.

Resolving Inflammation: Synthesis, Configurational Assignment, and Biological Evaluations of RvD1n-3 DPA.

Author information

1
Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo, PO Box 1068, 0316, Oslo, Norway.
2
Institute for Organic Chemistry, Leibniz University Hannover, Schneiderberg 1B, 30167 Hannover and Centre of Biomolecular Drug Research (BMWZ), Schneiderberg 38, 30167 Hannover (Germany), Helmholtz Centre for Infection Research GmbH (HZI), Inhoffenstraße 7, 38124, Braunschweig, Germany.
3
Lipid Mediator Unit, Center for Biochemical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
4
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, 02115, USA.

Abstract

New drugs that can resolve inflammation without immunosuppressive effects are at the medicinal chemistry frontier. Pro-resolving endogenously formed small molecules, that is, the resolvins, are excellent candidates displaying such bioactions. The first total synthesis of the specialized pro-resolving mediator RvD1n-3 DPA has been achieved using the underutilized sp3 -sp3 Negishi cross coupling reaction and an alkyne hydrosilylation-protodesilylation protocol. Biological evaluations revealed that this novel mediator displays low nanomolar pro-resolving properties and potently activates the human DRV1/GPR32 receptor. As such, this endogenous natural product is a lead compound for the development of novel immunoresolvents.

KEYWORDS:

Karstedt's catalyst; natural products; sp3-sp3 cross-coupling; specialized pro-resolving mediators; total synthesis

PMID:
30511787
PMCID:
PMC6368681
[Available on 2020-01-28]
DOI:
10.1002/chem.201806029
[Indexed for MEDLINE]

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