Resolving Inflammation: Synthesis, Configurational Assignment, and Biological Evaluations of RvD1 n-3 DPA

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

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.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / chemical synthesis*
  • Anti-Inflammatory Agents / metabolism
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use
  • Docosahexaenoic Acids / chemistry*
  • Fatty Acids, Unsaturated / chemistry*
  • Humans
  • Inflammation / pathology
  • Inflammation / prevention & control
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Neutrophils / cytology
  • Neutrophils / drug effects
  • Neutrophils / metabolism
  • Quantum Theory
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / metabolism
  • Stereoisomerism

Substances

  • Anti-Inflammatory Agents
  • Fatty Acids, Unsaturated
  • GPR32 protein, human
  • Receptors, G-Protein-Coupled
  • resolvin D1
  • Docosahexaenoic Acids
  • docosapentaenoic acid