2. Academic Validation
  3. Synthesis and biological evaluation of novel myrtucommulones and structural analogues that target mPGES-1 and 5-lipoxygenase

Synthesis and biological evaluation of novel myrtucommulones and structural analogues that target mPGES-1 and 5-lipoxygenase

  • Eur J Med Chem. 2015 Aug 28:101:133-49. doi: 10.1016/j.ejmech.2015.06.001.
Katja Wiechmann 1,  Hans Müller 2,  Volker Huch 3,  David Hartmann 2,  Oliver Werz 4,  Johann Jauch 5
Affiliations

Affiliations

  • 1 Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, D-07743 Jena, Germany.
  • 2 Organic Chemistry II, Saarland University, Campus C 4.2, D-66123 Saarbrücken, Germany.
  • 3 Institute for Inorganic Chemistry, Saarland University, Campus C 4.1, D-66123 Saarbrücken, Germany.
  • 4 Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, D-07743 Jena, Germany. Electronic address: oliver.werz@uni-jena.de.
  • 5 Organic Chemistry II, Saarland University, Campus C 4.2, D-66123 Saarbrücken, Germany. Electronic address: j.jauch@mx.uni-saarland.de.
PMID: 26123643 DOI: 10.1016/j.ejmech.2015.06.001
Abstract

The natural acylphloroglucinol myrtucommulone A (1) inhibits microsomal prostaglandin E2 synthase (mPGES)-1 and 5-lipoxygenase (5-LO), and induces Apoptosis of Cancer cells. Starting from 1 as lead, 28 analogues were synthesized following a straightforward modular strategy with high yielding convergent steps. Major structural variations concerned (I) replacement of the syncarpic acid moieties by dimedone or indandione, (II) cyclization of the syncarpic acid with the acylphloroglucinol core, and (III) substitution of the methine bridges and the acyl residue with isopropyl, isobutyl, n-pentyl or phenyl groups, each. The potency for mPGES-1 inhibition was improved by 12.5-fold for 43 (2-(1-(3-hexanoyl-2,4,6-trihydroxy-5-(1-(3-hydroxy-1-oxo-1H-inden-2-yl)-2-methylpropyl)phenyl)-2-methylpropyl)-3-hydroxy-1H-inden-1-one) with IC50 = 0.08 μM, and 5-LO inhibition was improved 33-fold by 47 (2-((3-hexanoyl-2,4,6-trihydroxy-5-((3-hydroxy-1-oxo-1H-inden-2-yl) (phenyl)methyl)phenyl) (phenyl)methyl)-3-hydroxy-1H-inden-1-one) with IC50 = 0.46 μM. SAR studies revealed divergent structural determinants for induction of cell death and mPGES-1/5-LO inhibition, revealing 43 and 47 as non-cytotoxic mPGES-1 and 5-LO inhibitors that warrant further preclinical assessment as anti-inflammatory drugs.

Keywords

5-Lipoxygenase; Acylphloroglucinol; Arachidonic acid; Cyclooxygenase; Myrtucommulone; mPGES-1.

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