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

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.

• Authors: Katja Wiechmann, Hans Müller, Volker Huch, David Hartmann, Oliver Werz, Johann Jauch
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 101 Pg. 133-49 (Aug 28 2015) ISSN: 1768-3254 [Electronic] France
• PMID: 26123643 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Lipoxygenase Inhibitors
• Phloroglucinol
• Arachidonate 5-Lipoxygenase
• Intramolecular Oxidoreductases
• PTGES protein, human
• Prostaglandin-E Synthases

Topics

• Arachidonate 5-Lipoxygenase (metabolism)
• Cell Death (drug effects)
• Crystallography, X-Ray
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Humans
• Intramolecular Oxidoreductases (antagonists & inhibitors, metabolism)
• Jurkat Cells
• Lipoxygenase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Models, Molecular
• Molecular Structure
• Phloroglucinol (analogs & derivatives, chemical synthesis, pharmacology)
• Prostaglandin-E Synthases
• Structure-Activity Relationship