title: 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.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, D-07743 Jena, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Wiechmann
authors.affiliation: Organic Chemistry II, Saarland University, Campus C 4.2, D-66123 Saarbrücken, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Müller
authors.affiliation: Institute for Inorganic Chemistry, Saarland University, Campus C 4.1, D-66123 Saarbrücken, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Huch
authors.affiliation: Organic Chemistry II, Saarland University, Campus C 4.2, D-66123 Saarbrücken, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Hartmann
authors.affiliation: Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, D-07743 Jena, Germany. Electronic address: oliver.werz@uni-jena.de.
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
authors.affiliation: Organic Chemistry II, Saarland University, Campus C 4.2, D-66123 Saarbrücken, Germany. Electronic address: j.jauch@mx.uni-saarland.de.
authors.forename: Johann
authors.initials: J
authors.lastname: Jauch
mesh_terms: D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019169:Jurkat Cells; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D010696:Phloroglucinol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D000071876:Prostaglandin-E Synthases; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D016859:Lipoxygenase Inhibitors; D010696:Phloroglucinol; D001094:Arachidonate 5-Lipoxygenase; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases
keywords: 5-Lipoxygenase; Acylphloroglucinol; Arachidonic acid; Cyclooxygenase; Myrtucommulone; mPGES-1