1213776-86-3Relevant academic research and scientific papers
Metal catalysed versus organocatalysed stereoselective synthesis: The concrete case of myrtucommulones
Charpentier, Ma?l,Jauch, Johann
, p. 6614 - 6623 (2017/10/23)
Myrtucommulones belong to a class of pharmacologically active natural compounds which offer various alternatives to the treatment of pain, inflammation and cancer. Their stereoselective synthesis remains therefore a key-challenge towards its use in the pharmaceutical industry. In the present work myrtucommulone A and B were synthesised through metal catalysis with 81 and 72% ee respectively. Thanks to the use of cinchonidine as an organocatalyst, 82 and 84% de were reached for myrtucommulone A and myrtucommulone F respectively. Simultaneously, a new synthetic method emerged and gave access to new range of possibilities for the preparation of myrtucommulone derivatives under mild conditions or through a one-pot reaction.
Synthesis and biological evaluation of novel myrtucommulones and structural analogues that target mPGES-1 and 5-lipoxygenase
Wiechmann, Katja,Müller, Hans,Huch, Volker,Hartmann, David,Werz, Oliver,Jauch, Johann
, p. 133 - 149 (2015/07/07)
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 Combining double low line 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 Combining double low line 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.
