Total synthesis and biological evaluation of seven new anti-inflammatory oxacyclododecindione-type macrolactones

Organic & Biomolecular Chemistry
Carina WeberTill Opatz

Abstract

Through variation of our previously published total synthesis of two highly active anti-inflammatory macrolactones from the oxacyclododecindione family (J. Tauber, M. Rohr, T. Walter, G. Erkel and T. Opatz, Org. Biomol. Chem., 2015, 13, 7813-7821), seven new representatives of this compound class were prepared. Substitution of the 14-hydroxy group in oxacyclododecindione with a methyl substituent provided a readily accessible non-natural analogue which has similar pharmacological properties to the scarcely available natural product. Since the producible amount of substance is therefore no longer restricted by low fermentation yields, extensive in vivo studies become possible for the first time. Based on this finding, further investigations on structure-activity relationships were undertaken by variation of the halogen atom, which showed that exchange or omission of the chloro substituent led to significantly lower binding affinities. Furthermore, it was found that elongation of the crucial and characteristic aliphatic side chain at C-10 also increased the IC50 value in the biological assays of interest.

References

Oct 12, 2000·Biochemical and Biophysical Research Communications·M WeidlerG Erkel
Jun 23, 2005·Journal of Agricultural and Food Chemistry·Antonios MichaelakisGeorge Koliopoulos
Jul 26, 2008·The Journal of Antibiotics·Gerhard ErkelTill Opatz
Jun 25, 2015·Organic & Biomolecular Chemistry·Johannes TauberTill Opatz
Apr 2, 2016·Organic & Biomolecular Chemistry·Johannes TauberTill Opatz
Jan 1, 2019·Journal of Asian Natural Products Research·Peng-Cheng LinSheng Lin

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