Anti-trypanosomal cadinanes synthesized by transannular cyclization of the natural sesquiterpene lactone nobilin.
Acid-catalyzed transannular cyclization of the germacrene-type sesquiterpene lactone nobilin 1 was investigated with the aim of obtaining new anti-trypanosomal cadinane derivatives. The reaction was regiospecific in all tested reaction conditions. Compounds were fully characterized by spectroscopic and computational methods, and the anti-trypanosomal activity was evaluated and compared to nobilin (IC50 3.19±1.69μM). The tricyclic derivative 11 showed most potent in vitro activity against Trypanosoma brucei rhodesiense bloodstream forms (IC50 0.46±0.01μM). Acid-catalyzed transannular cyclization of natural cyclodecadienes is an efficient strategy to generate new natural product derivatives with anti-protozoal activity.
Department of Pharmaceutical Biology, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: maria.demieri@unibas.ch.
Maria
M
De Mieri
Department of Medical Parasitology & Infection Biology, Swiss Tropical and Public Health Institute, Socinstrasse 57, 4000 Basel, Switzerland; University of Basel, Petersplatz 1, 4001 Basel, Switzerland.
Marcel
M
Kaiser
Department of Medical Parasitology & Infection Biology, Swiss Tropical and Public Health Institute, Socinstrasse 57, 4000 Basel, Switzerland; University of Basel, Petersplatz 1, 4001 Basel, Switzerland.
Reto
R
Brun
Institute of Pharma Technology, School of Life Sciences, University of Applied Sciences Northwestern Switzerland, Muttenz, Switzerland.
Ursula
U
Thormann
Institute of Pharma Technology, School of Life Sciences, University of Applied Sciences Northwestern Switzerland, Muttenz, Switzerland.
Georgios
G
Imanidis
Department of Pharmaceutical Biology, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
Matthias
M
Hamburger
D001632:Bibenzyls / Q000138:chemical synthesis* / Q000494:pharmacology; D031167:Chamaemelum; D003500:Cyclization; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis* / Q000494:pharmacology; D000081223:Polycyclic Sesquiterpenes; D012717:Sesquiterpenes / Q000138:chemical synthesis* / Q000494:pharmacology; D045788:Sesquiterpenes, Germacrane / Q000138:chemical synthesis* / Q000494:pharmacology; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects*
C511960:4,5-dihydroxy-3,3',alpha-trimethoxybibenzyl; D001632:Bibenzyls; D007783:Lactones; D000081223:Polycyclic Sesquiterpenes; D012717:Sesquiterpenes; D045788:Sesquiterpenes, Germacrane; D014344:Trypanocidal Agents; C508039:cadinane
Anti-trypanosomal activity; Heliangolide; Sesquiterpene lactones; Transannular cyclization