Cynaropicrin: The First Plant Natural Product with In Vivo Activity against Trypanosoma brucei

Abstract

A screen of 1800 plant and fungal extracts with subsequent HPLC-based activity profiling was done to identify new antiprotozoal leads from nature. This led to the identification of cynaropicrin (1) from the herb Centaurea salmantica L. (Asteraceae) as a potent in vitro inhibitor of Trypanosoma brucei rhodesiense. It preferentially inhibited T. b. rhodesiense (IC₅₀ of 0.3 µM) and T. brucei gambiense (IC₅₀ of 0.2 µM), compared to Trypanosoma cruzi (IC₅₀ of 4.4 µM) and Plasmodium falciparum (IC₅₀ of 3.0 µM). Testing against melarsoprol- and pentamidine-resistant strains (IC₅₀s of 0.3 µM and 0.1 µM, respectively) showed no cross-resistance. Intraperitoneal administration of 2 × 10 mg/kg body weight/day in the T. b. rhodesiense STIB 900 acute mouse model led to a 92 % reduction of parasitemia compared to untreated controls on day seven post-infection. Removal of the 2-hydroxymethyl-2-propenoyl moiety of cynaropicrin led to a loss of toxicity towards T. b. rhodesiense. Cytotoxicities against rat myoblasts (L6 cells), human colon adenocarcinoma cells, and murine peritoneal macrophages were measured, and selectivity indices of 7.8, 62, and 9.5 were determined. This is the first report of a plant natural product with potent in vivo activity against Trypanosoma brucei.

Centaurea salmantica L. - Asteraceae - antitrypanosomal - human African trypanosomiasis (HAT) - Trypanosoma brucei rhodesiense - sesquiterpene lactone - cynaropicrin

References

• 1 Vickerman K. Development cycles and biology of pathogenic trypanosomes.  Br Med Bull. 1985;  41 105-114
• 2 Brun R, Blum J, Chappuis F, Burri J. Human African trypanosomiasis.  Lancet. 2010;  375 148-159
• 3 Checchi F, Filipe J A, Haydon D T, Chandramohan D, Chappuis F. Estimates of the duration of the early and late stage of gambiense sleeping sickness.  BMC Infect Dis. 2008;  8 16
• 4 Buguet A, Bert J, Tapie P, Tabaraud F, Doua F, Lonsdorfer J. Sleep-wake cycle in human African trypanosomiasis.  J Clin Neurophysiol. 1993;  10 190-196
• 5 Adams M, Zimmermann S, Kaiser M, Brun R, Hamburger M. A protocol for HPLC-based activity profiling for natural products with activities against tropical parasites.  Nat Prod Commun. 2009;  4 1377-1381
• 6 Adams M, Christen M, Zimmermann S, Plitzko I, Kaiser M, Brun R, Hamburger M. New antiplasmodial lanostanes from Ganoderma lucidum mushroom.  J Nat Prod. 2010;  73 897-900
• 7 Potterat O, Hamburger M. Natural products in drug discovery – concepts and approaches for tracking bioactivity.  Curr Org Chem. 2006;  10 899-920
• 8 Ha T J, Jang D S, Lee J K, Lee K D, Lee J, Hwang S W. Cytotoxic effects of sesquiterpene lactones from flowers of Hemisteptia lyrata.  Arch Pharm Res. 2003;  26 925-928
• 9 Bernhard S C, Nerima B, Mäser P, Brun R. Melarsoprol- and pentamidine-resistant Trypanosoma brucei rhodesiense populations and their cross-resistance.  Int J Parasitol. 2007;  37 1443-1448
• 10 Ioset R. Natural products for neglected diseases: a review.  Curr Org Chem. 2008;  12 643-666
• 11 Gehrig S, Efferth T. Development of drug resistance in Trypanosoma brucei thodesiense and Trypanosome brucei gambiense. Treatment of human African trypanosomiasis with natural products.  Int J Mol Med. 2008;  22 411-419
• 12 Hannaert V. Sleeping sickness pathogen (Trypanosoma brucei) and natural products: therapeutic targets and screening systems.  Planta Med. 2011;  77 586-597
• 13 Schmidt T J, Nour A M M, Khalid S A, Kaiser M, Brun R. Quantitative structure – antiprotozoal activity relationships of sesquiterpene lactones.  Molecules. 2009;  1 2062-2076
• 14 Kupchan S M, Fessler D C, Eakin M A, Giacobbe T J. Reactions of alpha methylene lactone tumor inhibitors with model biological nucelophiles.  Science. 1970;  168 376-380
• 15 Kondo R, Sato M, Hara S, Zimmermann S, Hamburger M, Adams M, Usuki T. Synthetic study of sesquiterpene lactone cynaropicrin. Bangkok; 14th Asian Chemical Congress 2011