title: Structure-activity relationship study of sesquiterpene lactones and their semi-synthetic amino derivatives as potential antitrypanosomal products.
abstract: Sesquiterpene lactones (STLs) are natural products that have potent antitrypanosomal activity in vitro and, in the case of cynaropicrin, also reduce parasitemia in the murine model of trypanosomiasis. To explore their structure-antitrypanosomal activity relationships, a set of 34 natural and semi-synthetic STLs and amino-STLs was tested in vitro against T. b. rhodesiense (which causes East African sleeping sickness) and mammalian cancer cells (rat bone myoblast L6 cells). It was found that the α-methylene-γ-lactone moiety is necessary for both antitrypanosomal effects and cytotoxicity. Antitrypanosomal selectivity is facilitated by 2-(hydroxymethyl)acrylate or 3,4-dihydroxy-2-methylenebutylate side chains, and by the presence of cyclopentenone rings. Semi-synthetic STL amines with morpholino and dimethylamino groups showed improved in vitro activity over the native STLs. The dimethylamino derivative of cynaropicrin was prepared and tested orally in the T. b. rhodesiense acute mouse model, where it showed reduced toxicity over cynaropicrin, but also lost antitrypanosomal activity.
authors.affiliation: Department Pharmaceutical Biology, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. marcel.kaiser@unibas.ch.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Zimmermann
authors.affiliation: CSIR Biosciences, Meiring Naudé Road, Brummeria, Pretoria 0001, Gauteng, South Africa. gfouche@csir.co.za.
authors.forename: Gerda
authors.initials: G
authors.lastname: Fouché
authors.affiliation: Department Pharmaceutical Biology, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. maria.demieri@unibas.ch.
authors.forename: Maria
authors.initials: M
authors.lastname: De Mieri
authors.affiliation: Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioicho, Chiyoda, Tokyo 102-8554, Japan. tkmh-937@sophia.ac.jp.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Yoshimoto
authors.affiliation: Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioicho, Chiyoda, Tokyo 102-8554, Japan. t-usuki@sophia.ac.jp.
authors.forename: Toyonobu
authors.initials: T
authors.lastname: Usuki
authors.affiliation: CSIR Biosciences, Meiring Naudé Road, Brummeria, Pretoria 0001, Gauteng, South Africa. rnthambeleni@csir.co.za.
authors.forename: Rudzani
authors.initials: R
authors.lastname: Nthambeleni
authors.affiliation: School of Biomedical Sciences, Charles Sturt University, Orange, NSW 2800, Australia. cparkinson@csu.edu.au.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Parkinson
authors.affiliation: CSIR Biosciences, Meiring Naudé Road, Brummeria, Pretoria 0001, Gauteng, South Africa. cwvdwesthuyzen@csir.co.za.
authors.forename: Christiaan
authors.initials: C
authors.lastname: van der Westhuyzen
authors.affiliation: Department Medical Parasitology & Infection Biology, Swiss TPH, Socinstrasse 57, 4000 Basel, Switzerland. marcel.kaiser@unibas.ch.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.affiliation: Department Pharmaceutical Biology, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. matthias.hamburger@unibas.ch.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hamburger
authors.affiliation: Department Pharmaceutical Biology, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. michael.adams78@gmail.com.
authors.forename: Michael
authors.initials: M
authors.lastname: Adams
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D007783:Lactones / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D051379:Mice; D021261:Parasitic Sensitivity Tests; D051381:Rats; D012717:Sesquiterpenes / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects; D014353:Trypanosomiasis, African / Q000188:drug therapy / Q000469:parasitology
chemical_list: D007783:Lactones; D012717:Sesquiterpenes; D014344:Trypanocidal Agents