title: Synthesis and pharmacological evaluation of fluorescent and photoactivatable analogues of antiplasmodial naphthylisoquinolines.
abstract: The naphthylisoquinoline (NIQ) alkaloids from tropical Ancistrocladaceae and Dioncophyllaceae plants show high antiplasmodial activities in vitro and in vivo, even against chloroquine-resistant strains of the malaria pathogen. For the directed optimization of these activities, an investigation of the mode of action seems most rewarding. We have therefore embarked on the identification of the respective target protein in Plasmodium falciparum. For this purpose, we have developed a flexible pathway for the synthesis of a chemically divergent series of photoactive and fluorescent derivatives of such alkaloids and succeeded in preparing the first functionalized NIQ derivatives, 10, 12, and 35, suited for fluorescence and photoaffinity labeling experiments. Pharmacological investigations ensured that the modified alkaloid derivatives retained their antiplasmodial activity. The work may pave the way for a further improvement of the activity of these natural products and will thus increase their pharmacological potential as a valuable lead structure against the widespread tropical disease malaria.
authors.affiliation: Institute of Organic Chemistry, University of Würzburg, Am Hubland, D-97074 Würzburg, Germany. bringman@chemie.uni-wuerzburg.de
authors.forename: Gerhard
authors.initials: G
authors.lastname: Bringmann
authors.forename: Christian M
authors.initials: CM
authors.lastname: Gampe
authors.forename: Yanina
authors.initials: Y
authors.lastname: Reichert
authors.forename: Torsten
authors.initials: T
authors.lastname: Bruhn
authors.forename: Johan H
authors.initials: JH
authors.lastname: Faber
authors.forename: Martin
authors.initials: M
authors.lastname: Mikyna
authors.forename: Matthias
authors.initials: M
authors.lastname: Reichert
authors.forename: Matthias
authors.initials: M
authors.lastname: Leippe
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Christoph
authors.initials: C
authors.lastname: Gelhaus
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019920:Photoaffinity Labels / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000470:Alkaloids; D000962:Antimalarials; D005456:Fluorescent Dyes; D007546:Isoquinolines; D009281:Naphthalenes; D019920:Photoaffinity Labels; C104320:dioncophylline A