title: Indoleamine 2,3-dioxygenase inhibitory activity of derivatives of marine alkaloid tsitsikammamine A.
abstract: Tsitsikammamines are marine alkaloids whose structure is based on the pyrroloiminoquinone scaffold. These and related compounds have attracted attention due to various interesting biological properties, including cytotoxicity, topoisomerase inhibition, antimicrobial, antifungal and antimalarial activity. Indoleamine 2,3-dioxygenase (IDO1) is a well-established therapeutic target as an important factor in the tumor immune evasion mechanism. In this preliminary communication, we report the inhibitory activity of tsitsikammamine derivatives against IDO1. Tsitsikammamine A analogue 11b displays submicromolar potency in an enzymatic assay. A number of derivatives are also active in a cellular assay while showing little or no activity towards tryptophan 2,3-dioxygenase (TDO), a functionally related enzyme. This IDO1 inhibitory activity is rationalized by molecular modeling studies. An interest is thus established in this class of compounds as a potential source of lead compounds for the development of new pharmaceutically useful IDO1 inhibitors.
authors.affiliation: Namur Medicine & Drug Innovation Center, Namur Research Institute for Life Sciences, University of Namur, 61 Rue de Bruxelles, B-5000 Namur, Belgium. eduard.dolusic@fundp.ac.be
authors.forename: Eduard
authors.initials: E
authors.lastname: Dolušić
authors.forename: Pierre
authors.initials: P
authors.lastname: Larrieu
authors.forename: Céline
authors.initials: C
authors.lastname: Meinguet
authors.forename: Delphine
authors.initials: D
authors.lastname: Colette
authors.forename: Arnaud
authors.initials: A
authors.lastname: Rives
authors.forename: Sébastien
authors.initials: S
authors.lastname: Blanc
authors.forename: Thierry
authors.initials: T
authors.lastname: Ferain
authors.forename: Luc
authors.initials: L
authors.lastname: Pilotte
authors.forename: Vincent
authors.initials: V
authors.lastname: Stroobant
authors.forename: Johan
authors.initials: J
authors.lastname: Wouters
authors.forename: Benoît
authors.initials: B
authors.lastname: Van den Eynde
authors.forename: Bernard
authors.initials: B
authors.lastname: Masereel
authors.forename: Evelyne
authors.initials: E
authors.lastname: Delfourne
authors.forename: Raphaël
authors.initials: R
authors.lastname: Frédérick
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D001665:Binding Sites; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: D000470:Alkaloids; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D011758:Pyrroles; D011804:Quinolines; C508209:tsitsikammamine A