title: Structure-Based Design and Synthesis of Harmine Derivatives with Different Selectivity Profiles in Kinase versus Monoamine Oxidase Inhibition.
abstract: Dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is an emerging biological target with implications in diverse therapeutic areas such as neurological disorders (Down syndrome, in particular), metabolism, and oncology. Harmine, a natural product that selectively inhibits DYRK1A amongst kinases, could serve as a tool compound to better understand the biological processes that arise from DYRK1A inhibition. On the other hand, harmine is also a potent inhibitor of monoamine oxidase A (MAO-A). Using structure-based design, we synthesized a collection of harmine analogues with tunable selectivity toward these two enzymes. Modifications at the 7-position typically decreased affinity for DYRK1A, whereas substitution at the 9-position had a similar effect on MAO-A inhibition but DYRK1A inhibition was maintained. The resulting collection of compounds can help to understand the biological role of DYRK1A and also to assess the interference in the biological effect originating in MAO-A inhibition.
authors.affiliation: Servier Research Institute of Medicinal Chemistry, Záhony u. 7, 1031, Budapest, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Bálint
authors.affiliation: Servier Research Institute of Medicinal Chemistry, Záhony u. 7, 1031, Budapest, Hungary.
authors.forename: Csaba
authors.initials: C
authors.lastname: Wéber
authors.affiliation: Institute de Recherche Servier, 50 Rue Carnot, Suresnes, 92150, France.|Present address: Pierre Fabre R&D Centre, 3 Av. Hubert Curien, 31035, Toulouse Cedex 1, France.
authors.forename: Francisco
authors.initials: F
authors.lastname: Cruzalegui
authors.affiliation: Institute de Recherche Servier, 50 Rue Carnot, Suresnes, 92150, France.
authors.forename: Mike
authors.initials: M
authors.lastname: Burbridge
authors.affiliation: Servier Research Institute of Medicinal Chemistry, Záhony u. 7, 1031, Budapest, Hungary.
authors.forename: Andras
authors.identifier: 0000-0002-7675-3864
authors.initials: A
authors.lastname: Kotschy
mesh_terms: D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006247:Harmine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D013329:Structure-Activity Relationship; D000097603:Dyrk Kinases
chemical_list: D006247:Harmine; D008995:Monoamine Oxidase; D008996:Monoamine Oxidase Inhibitors; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases
keywords: X-ray diffraction; carbolines; enzymes; inhibitors; natural products