title: Rapid preparation of triazolyl substituted NH-heterocyclic kinase inhibitors via one-pot Sonogashira coupling-TMS-deprotection-CuAAC sequence.
abstract: The one-pot, three-component Sonogashira coupling-TMS-deprotection-CuAAC ("click") sequence is the key reaction for the rapid synthesis of triazolyl substituted N-Boc protected NH-heterocycles, such as indole, indazole, 4-, 5-, 6-, and 7-azaindoles, 4,7-diazaindole, 7-deazapurines, pyrrole, pyrazole, and imidazole. Subsequently, the protective group was readily removed to give the corresponding triazolyl derivatives of these tremendously important NH-heterocycles. All compounds have been tested in a broad panel of kinase assays. Several compounds, 8f, 8h, 8k, and 8l, have been shown to inhibit the kinase PDK1, a target with high oncology relevance, and thus they are promising lead structures for the development of more active derivatives. The X-ray structure analysis of compound 8f in complex with PDK1 has revealed the detailed binding mode of the molecule in the kinase.
authors.affiliation: Lehrstuhl für Organische Chemie, Institut für Organische Chemie und Makromolekulare Chemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstraße 1, D-40225, Düsseldorf, Germany.
authors.forename: Eugen
authors.initials: E
authors.lastname: Merkul
authors.forename: Fabian
authors.initials: F
authors.lastname: Klukas
authors.forename: Dieter
authors.initials: D
authors.lastname: Dorsch
authors.forename: Ulrich
authors.initials: U
authors.lastname: Grädler
authors.forename: Hartmut E
authors.initials: HE
authors.lastname: Greiner
authors.forename: Thomas J J
authors.initials: TJ
authors.lastname: Müller
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000480:Alkynes / Q000737:chemistry*; D001386:Azides / Q000737:chemistry*; D002384:Catalysis; D003300:Copper / Q000737:chemistry*; D018360:Crystallography, X-Ray; D003500:Cyclization; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology; D014297:Trimethylsilyl Compounds / Q000737:chemistry*
chemical_list: D000480:Alkynes; D001386:Azides; D006571:Heterocyclic Compounds; D047428:Protein Kinase Inhibitors; D014230:Triazoles; D014297:Trimethylsilyl Compounds; D003300:Copper; D064413:3-Phosphoinositide-Dependent Protein Kinases; D017346:Protein Serine-Threonine Kinases