title: Optimization of three- and four-component reactions for polysubstituted piperidines: application to the synthesis and preliminary biological screening of a prototype library.
abstract: Several solid- and solution-phase strategies were evaluated for the preparation of libraries of polysubstituted piperidines of type 7 using the tandem aza[4+2]cycloaddition/allylboration multicomponent reaction between 1-aza-4-boronobutadienes, maleimides, and aldehydes. A novel four-component variant of this chemistry was developed in solution phase, and it circumvents the need for pre-forming the azabutadiene component. A parallel synthesis coupled with compound purification by HPLC with mass-based fraction collection allowed the preparation of a library of 944 polysubstituted piperidines in a high degree of purity suitable for biological screening. A representative subset of 244 compounds was screened against a panel of phosphatase enzymes, and despite the modest levels of activity obtained, this study demonstrated that piperidines of type 7 display the right physical properties (e.g., solubility) to be assayed effectively in high-throughput enzymatic tests.
authors.affiliation: Department of Chemistry, University of Alberta, Edmonton, Alberta, T6H 3L7, Canada.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Ulaczyk-Lesanko
authors.forename: Eric
authors.initials: E
authors.lastname: Pelletier
authors.forename: Maria
authors.initials: M
authors.lastname: Lee
authors.forename: Heino
authors.initials: H
authors.lastname: Prinz
authors.forename: Herbert
authors.initials: H
authors.lastname: Waldmann
authors.forename: Dennis G
authors.initials: DG
authors.lastname: Hall
mesh_terms: D000447:Aldehydes / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008301:Maleimides / Q000737:chemistry; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D012996:Solutions
chemical_list: D000447:Aldehydes; D004791:Enzyme Inhibitors; D008301:Maleimides; D010880:Piperidines; D012996:Solutions; C043592:maleimide; D017027:Protein Tyrosine Phosphatases