title: Structure-based design of new KSP-Eg5 inhibitors assisted by a targeted multicomponent reaction.
abstract: An integrated multidisciplinary approach that combined structure-based drug design, multicomponent reaction synthetic approaches and functional characterization in enzymatic and cell assays led to the discovery of new kinesin spindle protein (KSP) inhibitors with antiproliferative activity. A focused library of new benzimidazoles obtained by a Ugi+Boc removal/cyclization reaction sequence generated low-micromolar-range KSP inhibitors as promising anticancer prototypes. The design and functional studies of the new chemotypes were assessed by computational modeling and molecular biology techniques. The most active compounds-20 (IC50 =1.49 μM, EC50 =3.63 μM) and 22 (IC50 =1.37 μM, EC50 =6.90 μM)-were synthesized with high efficiency by taking advantage of the multicomponent reactions.
authors.affiliation: Center for Research in Biological Chemistry and Molecular Materials, University of Santiago de Compostela, Jenaro de la Fuente s/n, Campus Vida, Santiago de Compostela 15782 (Spain).
authors.forename: Carlos
authors.initials: C
authors.lastname: Carbajales
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Prado
authors.forename: Hugo
authors.initials: H
authors.lastname: Gutiérrez-de-Terán
authors.forename: Angel
authors.initials: A
authors.lastname: Cores
authors.forename: Jhonny
authors.initials: J
authors.lastname: Azuaje
authors.forename: Silvia
authors.initials: S
authors.lastname: Novio
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Nuñez
authors.forename: Belén
authors.initials: B
authors.lastname: Fernández-García
authors.forename: Eddy
authors.initials: E
authors.lastname: Sotelo
authors.forename: Xerardo
authors.initials: X
authors.lastname: García-Mera
authors.forename: Pedro
authors.initials: P
authors.lastname: Sánchez-Lazo
authors.forename: Manuel
authors.initials: M
authors.lastname: Freire-Garabal
authors.forename: Alberto
authors.initials: A
authors.lastname: Coelho
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; C470243:KIF11 protein, human; D054852:Small Molecule Libraries; D016547:Kinesins
keywords: antitumor agents; drug design; inhibitors; kinesin spindle protein; multicomponent reactions