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Structure‐Based Design of New KSP‐Eg5 Inhibitors Assisted by a Targeted Multicomponent Reaction
Author(s) -
Carbajales Carlos,
Prado Miguel Ángel,
GutiérrezdeTerán Hugo,
Cores Ángel,
Azuaje Jhonny,
Novio Silvia,
Nuñez María Jesús,
FernándezGarcía Belén,
Sotelo Eddy,
GarcíaMera Xerardo,
SánchezLazo Pedro,
FreireGarabal Manuel,
Coelho Alberto
Publication year - 2014
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201402089
Subject(s) - combinatorial chemistry , chemistry , kinesin , drug discovery , computational biology , nanotechnology , biochemistry , materials science , biology , microtubule , microbiology and biotechnology
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 (IC 50 =1.49 μ M , EC 50 =3.63 μ M ) and 22 (IC 50 =1.37 μ M , EC 50 =6.90 μ M )—were synthesized with high efficiency by taking advantage of the multicomponent reactions.