Structure‐Based Design of New KSP‐Eg5 Inhibitors Assisted by a Targeted Multicomponent Reaction. Issue 10 (18th June 2014)

• Record Type: Journal Article
• Authors: Carbajales, Carlos; Prado, Miguel Ángel; Gutiérrez‐de‐Terán, Hugo; Cores, Ángel; Azuaje, Jhonny; Novio, Silvia; Nuñez, María Jesús; Fernández‐García, Belén; Sotelo, Eddy; García‐Mera, Xerardo; Sánchez‐Lazo, Pedro; Freire‐Garabal, Manuel; Coelho, Alberto
• Is Part Of: Chembiochem. Volume 15:Issue 10(2014)
• Page Start: 1471
• Page End: 1480
• Publication Date: 2014-06-18
• Subjects: Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201402089
• Languages: English
• ISSNs: 1439-4227

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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—<bold>20</bold> (IC₅₀=1.49 μ<sc>M</sc>, EC₅₀=3.63 μ<sc>M</sc>) and <bold>22</bold> (IC₅₀=1.37 μ<sc>M</sc>, EC₅₀=6.90 μ<sc>M</sc>)—were synthesized with high efficiency by taking advantage of the multicomponent reactions.</p> </abstract>