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Structure-Based Design of New KSP-Eg5 Inhibitors Assisted by a Targeted Multicomponent Reaction
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
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2014 (English)In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 15, no 10, 1471-1480 p.Article in journal (Refereed) Published
Abstract [en]

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 mu m, EC50=3.63 mu m) and 22 (IC50=1.37 mu m, EC50=6.90 mu m)-were synthesized with high efficiency by taking advantage of the multicomponent reactions.

Place, publisher, year, edition, pages
2014. Vol. 15, no 10, 1471-1480 p.
Keyword [en]
antitumor agents, drug design, inhibitors, kinesin spindle protein, multicomponent reactions
National Category
Biological Sciences
URN: urn:nbn:se:uu:diva-229714DOI: 10.1002/cbic.201402089ISI: 000338769300015OAI: oai:DiVA.org:uu-229714DiVA: diva2:738524
Available from: 2014-08-18 Created: 2014-08-12 Last updated: 2014-08-18Bibliographically approved

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Gutierrez-de-Teran, Hugo
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