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Structure‐Based Design of New KSP‐Eg5 Inhibitors Assisted by a Targeted Multicomponent Reaction |
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| Authors: | Carlos Carbajales Dr. Miguel Ángel Prado Dr. Hugo Gutiérrez‐de‐Terán Ángel Cores Dr. Jhonny Azuaje Dr. Silvia Novio Prof. María Jesús Nuñez Dr. Belén Fernández‐García Prof. Eddy Sotelo Prof. Xerardo García‐Mera Prof. Pedro Sánchez‐Lazo Prof. Manuel Freire‐Garabal Prof. Alberto Coelho |
| Affiliation: | 1. 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);2. Harvard Medical School, Department of Cell Biology, 240 Longwood Avenue, Boston, MA 02115 (USA);3. Department of Cell and Molecular Biology, Uppsala University, Biomedical Center, Box 596, 751 24 Uppsala (Sweden);4. Department of Pharmacology, University of Santiago de Compostela, Lennart Levi Stress and Neuroimmunology Laboratory, School of Medicine, C/San Francisco, s/n. Santiago de Compostela, 15782 (Spain);5. Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Department of Biochemistry and Molecular Biology, University of Oviedo, Campus of “El Cristo”. Santiago Gascón Building, 33006 Oviedo (Spain);6. Department of Organic Chemistry, University of Santiago de Compostela, Avda. das Ciencias, s/n. Campus sur Santiago de Compostela, 15782 (Spain) |
| 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. |
| Keywords: | antitumor agents drug design inhibitors kinesin spindle protein multicomponent reactions |