Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 145, Issue -, Pages 51-63Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2017.12.098
Keywords
Isoquinolines; Dioxigenated compounds; Antitumor; KRas; Molecular dynamics; Allosteric sites; Drug design
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Funding
- Spanish Minister [CTQ2011-29285-C02-02]
- Generalitat de Catalunya [SGR(2014)-1017]
- Laboratories Servier (France) [BG-UB-2012]
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This work deals with the molecular design, synthesis and biological activity of a series of tetrahydro[1,4] dioxanisoquinolines and dimethoxyisoquinoline analogues. This study describes the synthesis strategy of these potential antitumor compounds, their multi-step synthesis and their optimization. A series of tetrahydroisoquinolines was synthesized and their cytotoxicity evaluated. Some of these tetrahydroisoquinolines showed promising KRas inhibition, antiangiogenesis activity and antiosteoporosis properties. Molecular modeling studies showed that compound 12 bind in the p1 pocket of the KRas protein making interactions with the hydrophobic residues Leu56, Tyr64, Tyr71 and Thr74 and hydrogen bonds with residues Glu37 and Asp38. (C) 2018 Elsevier Masson SAS. All rights reserved.
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