Laboratori de Química Farmacèutica (Unitat associada al CSIC), Facultat de Farmàcia, Universitat de Barcelona, Spain.
Department of Physical Chemistry, Faculty of Chemistry, University of Barcelona and the Institut de Recerca en Química Teòrica i Computacional (IQTCUB), Barcelona, Spain.
Eur J Med Chem. 2018 Feb 10;145:51-63. doi: 10.1016/j.ejmech.2017.12.098. Epub 2018 Jan 3.
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.
本工作涉及一系列四氢[1,4]二氧杂萘并异喹啉和二甲氧基异喹啉类似物的分子设计、合成和生物活性。本研究描述了这些潜在抗肿瘤化合物的合成策略、多步合成及其优化。合成了一系列四氢异喹啉，并对其细胞毒性进行了评价。其中一些四氢异喹啉显示出有希望的 KRas 抑制、抗血管生成活性和抗骨质疏松特性。分子模拟研究表明，化合物 12 结合在 KRas 蛋白的 p1 口袋中，与疏水性残基 Leu56、Tyr64、Tyr71 和 Thr74 相互作用，并与残基 Glu37 和 Asp38 形成氢键。
