School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff, CF10 3NB, Wales, UK.
Eur J Med Chem. 2012 Oct;56:263-70. doi: 10.1016/j.ejmech.2012.08.009. Epub 2012 Aug 14.
A series of novel indole-containing diarylisoxazoles has been synthesised, based on our previous work on the synthesis and pro-apoptotic antitumour activity of indole-based diaryl 1,2,4-oxadiazoles. Concise synthetic routes to both 3-(indol-2-yl)-5-phenylisoxazoles and 5-(indol-2-yl)-3-phenylisoxazoles have been developed with full regiochemical control, bearing substituents on the indole ring, indole nitrogen, and/or phenyl group. Additionally a series of the related 5-(1H-indol-5-yl)-3-phenylisoxazoles has been prepared. In vitro evaluation in human cancer cell lines Colo320 (colon) and Calu-3 (lung) revealed preferential antiproliferative activity within the 5-(indol-5-yl)-3-phenylisoxazole series (low micromolar IC(50)). Further analysis revealed the ability of the indol-5-yl series to induce expression of effector caspases-3 and -7, and retention of viability of the human bronchial smooth muscle cell (BSMC) control cell population (particularly for compounds 18c and 18e).
我们基于之前关于吲哚基二芳基 1,2,4-噁二唑的合成和促凋亡抗肿瘤活性的研究，合成了一系列新型含吲哚的二苯并异恶唑。我们开发了具有完全区域化学控制的 3-(吲哚-2-基)-5-苯基异恶唑和 5-(吲哚-2-基)-3-苯基异恶唑的简洁合成路线，其吲哚环、吲哚氮和/或苯基上带有取代基。此外，还制备了一系列相关的 5-(1H-吲哚-5-基)-3-苯基异恶唑。在人类癌细胞系 Colo320（结肠）和 Calu-3（肺）中的体外评估显示，5-(吲哚-5-基)-3-苯基异恶唑系列具有优先的抗增殖活性（低微摩尔 IC50）。进一步的分析表明，吲哚-5-基系列能够诱导效应半胱天冬酶-3 和 -7 的表达，并保持人支气管平滑肌细胞（BSMC）对照细胞群的活力（特别是化合物 18c 和 18e）。
