Department of Applied Chemistry, National Chiao Tung University, Hsinchu, 300-10, Taiwan.
Org Biomol Chem. 2011 Mar 21;9(6):1917-26. doi: 10.1039/c0ob00547a. Epub 2011 Feb 1.
An efficient soluble polymer-supported method has been developed for the parallel synthesis of substituted benzimidazole linked benzoxazoles using focused microwave irradiation. The key step involves the amidation of 4-hydroxy-3-nitrobenzoic acid with polymer-immobilized o-phenylenediamine. Application of mild acidic conditions promoted the ring closure to furnish the benzimidazole ring. After hydrogenation of the nitro-group to amine, the resulted polymer conjugates underwent efficient ring closure with various alkyl, aryl and heteroaryl isothiocyanates to generate the polymer-bound benzimidazolyl benzoxazoles. The polymer-bound compounds were finally cleaved from the support to furnish benzimidazole linked benzoxazole derivatives. The efficacy of the resultant angular bis-heterocyclic library was studied against vascular endothelial growth factor receptor (VEGFR-3). The preliminary screening of these novel compounds exhibits moderate to high inhibition (IC(50) = 0.56-1.42 μM). This protocol provides an easy access to novel angular bis-heterocycles which have potential for the discovery of novel leads for targeted cancer therapeutics.
一种高效的可溶性聚合物支撑的方法已经被开发出来，用于通过聚焦微波辐射平行合成取代的苯并咪唑连接的苯并恶唑。关键步骤涉及 4-羟基-3-硝基苯甲酸与聚合物固定化邻苯二胺的酰胺化。温和酸性条件的应用促进了环合，得到苯并咪唑环。硝基还原为胺后，得到的聚合物缀合物与各种烷基、芳基和杂芳基异硫氰酸酯发生高效环合，生成聚合物结合的苯并咪唑基苯并恶唑。聚合物结合的化合物最后从载体上裂解，得到苯并咪唑连接的苯并恶唑衍生物。所得角双杂环文库的功效已针对血管内皮生长因子受体 (VEGFR-3) 进行了研究。对这些新型化合物的初步筛选显示出中等至高度抑制（IC50=0.56-1.42 μM）。该方案提供了一种获得新型角双杂环的简便方法，这些双杂环可能为靶向癌症治疗的新型先导化合物的发现提供了潜力。
