Polymer supported synthesis of novel benzoxazole linked benzimidazoles under microwave conditions: In vitro evaluation of VEGFR-3 kinase inhibition activity

• Published in: Organic & biomolecular chemistry Vol. 9; no. 6; pp. 1917 - 1926
• Main Authors: Chanda, Kaushik, Maiti, Barnali, Yellol, Gorakh S., Chien, Ming-Hsien, Kuo, Min-Liang, Sun, Chung-Ming
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 21.03.2011
• Subjects: Benzimidazoles - chemistry; Benzoxazoles - chemical synthesis; Cell Line, Tumor; Chemistry; Chemistry, Organic; Humans; Inhibitory Concentration 50; Microwaves; Models, Molecular; Molecular Structure; Physical Sciences; Polymers - chemistry; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - pharmacology; Science & Technology; Vascular Endothelial Growth Factor Receptor-3 - antagonists & inhibitors; COMPREHENSIVE SURVEY; POTENT; METASTASIS; ANGIOGENESIS; TUMOR LYMPHANGIOGENESIS; DRUG DISCOVERY; BIOLOGY; SUNITINIB; PARALLEL SYNTHESIS; CHEMICAL LIBRARIES
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/c0ob00547a

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 (IC50 = 0.56-1.42 mM). This protocol provides an easy access to novel angular bis-heterocycles which have potential for the discovery of novel leads for targeted cancer therapeutics.