Kumar Dalip, Patel Gautam, Chavers Angela K, Chang Kuei-Hua, Shah Kavita
Department of Chemistry, Birla Institute of Technology and Science, Pilani, Rajasthan 333 031, India.
Eur J Med Chem. 2011 Jul;46(7):3085-92. doi: 10.1016/j.ejmech.2011.03.031. Epub 2011 Mar 21.
A library of 3,5-disubstituted-1,2,4-oxadiazoles 7-9 and their bioisosters, 1,3,4-oxadiazole 14 and 1,3,4-thiadiazole 16, were synthesized and evaluated in vitro for their anticancer potential against a panel of six human cancer cell lines. The key step in the synthesis of oxadiazoles 7-9 involve coupling of amidoxime 6 with an appropriate carboxylic acid followed by thermal cyclization. The bioisosteres, 1,3,4-oxadiazole 14 and 1,3,4-thiadiazole 16 were prepared from the reaction of a common precursor diacylhydrazine 13 with thionyl chloride and Lawesson's reagent, respectively. The anticancer studies on the synthesized compounds revealed that presence of a cyclopentyloxy or n-butyloxy on the C-3 aryl ring and piperdin-4-yl or trichloromethyl at the C-5 position of 1,2,4-oxadiazole is essential for good activity. In particular, 1,2,4-oxadiazole 7i and analogue 1,3,4-thiadiazole 16 exhibited significant activity against DU145 (IC(50): 9.3 μM) and MDA-MB-231 (IC(50): 9.2 μM) cell lines, respectively.
合成了一个包含3,5-二取代-1,2,4-恶二唑7-9及其生物电子等排体1,3,4-恶二唑14和1,3,4-噻二唑16的文库，并在体外评估了它们对六种人类癌细胞系的抗癌潜力。恶二唑7-9合成中的关键步骤包括偕胺肟6与适当的羧酸偶联，然后进行热环化。生物电子等排体1,3,4-恶二唑14和1,3,4-噻二唑16分别由常见前体二酰肼13与亚硫酰氯和劳森试剂反应制备。对合成化合物的抗癌研究表明，在1,2,4-恶二唑的C-3芳环上存在环戊氧基或正丁氧基以及在C-5位存在哌啶-4-基或三氯甲基对于良好的活性至关重要。特别是，1,2,4-恶二唑7i和类似物1,3,4-噻二唑16分别对DU145（IC(50)：9.3 μM）和MDA-MB-231（IC(50)：9.2 μM）细胞系表现出显著活性。
