Shaw Jiajiu, Chen Ben, Bourgault Jean P, Jiang Hao, Kumar Narendra, Mishra Jayshree, Valeriote Frederick A, Media Joe, Bobbitt Kevin, Pietraszkiewicz Halina, Edelstein Matthew, Andreana Peter R
21 Century Therapeutics, Inc., Ferndale, MI 48220, USA.
Department of Internal Medicine, Wayne State University, Detroit, Michigan 48201, USA.
Am J Biomed Sci. 2012;4(1):14-25. doi: 10.5099/aj120100014.
A new series of isoxazole derivatives, -phenyl-5-carboxamidyl isoxazoles, was investigated for their anticancer activity with solid tumor selectivity. Six -phenyl-5-carboxamidylisoxazoles were chemically synthesized and evaluated by the disk-diffusion assay and IC cytotoxicity determination. The results showed that one of the derivatives, compound -(4-chlorophenyl)-5-carboxamidyl isoxazole, was the most active against colon 38 and CT-26 mouse colon tumor cells with an IC of 2.5 μg/mL for both cell lines. Western blot analysis showed that compound significantly down-regulated the expression of phosphorylated STAT3 in both human and mouse colon cancer cells indicating that the mechanism of action for compound may involve the inhibition of JAK3/STAT3 signaling pathways. Flow cytometric analysis with Annexin V staining showed that the death induced by compound is mediated through cell necrosis and not apoptotic pathway. In summary, our results show that compound is a new -phenyl-5-carboxamidyl isoxazole with potential anticancer activity. Compound inhibits the phosphorylation of STAT3, a novel target for chemotherapeutic drugs, and is worthy of further investigation as a potential chemotherapeutic agent for treating colon cancer.
研究了一系列新的异恶唑衍生物，即α-苯基-5-羧酰胺基异恶唑，考察其对实体瘤的抗癌活性及选择性。通过化学合成得到6种α-苯基-5-羧酰胺基异恶唑，并采用纸片扩散法和IC50细胞毒性测定法进行评估。结果表明，其中一种衍生物，即化合物α-(4-氯苯基)-5-羧酰胺基异恶唑，对结肠38和CT-26小鼠结肠肿瘤细胞的活性最强，两种细胞系的IC50均为2.5μg/mL。蛋白质免疫印迹分析表明，该化合物在人和小鼠结肠癌细胞中均显著下调磷酸化STAT3的表达，提示该化合物的作用机制可能涉及抑制JAK3/STAT3信号通路。用膜联蛋白V染色进行的流式细胞术分析表明，该化合物诱导的细胞死亡是通过细胞坏死介导的，而非凋亡途径。总之，我们的结果表明，该化合物是一种具有潜在抗癌活性的新型α-苯基-5-羧酰胺基异恶唑。该化合物抑制STAT3的磷酸化，STAT3是化疗药物的一个新靶点，作为一种潜在的治疗结肠癌的化疗药物，值得进一步研究。
