Centre for Research and Development, PRIST University, Thanjavur 613 403, Tamilnadu, India.
Department of Biochemistry, Institute of Science, GITAM University, Visakhapatnam 530 045, Andhra Pradesh, India.
Eur J Med Chem. 2016 Apr 13;112:289-297. doi: 10.1016/j.ejmech.2016.02.025. Epub 2016 Feb 10.
Secretory phospholipase A2 (sPLA2) is an important enzyme that plays a key role in various inflammatory diseases including cancer and its inhibitors have been developed as preventive or therapeutic agents. In the present study, a series of new indole containing isoxazole derivatives (10a-10o) is synthesized and evaluated for their sPLA2 inhibitory activities. All compounds (10a-10o) showed significant sPLA2 inhibition activities both in vitro and in vivo studies which is substantiated in in silico studies. Among all the tested compounds, 10o showed potent sPLA2 inhibition activity, that is comparable or more to ursolic acid (positive control). Further studies demonstrated that 10o showed in vitro antiproliferative activity when tested against MCF-7 breast and DU145 prostate cancer cells. Furthermore, compounds 10a-10o obeyed lipinsky's rule of 5 and suggesting druggable properties. The in vitro, in vivo and in silico results are encouraging and warrant pre-clinical studies to develop sPLA2-inhibitory compound 10o as novel therapeutic agent for various inflammatory disorders and several malignancies.
分泌型磷脂酶 A2（sPLA2）是一种重要的酶，在包括癌症在内的各种炎症性疾病中发挥关键作用，其抑制剂已被开发为预防或治疗药物。在本研究中，合成了一系列新型含吲哚的异噁唑衍生物（10a-10o），并对其 sPLA2 抑制活性进行了评价。所有化合物（10a-10o）均在体外和体内研究中表现出显著的 sPLA2 抑制活性，这在计算研究中得到了证实。在所测试的化合物中，10o 表现出很强的 sPLA2 抑制活性，与熊果酸（阳性对照）相当或更强。进一步的研究表明，10o 在测试对 MCF-7 乳腺癌和 DU145 前列腺癌细胞的体外增殖活性时表现出活性。此外，化合物 10a-10o 符合 Lipinski 的 5 规则，提示具有成药性。体外、体内和计算结果令人鼓舞，有必要进行临床前研究，以开发 sPLA2 抑制化合物 10o 作为治疗各种炎症性疾病和多种恶性肿瘤的新型治疗剂。
