发现新型溴酚 3,4-二溴-5-[2-溴-3,4-二羟基-6-(异丁氧基甲基)苄基]苯-1,2-二醇作为蛋白酪氨酸磷酸酶 1B 抑制剂及其在 C57BL/KsJ-db/db 小鼠中的抗糖尿病作用。
Discovery of novel bromophenol 3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(isobutoxymethyl)benzyl)benzene-1,2-diol as protein tyrosine phosphatase 1B inhibitor and its anti-diabetic properties in C57BL/KsJ-db/db mice.
机构信息
Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China.
出版信息
Eur J Med Chem. 2013 Jun;64:129-36. doi: 10.1016/j.ejmech.2013.03.037. Epub 2013 Apr 1.
In an effort to develop novel small molecule PTP1B inhibitors, a series of bromophenol derivatives were designed, synthesized and evaluated in vitro and in vivo. All of the synthesized compounds displayed weak to potent PTP1B inhibitory activities (5.62-96.25%) at 20 μg/mL. Among these compounds, 3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(isobutoxymethyl)benzyl)benzene-1,2-diol (9) exhibited enhanced PTP1B inhibitory activity (IC50 = 1.50 μM) than the lead compound BDDPM (IC50 = 2.42 μM) and high selectivity against other PTPs (TCPTP, LAR, SHP-1 and SHP-2). Results of anti-diabetic assay using C57BL/KsJ-db/db mouse model demonstrated that compound 9 was effective at lowering blood glucose, total cholesterol and HbA1c (P < 0.01).
为了开发新型小分子 PTP1B 抑制剂，设计、合成并评价了一系列溴酚衍生物的体外和体内活性。所有合成的化合物在 20μg/mL 时均显示出弱至强的 PTP1B 抑制活性（5.62-96.25%）。在这些化合物中，3,4-二溴-5-(2-溴-3,4-二羟基-6-(异丁氧甲基)苄基)苯-1,2-二醇（9）表现出比先导化合物 BDDPM（IC50=2.42μM）更强的 PTP1B 抑制活性（IC50=1.50μM），并且对其他 PTPs（TCPTP、LAR、SHP-1 和 SHP-2）具有高选择性。在 C57BL/KsJ-db/db 小鼠模型中进行的抗糖尿病测定结果表明，化合物 9 有效降低了血糖、总胆固醇和 HbA1c（P<0.01）。
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