Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China.
Mar Drugs. 2013 Jan 30;11(2):350-62. doi: 10.3390/md11020350.
3,4-Dibromo-5-(2-bromo-3,4-dihydroxy-6-(isopropoxymethyl)benzyl)benzene-1,2-diol (HPN) is a synthetic analogue of 3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(ethoxymethyl)benzyl)benzene-1,2-diol (BPN), which is isolated from marine red alga Rhodomela confervoides with potent protein tyrosine phosphatase 1B (PTP1B) inhibition (IC(50) = 0.84 μmol/L). The in vitro assay showed that HPN exhibited enhanced inhibitory activity against PTP1B with IC(50) 0.63 μmol/L and high selectivity against other PTPs (T cell protein tyrosine phosphatase (TCPTP), leucocyte antigen-related tyrosine phosphatase (LAR), Src homology 2-containing protein tyrosine phosphatase-1 (SHP-1) and SHP-2). The results of antihyperglycemic activity using db/db mouse model demonstrated that HPN significantly decreased plasma glucose (P < 0.01) after eight weeks treatment period. HPN lowered serum triglycerides and total cholesterol concentration in a dose-dependent manner. Besides, both of the high and medium dose groups of HPN remarkably decreased HbA1c levels (P < 0.05). HPN in the high dose group markedly lowered the insulin level compared to the model group (P < 0.05), whereas the effects were less potent than the positive drug rosiglitazone. Western blotting results showed that HPN decreased PTP1B levels in pancreatic tissue. Last but not least, the results of an intraperitoneal glucose tolerance test in Sprague-Dawley rats indicate that HPN have a similar antihyperglycemic activity as rosiglitazone. HPN therefore have potential for development as treatments for Type 2 diabetes.
3,4-二溴-5-(2-溴-3,4-二羟基-6-(异丙氧甲基)苄基)苯-1,2-二醇（HPN）是一种合成类似物，3,4-二溴-5-(2-溴-3,4-二羟基-6-(乙氧甲基)苄基)苯-1,2-二醇（BPN），从海洋红藻 Rhodomela confervoides 中分离出来，具有很强的蛋白酪氨酸磷酸酶 1B（PTP1B）抑制活性（IC50=0.84μmol/L）。体外实验表明，HPN 对 PTP1B 的抑制活性增强，IC50 为 0.63μmol/L，对其他 PTPs（T 细胞蛋白酪氨酸磷酸酶（TCPTP）、白细胞相关酪氨酸磷酸酶（LAR）、Src 同源 2 含蛋白酪氨酸磷酸酶-1（SHP-1）和 SHP-2）具有高选择性。在 db/db 小鼠模型中的抗高血糖活性研究表明，HPN 在八周的治疗期间可显著降低血浆葡萄糖（P<0.01）。HPN 呈剂量依赖性降低血清甘油三酯和总胆固醇浓度。此外，HPN 的高剂量组和中剂量组均可显著降低 HbA1c 水平（P<0.05）。与模型组相比，HPN 高剂量组可显著降低胰岛素水平（P<0.05），但其作用不如阳性药物罗格列酮强。Western blot 结果表明，HPN 可降低胰腺组织中的 PTP1B 水平。最后但并非最不重要的一点是，在 Sprague-Dawley 大鼠的腹腔葡萄糖耐量试验中的结果表明，HPN 具有与罗格列酮相似的降血糖活性。因此，HPN 有潜力开发为 2 型糖尿病的治疗药物。
