药学学报, 2017, 52(8): 1287-1298
引用本文:
黄敏, 许荩, 范莉, 刘红萍, 张坤, 冯计周, 杨大成. 5-芳亚甲基噻唑烷-2,4-二酮衍生物的设计合成及抗糖尿病活性研究[J]. 药学学报, 2017, 52(8): 1287-1298.
HUANG Min, XU Jin, FAN Li, LIU Hong-ping, ZHANG Kun, FENG Ji-zhou, YANG Da-cheng. Design,synthesis and antidiabetic activities of 5-arylmethylene thiazolidine-2,4-dione derivatives[J]. Acta Pharmaceutica Sinica, 2017, 52(8): 1287-1298.

5-芳亚甲基噻唑烷-2,4-二酮衍生物的设计合成及抗糖尿病活性研究
黄敏, 许荩, 范莉, 刘红萍, 张坤, 冯计周, 杨大成
西南大学化学化工学院, 重庆市高校应用化学重点实验室, 生物有机与药物化学研究所, 重庆 400715
摘要:
以本研究室发现的高活性噻唑烷-2,4-二酮类(TZDs)化合物为先导物,对其TZD母核的3位氨基修饰,设计并合成了目标分子TM1TM2;利用生物电子等排和拼合原理,设计并合成了含绕丹宁结构单元的目标分子TM3~TM6;将含酚羟基的目标分子与Linker和咔唑连接,设计并合成了与传统TZDs结构类似的目标分子TM7。体外过氧化物酶体增殖物激活受体反应元件(PPRE)激动活性、α-葡萄糖苷酶抑制活性与蛋白质酪氨酸磷酸酶-1B(PTP-1B)抑制活性测定结果显示,多数目标化合物的活性均较弱,但化合物TM2-6TM7b-2TM7b-4的PTP-1B抑制活性很好,其中TM2-6抑制活性高达96.71%、IC50低至1.48 mg·L-1,优于阳性对照物。构效关系表明,TZD环改变,PPAR激动活性变弱。毒性预测显示,高活性化合物几乎无毒性。这些结果对新型抗糖尿病药物的研制具有一定的借鉴意义。
关键词:   
Design,synthesis and antidiabetic activities of 5-arylmethylene thiazolidine-2,4-dione derivatives
HUANG Min, XU Jin, FAN Li, LIU Hong-ping, ZHANG Kun, FENG Ji-zhou, YANG Da-cheng
Key Laboratory of Applied Chemistry of Chongqing Municipality, Institute of Bioorganic and Medicinal Chemistry, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
Abstract:
In order to find highly active antidiabetic agents, the 3-amino group of skeletal structure of thiazolidine-2,4-diones (TZDs) was modified to generate the new molecules TM1 and TM2 in the present research. The new molecules TM3-TM6 containing rhodanine structural units were designed based upon the bioisostere and combination principles. The target molecules TM7, which is similar to the traditional TZDs structurally, were designed by connecting the phenolic hydroxyl of the above target molecules to carbazole through a linker. All of these target compounds were synthesized successfully by selecting suitable synthetic routes with optimized procedures. The assay results of peroxisome proliferator activated receptor response element (PPRE) agonist activity revealed that the PPAR agonist activity was decreased due to the change of TZD ring. The assay of α-glucosidase inhibitory activity and protein tyrosine phosphatase-1B (PTP-1B) inhibitory activity showed that most of the seven serials target molecules have weak activities in vitro. However, 3 of the compounds exhibited strong PTP-1B inhibitory activities. TM2-6 exhibited the highest inhibitory activities, which reached 96.71% with IC50 1.48 mg·L-1. In addition, the toxicity prediction disclosed that the highly active compounds were almost non-toxic. These results provide a hint for the development of new antidiabetic
Key words:   
收稿日期: 2017-02-22
DOI: 10.16438/j.0513-4870.2017-0147
基金项目: 国家自然科学基金应急项目资助(21542003).
通讯作者: 杨大成,Tel:86-13640566978,E-mail:hxydc@swu.edu.cn
Email: hxydc@swu.edu.cn
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