Imai Masahiko, Kumaoka Takaya, Hosaka Makiko, Sato Yui, Li Chuan, Sudoh Masashi, Tamada Yoshiko, Yokoe Hiromasa, Saito Setsu, Tsubuki Masayoshi, Takahashi Noriko
Laboratory of Physiological Chemistry, Institute of Medicinal Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan.
Laboratory of Bioorganic Chemistry, Institute of Medicinal Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan.
Bioorg Med Chem. 2015 Jul 1;23(13):3788-95. doi: 10.1016/j.bmc.2015.03.086. Epub 2015 Apr 9.
Obesity is a risk factor associated with several lifestyle-related diseases, for example, diabetes, high blood pressure, hyperlipidemia and cancer. Caffeic acid 2-phenylethyl ester (CAPE, 1), a naturally-occurring compound found in various plants and propolis, which exhibits anti-inflammatory, immunomodulatory and cytotoxic activities and inhibits 3T3-L1 differentiation to adipocytes. As part of our efforts to moderate lifestyle-related diseases, we synthesized analogs of 1 and studied their effects on pancreatic lipase activities, lipid absorption, and 3T3-L1 differentiation. We found that catechols 1-4 show inhibitory activities against pancreatic lipase in a dose-dependent manner in vitro. Compounds 1-3 proved to be more potent inhibitors of pancreatic lipase than 5, 6, 8, and 9, which have one hydroxyl group, respectively. Compound 7 has three aromatic hydroxyl groups and restrains greater lipase inhibitory activity than the other compounds. In addition, 7 and 3 significantly suppress a rise in blood triglyceride (TG) levels in mice given corn oil orally. Furthermore, 2 and 3 are more potent at preventing 3T3-L1 differentiation (lipid accumulation) than 1, while 7 is more potent than 3, 8, and 9 in these assays. Compounds 2, 3, and 7 inhibit lipid absorption and accumulation, with new compound 7 being the most potent. These results indicate that 7 may have potential benefits as a health agent with anti-obesity properties.
肥胖是一种与多种生活方式相关疾病有关的风险因素，例如糖尿病、高血压、高脂血症和癌症。咖啡酸2-苯乙酯（CAPE，1）是一种存在于各种植物和蜂胶中的天然化合物，具有抗炎、免疫调节和细胞毒性活性，并能抑制3T3-L1细胞向脂肪细胞分化。作为我们缓解生活方式相关疾病努力的一部分，我们合成了1的类似物，并研究了它们对胰脂肪酶活性、脂质吸收和3T3-L1细胞分化的影响。我们发现儿茶酚1-4在体外对胰脂肪酶具有剂量依赖性的抑制活性。化合物1-3被证明是比分别具有一个羟基的5、6、8和9更有效的胰脂肪酶抑制剂。化合物7有三个芳香羟基，其对脂肪酶的抑制活性比其他化合物更强。此外，7和3能显著抑制口服玉米油的小鼠血液中甘油三酯（TG）水平的升高。此外，在这些实验中，2和3在防止3T3-L1细胞分化（脂质积累）方面比1更有效，而7比3、8和9更有效。化合物2、3和7抑制脂质吸收和积累，新化合物7最为有效。这些结果表明，7作为一种具有抗肥胖特性的健康剂可能具有潜在益处。
