Chemical Constituents of Euonymus alatus (Thunb.) Sieb. and Their PTP1B and α-Glucosidase Inhibitory Activities Su-Yang Jeong, 1 Phi-Hung Nguyen, 1 Bing-Tian Zhao, 1 Md Yousof Ali, 2 Jae-Sue Choi, 2 Byung-Sun Min 1 and Mi-Hee Woo 1 * 1 College of Pharmacy, Catholic University of Daegu, Gyeongsan 712-702, Korea 2 Department of Food Science & Nutrition, Pukyong National University, Busan 608-737, Korea Phytochemical study on the corks of Euonymus alatus resulted in the isolation of a novel 3- hydroxycoumarinflavanol (23), along with ten triterpenoids (1–10), ten phenolic derivatives (11–20), and two flavonoid glycosides (21 and 22). Their structures were determined by extensive 1D and 2D-nuclear magnetic resonance spectroscopic and mass spectrometry data analysis. Furthermore, their inhibitory effects against the protein tyrosine phosphatases 1B (PTP1B) and α-glucosidase enzyme activity were evaluated. Compounds 6, 7, 9, 15, 19, and 23 were non-competitive inhibitors, exhibiting most potency with IC 50 values ranging from 5.6 ± 0.9 to 18.4 ± 0.3 μM, against PTP1B. Compound 3 (competitive), compounds 5 and 15 (mixed-competitive) displayed potent inhibition with IC 50 values of 15.1 ± 0.7, 23.6 ± 0.6 and 14.8 ± 0.9 μM, respectively. Moreover, compounds 15, 20, and 23 exhibited potent inhibition on α-glucosidase with IC 50 values of 10.5 ± 0.8, 9.5 ± 0.6, and 9.1 ± 0.5 μM, respectively. Thus, these active ingredients may have value as new lead compounds for the development of new antidiabetic agents. Copyright © 2015 John Wiley & Sons, Ltd. Keywords: Euonymus alatus; PTP1B inhibitors; α-glucosidase; flavanol; triterpenoids. Diabetes mellitus, long regarded as a disease of minor consequence to world health, occupies now as one of the main causes of serious maladies in the 21st century. The number of people with diabetes anticipate rising from current estimate of 150–220 million in 2010, and 300 million in 2025 (Zimmet et al., 2001). Lifestyle pat- terns in industrialized societies comprise an increasing availability and ingestion of high-caloric food in the prevalence of a sedentary lifestyle. These factors are emerging as the fundamental causes of this fast-spread ‘epidemic’ (Friedman, 2003). Type-2 diabetes (DM2) is characterized by a resistance of insulin-sensitive tissues, such as muscle, liver, and fat, to insulin action. Although the mechanism of the insulin resistance is unknown, it is tightly associated with obesity. Approximately three- quarters of obese individuals will develop DM2 (Hossain et al., 2007). This metabolic disorder accounts for 90% of the global DM incidents and plays a predis- posing role in cardiovascular diseases from which about 18 million people die annually. Protein tyrosine phos- phatases (PTPs) are involved in the down regulation of cellular signal transduction mediated by receptor tyro- sine kinases such as insulin receptor and epidermal growth factor receptor (Burke and Zhang, 1998). Protein tyrosine phosphatases 1B (PTP1B), a member of the PTP family, is thought to function as a negative regulator of insulin signal transduction. PTP1B directly interacts with activated insulin receptor or insulin receptor substrate-1 (IRS-1) to dephosphorylate phos- photyrosine residues, resulting in down regulation of insulin action (Goldstein et al., 2000). PTP1B knock- down mice show enhanced insulin sensitivity in glucose and insulin tolerance tests, indicating that PTP1B is a major player in the modulation of insulin sensitivity (Elchebly et al., 1999; Klaman et al., 2000). Increased ex- pression of PTP1B in adipose tissue and muscle of obese humans and rodents is thought to be related to insulin resistance (Wu et al., 2001), whereas the increased insulin sensitivity from weight loss is accompanied by re- duced PTP1B activity (Ahmad et al., 1997). PTP1B overexpression in rat primary adipose tissues and 3T3/L1 adipocytes has been shown to decrease insulin- sensitive Glut4 translocation (Chen et al., 1999) and insulin receptor and IRS-1 phosphorylation (Venable et al., 2000), respectively. As with the insulin signaling pathway, the leptin signaling pathway can be attenuated by PTPs, and there is compelling evidence that PTP1B is also involved in this process. Therefore, it has been suggested that compounds that reduce PTP1B activity or expression levels cannot only be used for treating type 2 diabetes but also obesity (Moller, 2001). Although, there have been a number of reports on the design and development of the PTP1B inhibitors, in- cluding ertiprotafib, trodusquemine (He et al., 2014), difluoromethylene phosphonates, 2-carbomethoxy- benzoic acids, 2-oxalylaminobenzoic acids, and several lipophilic compounds (Andersen et al., 2000; Bialy and Waldmann, 2003; Burke et al., 1994; Liljebris et al., 2002; Zhang and Zhang, 2007). However, new types of PTP1B inhibitors with suitable pharmacological proper- ties still remain to be discovered. Euonymus alatus (Thunb.) Sieb. (Celastraceae), known as ‘gui-jun woo’ in Korea, was used in folk medicine for regulating blood circulation, relieving pain, * Correspondence to: Mi Hee Woo, College of Pharmacy, Catholic Uni- versity of Daegu Gyeongsan 712-702, Korea. E-mail: woomh@cu.ac.kr PHYTOTHERAPY RESEARCH Phytother. Res. 29: 1540–1548 (2015) Published online 14 July 2015 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ptr.5411 Copyright © 2015 John Wiley & Sons, Ltd. Received 24 December 2014 Accepted 13 June 2015