20(S)-Ginsenoside Rh2 as aldose reductase inhibitor from Panax ginseng Sri Fatmawati a,b , Taslim Ersam b , Hongshan Yu c , Chunzhi Zhang c , Fengxie Jin c , Kuniyoshi Shimizu a,⇑ a Department of Agro-environmental Sciences, Faculty of Agriculture, Kyushu University, Fukuoka 812-8581, Japan b Department of Chemistry, Faculty of Mathematics and Natural Sciences, Institut Teknologi Sepuluh Nopember, Kampus ITS-Sukolilo, Surabaya 60111, Indonesia c College of Biotechnology, Dalian Polytechnic University, Dalian 116034, China article info Article history: Received 2 July 2014 Revised 1 August 2014 Accepted 5 August 2014 Available online 12 August 2014 Keywords: Panax ginseng Structure–activity relationships Ginsenoside Aldose reductase inhibitor abstract The root of Panax ginseng C. A. Meyer (Araliaceae) is a well-known herbal medicine in East Asia. The major bioactive metabolites in this root are commonly identified as ginsenosides. A series of ginsenosides were determined for in vitro human recombinant aldose reductase. This Letter aims to clarify the structural requirement for aldose reductase inhibition. We discovered that only ginsenoside 20(S)-Rh2 showed potent against aldose reductase, with an IC 50 of 147.3 lM. These results implied that the stereochemistry of the hydroxyl group at C-20 may play an important role in aldose reductase inhibition. An understand- ing of these requirements is considered necessary in order to develop a new type of aldose reductase inhibitor. Furthermore, P. ginseng might be an important herbal medicine in preventing diabetic complications. Ó 2014 Elsevier Ltd. All rights reserved. Diabetes Mellitus is a complex and chronic metabolic disease characterized by hyperglycemia. As one of the most prevalent met- abolic syndromes worldwide, this disease is very common around the world and has major effect on public health. Hyperglycemia is the condition in which significant part of the glucose enters into polyol pathway which is measured as the main cause of pathogen- esis of long-term diabetic complications, including neuropathy, retinopathy, nephropathy, and cataract. 1–4 Aldose reductase (ALR2, EC 1.1.1.21) is a member of aldo–keto reductase superfamily and the first enzyme which catalyzes the NADPH-dependent reduction of glucose to sorbitol in the rate determining step of polyol pathway. 5,6 The sorbitol accumulation together with imbalance of NADPH/NADP + and NAD + /NADH cofac- tors and following oxidative stress within the cells are considered to be key causes of cellular damage that raise diabetic complica- tions. Because of this reason, ALR2 inhibitors can be alternative to prevent and delay the development of diabetic complications. 7 Furthermore many compounds have been isolated from medicinal plants 8–13 and also have been synthesized to obtain active ALR2 inhibitors. 14–16 Ginseng, the root of Panax ginseng C. A. Meyer (Araliaceae), has been used as traditional medicines in Korea, China and other East Asia countries for thousands of years. Many of medicinal effects of ginseng are recognized to the main active constituents of ginseng which are known as ginsenosides (triterpene glycosides). More than 50 ginsenosides have been clarified. Generally ginseno- sides are divided into three types; first type is protopanaxadiol type ginsenosides (PPD) including Ra 1 –Ra 3 , Rb 1 –Rb 3 , etc. Second type is protopanaxatriol type ginsenosides (PPT) such as Re, Rg 1 , Rg 2 , etc. Third type is oleanonic acid type such as ginsenoside Ro. 17 Many of the pharmacological effects of ginseng, including antitumor activities, 18 anti-oxidant and oxidative stress, 19–22 anti hyperalgesic, 23 etc. Ginseng has been reported to be effective in the prevention and treatment of diabetic complications such as nephropathy. 24,25 Recently, it was also reported that after eight weeks of hydrolyzed ginseng extract supplementation on diabetic participants were sig- nificantly reduced fasting plasma glucose and postprandial glucose compared to the placebo group. Furthermore, there is no clinically significant changes in any safety parameter were observed. 26 These scientific evidences have been proved that ginseng can be used as potential supplement to reduce the risk of diabetic complications. Therefore, in the course of our studies on compounds made from natural products for anti diabetic complication agents, we have determined ginsenosides isolated from P. ginseng against aldose reductase. In the current study, we determine aldose reductase inhibition of ginsenoside 20(S)-Rh2, ginsenoside 20(R)-Rh2, ginsenoside 20(RS)-Rh2, ginsenoside 20(S)-Rg3, ginsenoside 20(R)-Rg3, ginse- noside 20(S)-Rg2, ginsenoside 20(S)-Rh1, ginsenoside Compound K and quercetin as positive control. From our experiment, all http://dx.doi.org/10.1016/j.bmcl.2014.08.009 0960-894X/Ó 2014 Elsevier Ltd. All rights reserved. ⇑ Corresponding author. Tel./fax: +81 92 642 3002. E-mail address: shimizu@agr.kyushu-u.ac.jp (K. Shimizu). Bioorganic & Medicinal Chemistry Letters 24 (2014) 4407–4409 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl