Salacinol and related analogs: new leads for type 2 diabetes therapeutic candidates from the Thai traditional natural medicine Salacia chinensis.
The antidiabetic effect of a hot water extract of stems of Salacia chinensis (SCE) was evaluated in vivo in KK-Ay mice, a typical type 2 diabetes mellitus mice model. Administration of CE-2 dietary feed containing 0.25 and/or 0.50% of SCE for three weeks to KK-Ay mice significantly suppressed the elevation of both blood glucose and HbA1c levels without significant changes in body weight or food intake. Glucose tolerance was improved by administration to KK-Ay mice for 27 days of AIN93M purified dietary feed containing 0.12% of SCE. No suppressive effect with respect to HbA1c level was observed when AIN93M/Glc dietary feed in which all digestible glucides were replaced with glucose was administered with SCE. Thus, α-glucosidase inhibitory activity approved as the mechanism of action of the antidiabetic effect of SCE by in vitro investigation was reconfirmed also in in vivo studies. Evaluation of the α-glucosidase inhibitory activity of the active constituents, salacinol (1), kotalanol (3), and neokotalanol (4), by employing human α-glucosidases revealed that these compounds inhibited them as potently (IC50 = 3.9-4.9 μM for maltase) as they inhibited rat small intestinal α-glucosidase. The principal sulfonium constituents (1-4) were highly stable in an artificial gastric juice. In addition, 1-4 were hardly absorbed from the intestine in an experiment using the in situ rat ligated intestinal loop model. The results indicate that these sulfoniums are promising leads for a new type of anti-diabetic agents.
Pharmaceutical Research and Technology Institute, Kinki University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan. morikawa@kindai.ac.jp.|Antiaging Center, Kinki University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan. morikawa@kindai.ac.jp.
Toshio
T
Morikawa
Pharmaceutical Research and Technology Institute, Kinki University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan. g-tanabe@phar.kindai.ac.jp.|Faculty of Pharmacy, Kinki University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan. g-tanabe@phar.kindai.ac.jp.|Central R & D Laboratory, Kobayashi Pharmaceutical Co., Ltd., 1-30-3, Toyokawa, Ibaraki, Osaka 567-0057, Japan. g-tanabe@phar.kindai.ac.jp.
Junji
J
Akaki
Pharmaceutical Research and Technology Institute, Kinki University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan. ninomiya@phar.kindai.ac.jp.|Antiaging Center, Kinki University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan. ninomiya@phar.kindai.ac.jp.
Kiyofumi
K
Ninomiya
Pharmaceutical Research and Technology Institute, Kinki University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan. 1011610048n@kindai.ac.jp.
Eri
E
Kinouchi
Faculty of Pharmacy, Kinki University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan. g-tanabe@phar.kindai.ac.jp.
Genzoh
G
Tanabe
Faculty of Science and Technology, Rajamangala University of Technology Srivijaya, Thungyai, Nakhon Si Thammarat 80240, Thailand. yutanap@hotmail.com.
Yutana
Y
Pongpiriyadacha
Pharmaceutical Research and Technology Institute, Kinki University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan. m-yoshikawa@leto.eonet.ne.jp.
Masayuki
M
Yoshikawa
Pharmaceutical Research and Technology Institute, Kinki University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan. muraoka@phar.kindai.ac.jp.|Antiaging Center, Kinki University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan. muraoka@phar.kindai.ac.jp.|Faculty of Pharmacy, Kinki University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan. muraoka@phar.kindai.ac.jp.
Osamu
O
Muraoka
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004195:Disease Models, Animal; D006442:Glycated Hemoglobin / Q000378:metabolism; D065089:Glycoside Hydrolase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007421:Intestine, Small / Q000378:metabolism; D008297:Male; D051379:Mice; D009005:Monosaccharides / Q000494:pharmacology / Q000627:therapeutic use*; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D049918:Salacia / Q000737:chemistry*; D013402:Sugar Alcohols / Q000494:pharmacology / Q000627:therapeutic use*; D013431:Sulfates / Q000494:pharmacology / Q000627:therapeutic use*; D013452:Sulfonium Compounds / Q000494:pharmacology / Q000627:therapeutic use; D000520:alpha-Glucosidases / Q000378:metabolism
D001786:Blood Glucose; D006442:Glycated Hemoglobin; D065089:Glycoside Hydrolase Inhibitors; D009005:Monosaccharides; D010936:Plant Extracts; D013402:Sugar Alcohols; D013431:Sulfates; D013452:Sulfonium Compounds; D000520:alpha-Glucosidases; C114502:Kotalanol; C427963:salacinol