PTP1B Inhibitory Effect of Abietane Diterpenes Isolated from Salvia miltiorrhiza

Abstract

The reversible protein tyrosine phosphorylation by protein tyrosine kinases (PTK) and protein tyrosine phosphatases (PTP) is a key element of the signaling pathways induced by environmental stimuli.1,2) One of the intracellular PTPases, protein tyrosine phosphatase 1B (PTP1B) has been implicated in the negative regulation of insulin signaling by dephosphorylating the insulin receptor (IR) as well as its substrate, insulin receptor substrate-1 (IRS-1) and insulin receptor substrate-2 (IRS-2).3-5) The protein levels are increased in insulin-resistant diabetes patients and the deletion of PTP1B in mice has been shown to increase insulin sensitivity.6-8) Thus, inhibiting PTP1B action by using antisense oligonucleotides or small molecule inhibitors represents one of the novel therapeutic approaches for the treatment of insulin resistance.9,10) There have been a number of reports on the designing and development of synthetic PTP1B inhibitors, 11) and several classes of plant-derived secondary metabolites have been described as PTP1B inhibitors. 12)The dried root of Salvia miltiorrhiza BUNGE (Labiatae), called 'Danshen' in China, is one of the most popular traditional Chinese medicines. This plant has been used for the treatment of various diseases such as menstrual disorder, menorrhalgia, insomnia, blood circulation diseases, angina pectoris, and inflammation. Particularly, the drug is valuable in the treatment of coronary heart diseases.13) The major constituents in the root of S. miltiorrhiza are abietane-type diterpene pigments, so called tanshinones, which have ortho-or para-naphthoquinone chromophores. 14) They are unique components found in the Salvia genus and many of them exhibit diverse biological activities. [15][16][17][18] In the study, the MeOH extract of the dried root of S. miltiorrhiza displayed significant PTP1B inhibitory effect and the further study was conducted to isolate and identify the active principles. MATERIALS AND METHODS Plant MaterialsThe dried roots of S. miltiorrhiza were purchased from Il-sin Pharmaceutical Co., Ltd. in Daejeon, Korea. A voucher specimen (no. 162) has been deposited in the author's laboratory.Extraction and Isolation The dried roots of S. miltiorrhiza (1 kg) were extracted with MeOH (4 l) for 24 h. A portion (300 ml) of the resulting MeOH extract was concentrated. The dried extract (2.64 g) was subjected to silica gel column chromatography (Merck Kieselgel 60; 100 g; 0.015-0.040 mm particle size; 4.5ϫ18.5 cm). The column was eluted with a gradient consisting of hexane-EtOAc (95 : 5, 1800 ml; 93 : 7, 400 ml; 90 : 10, 400 ml; 80 : 20, 400 ml; 70 : 30, 200 ml; 50 : 50, 200 ml; 40 : 60, 200 ml; 20 : 80, 200 ml; 100% EtOAc 200 ml; collecting 200 ml fraction) and 200 ml; 80 : 20, 200 ml; 70 : 30, 200 ml; collecting 200 ml fraction). Fractions of similar composition as determined by TLC analysis were pooled, affording 11 fractions (fr. 1-11). Fr. 2 (23 mg, eluted between 700 to 800 ml) yielded 1 (4.6 mg) by preparative reversed phase HPLC using a gradient from 60 to 100% C...

Natural products possessing protein tyrosine phosphatase 1B (PTP1B) inhibitory activity found in the last decades

“…An enantioselective synthesis of 221 is described by Ling et al [146] . Bioassay-guided fractionation and purification of the MeOH extract of the dried root of the plant Salvia miltiorrhiza called 'Dan-Shen' in China, produced three related abietanetype diterpene metabolites, namely isotanshinone IIA 228, dihydroisotanshinone I 229, and isocryptotanshinone 230 [147] . [148] , which were also obtained by partial synthesis from 16-hydroxycarnosol [149] .…”

Tanshinone IIA inhibits osteoclast differentiation through down-regulation of c-Fos and NFATc1

“…Tanshinones have been widely used to treat menorrhalgia, insomnia, coronary disease, and cardiovascular disease (Takahashi et al, 2002;Han et al, 2005). Furthermore, tanshinone IIA has been shown to be a potent antioxidant and to have anticancer activity against various cancer cells (Wu et al, 1998;Wang et al, 2005).…”

Protective Effect of Salvianic Acid A on Acute Liver Injury Induced by Carbon Tetrachloride in Rats

“…5) S. miltiorrhiza BGE (Danshen) is a well-known Chinese medicinal herb widely used to treat heart and cerebral diseases, 6) hepatitis, hemorrhage, and type 2 diabetes. 7,8) Salvianic acid A [2-(3,4-dihydroxyphenyl)-2-hydroxy-propanoic acid, SA] is one of the main active components of S. miltiorrhiza BGE. Previous studies have shown that SA is effectively able to protect myocardial mitochondrial membrane from ischemia-reperfusion injury, 9) inhibit lipid peroxidation of mitochondrial membrane of hepatic cells, 10) and prevent apoptosis of human neuroblastoma SH-SY5Y cells by antioxidant mechanism in vitro.…”