Chemical Constituents from Sambucus adnata and Their Protein-Tyrosine Phosphatase 1B Inhibitory Activities

Abstract

Type-2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by b-cell dysfunction and insulin resistance, and its prevalence has reached epidemic proportions worldwide.1-3) Protein-tyrosine phosphatase 1B (PTP1B) is a major non-transmembrane phosphotyrosine phosphatase expressing ubiquitously in the classical insulin-targeted tissues 4,5) and functions as a negative regulator of the insulinsignaling pathway.6,7) Inhibition of PTP1B has been demonstrated to be an effective therapeutic approach to treatment of T2DM and much attention has been paid to PTP1B inhibitors for antidiabetic drug design. 8,9) Sambucus adnata (Caprifoliaceae) is a perennial herbaceous plant distributed in Southwest of China, and has long been used in Traditional Chinese Medicine (TCM) to treat bastard measles and acute nephritis.10) The chemical constituents of S. adnata and their bioactive activities are still not well understood, but has been reported to contain triterpenes, lignans, flavonols and sterols, and the isolated flavonols shows angiotensin-converting enzyme inhibitory activity. 11,12)During our PTP1B inhibitor screening program from TCM, 13) the MeOH extract of S. adnata showed significant inhibitory activity against PTP1B with an IC 50 value of 0.96Ϯ0.09 mg/ml. Further bioassay-guided fractionation of this extract resulted in the isolation of a novel acylated triterpene (1), together with other twelve known compounds (2-13). Herein, we report the isolation, structural determination, and evaluation of the PTP1B inhibitory activities of these compounds. The MeOH extract from the whole plants of Sambucus adnata has shown significant protein-tyrosine phosphatase 1B (PTP1B) inhibitory activity. Chemical study on the extract resulted in the isolation of thirteen compounds, including a novel triterpene (1). The structure of 1 was determined to be 1a a,3b b-dihydroxy-urs-12-en-11-one-3-yl palmitate on the basis of extensive spectroscopic analyses. Among the isolated compounds, ursolic acid, oleanolic acid and (؎)-boehmenan showed the most potent PTP1B inhibitory activity in vitro with the IC 50 values of 4.1, 14.4 and 43.5 m mm, respectively. The kinetic analysis indicated that (؎)-boehmenan inhibits PTP1B activity in a competitive manner.

Evaluation of 147 Kampo prescriptions as novel protein tyrosine phosphatase 1B (PTP1B) inhibitory agents

“…The nonenzymatic hydrolysis of 2 mM p -NPP was corrected by measuring the increase in absorbance at 405 nm, which was obtained in the absence of PTP1B. In this study, ursolic acid, a known PTP1B inhibitor, was used as the positive control and exhibited an IC 50 (50% inhibition concentration) of 4.3 μM, which was consistent with a previous report [16]. …”

Secondary metabolites from Sambucus ebulus

“…These data were indicative of the presence of an isovaleryl moiety. The signals at 22.3 (2C), 25.6, 42.9, and 171.7 in the 13 C NMR spectrum supported this assumption. 14 Moreover, the presence of 2 acetoxy groups was evident from the signals at δ H 2.05 (3H) and 2.04 (3H) and the corresponding carbon resonances at δ C 21.0, 20.8, and 170.2 (2C).…”

“…9-12 with EtOAc/n-hexane (15%-80%) as eluent system yielded sambulin B (1). [2M+Na] + , 1 H NMR (600 MHz, CDCl 3 ) and 13 C NMR (150 MHz, CDCl 3 ) Table 1. 3.…”

Chemistry and Pharmacognosy of the Genus Durio

“…Boehmenan, isolated from Hibiscus taiwanensis (Malvaceae), was moderately cytotoxic to the A549 (human lung adenocarcinoma epithelial cell line) and MCF-7 cell lines with EC 50 values of 18.4 and 10.9 μg/mL, respectively, and inhibited HIV replication in H9 lymphocyte cells with an IC 50 value of 19.43 μg/mL [66]. Moreover, boehmenan obtained from a methanolic extract of whole plants of Sambucus adnata (Caprifoliaceae) inhibited PTP1B (protein-tyrosine phosphatase 1B) with an IC 50 value of 43.5 g/mL [67]. Erythro-carolignan E (13) showed cytotoxic activity against A549 and MCF-7 cell lines with EC 50 values of 10.6 and 8.5 g/mL, respectively [66].…”