Aglaiabbrevins A–D, New Prenylated Bibenzyls from the Leaves of <i>Aglaia abbreviata</i> with Potent PTP1B Inhibitory Activity

Abstract

Four new prenylated bibenzyls, named aglaiabbrevins A-D (2, 4-6), were isolated from the leaves of Aglaia abbreviata, along with two known related analogues, 3,5-dihydroxy-2-[3,7-dimethyl-2(E),6-octadienyl] bibenzyl (7) and 3,5-dihydroxy-2-(3-methyl-2-butenyl)bibenzyl (8). The structures of the new compounds were elucidated on the basis of extensive spectroscopic experiments, mainly one and two dimensional (1D-and 2D)-NMR, and the absolute configuration of 5 was determined by the measurement of specific rotation. The isolated compounds were evaluated for their protein tyrosine phosphatase-1B (PTP1B) inhibitory activity. The results showed that compounds 5-7 exhibited more potent PTP1B inhibitory effects with IC 50 values of 2.58 0.52, 2.44 0.35, and 2.23 0.14 µM, respectively, than the positive control oleanolic acid (IC 50 2.74 0.20 µM). On the basis of the data obtained, these bibenzyls with the longer C-2 prenyl groups may be considered as potential lead compounds for the development of new anti-obesity and anti-diabetic agents. Also, the PTP1B inhibitory effects for prenylated bibenzyls are being reported for the first time.Key words Aglaia abbreviata; prenylated bibenzyl; aglaiabbrevin; protein tyrosine phosphatase-1B inhibitor; potential lead compound Type 2 diabetes (T2D) is a chronic disorder characterized by hyperglycemia associated with a gradual decline in insulin sensitivity and/or insulin secretion, and has become one of the most serious health problems worldwide. On the other hand, obesity is one of the major risk factors for developing T2D due to insulin resistance. 1) Protein tyrosine phosphatases (PTPs) are responsible for the dephosphorylation of tyrosine residues and are considered negative regulators of insulin signaling.2) Among the various members of the PTP superfamily, PTP1B plays a critical role in metabolic signaling pathways, which places it in an ideal position as a therapeutic drug target for diabetes and obesity.3) Therefore, PTP1B is a promising drug target for the treatment of T2D and obesity and is also involved in cancer. Although there have been a number of reports on the design and development of PTP1B inhibitors, new types of such compounds with suitable pharmacological properties remain to be discovered.The plant Aglaia abbreviata C. Y. WU (Meliaceae), which is a wild evergreen shrub found on mountain slopes at up to ca. 500-1600 m altitude, is widely distributed throughout southwestern China. 4) Members of the genus Aglaia have been studied extensively, resulting in the isolation of many types of interesting secondary metabolites, particularly of various triterpenoids (e.g., cycloartanes, dammaranes, tirucallanes) and flavaglines (e.g., cyclopenta [b] [8][9][10] In an ongoing research for biologically active substances from various natural sources, 11-15) the plant A. abbreviata attracted our attention because the ethyl acetate (EtOAc) extract of the leaves of this plant showed inhibitory activity against PTP1B with an 65.2% inhibition at the concentration of 20 µg/mL. A...

Rearranged Diels–Alder Adducts and Prenylated Flavonoids as Potential PTP1B Inhibitors from Morus nigra

“…The recombinant PTP1B catalytic domain was expressed and purified according to the methodology as previously reported. − The enzymatic activities of the PTP1B catalytic domain were determined at 30 °C by monitoring the hydrolysis of p NPP. Dephosphorylation of p NPP generated the product p NP, which was monitored at an absorbance of 405 nm with an EnVision multilabel plate reader (Perkin–Elmer Life Sciences, Boston, MA, USA).…”

An Overview on the Biological Perspectives of Aglaia Species

“…Leading to apoptosis [34].Antidiabetic activitySun et al confirmed prenylated bibenzyls named aglaiabbrevins A-D isolated from the leaves of Aglaia abbriviata inhibits protein tyrosine phosphatase-1B (PTP1B). These prenylated bibenzyls may be considered as lead compounds for the development of new antiobesity and antidiabetic agents[35].Anti-inflammatory activityLiu et al derived anti-inflammatory activity and other antioxidant, antimicrobial activities from the medicinal plants honey, made from different floral sources. Floral honey from Aglaia formosana was involved in testing of anti-inflammatory activity [36]…”