PTP1B x α-glucosidase

Twelve flavonoid glycosides including five undescribed ones, lepisativutimines Q-U, were isolated and identified from Lepidium sativum seeds. Acid hydrolysis followed by acetic derivatization and GC analysis were conducted to determine the absolute configurations for sugars. Lepisativutimine U and beitingxinhuangtong A were uncommon kaempferol 8-S-glycosides, and complete NMR data of beitingxinhuangtong A were provided for the first time. Mass fragmentation pathways of isolated compounds were deduced based on their MS/MS data, and characteristic mass fragmentation patterns were summarized. Lepisativutimine U and kaempferol-7-O-α-l-rhamnopyranoside exhibited weak anti-diabetic activity against PTP1B with IC₅₀ values of 60.58 ± 3.53 and 33.90 ± 2.89 μM, respectively, quercetin-7-O-α-l-rhamnopyranoside displayed significant anti-diabetic activity against α-glucosidase with an IC₅₀ value of 25.96 ± 0.30 μM, and kaempferol 3-O-β-d-glucopyranosyl-(1 → 2)-β-d-galactopyranoside-7-O-α-l-rhamnopyranoside and kaempferol-7-O-α-l-rhamnopyranoside showed weak inhibitory activity against NO release in LPS-induced RAW264.7 cells with IC₅₀ values of 92.28 ± 4.19 and 40.77 ± 1.50 μM, respectively.

α-d-Glucose-conjugated thioureas 8a-w of substituted 4,6-diaryl-2-aminopyrimindines were designed, synthesized, and screened for their antidiabetic inhibitory activity. The thioureas with the strongest potential inhibitory activity included 8f (IC₅₀ = 11.32 ± 0.34 μM for α-amylase), 8g (IC₅₀ = 10.35 ± 0.88 μM for α-glucosidase), 8e (IC₅₀ = 2.53 ± 0.03 nM for DPP-4), and 8c (IC₅₀ = 3.93 ± 0.03 nM for PTP1B). The inhibitors 8g, 8e, and 8c were competitive α-glucosidase, non-competitive DDP-4, and non-competitive PTP1B inhibitors, respectively. In addition, compounds 8a, 8c, 8e, 8f, 8g, 8h, and 8j were noncytotoxic for 3T3 cell line. Induced fit docking study showed the key active interactions of each ligand with residues in the active site of each of these enzymes. Molecular dynamics simulation study on the representative complexes 8f/4W93 and 8e/3W2T in enzymes 4W93 and 3W2T, respectively, displayed the bioactive interactions between the residues and the corresponding potent inhibitor in the active site. Some of the various effects of the electron-donating and electron-withdrawing substituents on benzene of pyrimidine ring to inhibitory activities against enzymes related to T2DM were discussed. The calculations based on MM-GBSA showed the effects of the solvation to the active binding of the specific ligand in the active pocket of an enzyme.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease mainly caused by insulin resistance, which can lead to a series of complications such as cardiovascular disease, retinopathy, and its typical clinical symptom is hyperglycaemia. Glucosidase inhibitors, including Acarbose, Miglitol, are commonly used in the clinical treatment of hypoglycaemia. In addition, Protein tyrosine phosphatase 1B (PTP1B) is also an important promising target for the treatment of T2DM. Gynostemma pentaphyllum is a well-known oriental traditional medicinal herbal plant, and has many beneficial effects on glucose and lipid metabolism. In the present study, three new and nine known dammarane triterpenoids isolated from G. pentaphyllum, and their structures were elucidated by spectroscopic methods including HR-ESI-MS,¹H and ¹³C NMR and X-ray crystallography. All these compounds were evaluated for inhibitory activity against α-glucosidase, α-amylase and PTP1B. The results suggested that compounds 7∼10 were potential antidiabetic agents with significantly inhibition activity against PTP1B in a dose-dependent manner.