A pair of new lignan enantiomers from Croton tiglium

A pair of new 3′,7-epoxy-8,4′-oxyneolignan enantiomers [(+)-1 and (−)-1] as well as a known phenylpropanoid (2) were isolated from the seeds of Croton tiglium Linn. Their structures were established based on extensive spectroscopic analyses. The absolute configurations of (+)-1 and (−)-1 were determined by NMR data calculations and electronic circular dichroism calculations. All compounds were isolated from the genus Croton for the first time. Particularly, (+)-1 and (−)-1 were the first 3′,7-epoxy-8,4′-oxyneolignanes reported in Croton. The chemotaxonomic significance of these compounds was discussed.     

Two new diphenyl ethers from Acanthopanax senticosus (Rupr. & Maxim.) Harms with PTP1B inhibitory activity

Bioassay-guided fractionation of an EtOAc-soluble extract of Acanthopanax senticosus (Rupr. & Maxim.) Harms yielded two new diphenyl ethers, 3-[3′-methoxy-4′-(4″-formyl-2″,6″-dimethoxy-phenoxy)-phenyl]-propenal (1) and 3-[3′,5′-dihydroxy-4′-(4″-hydroxymethyl-3″,5″-dimethoxy-phenoxy)-phenyl]-propenal (2), along with eight other known compounds (3–10). The structures of these new ethers were elucidated with spectroscopic and physico-chemical analyses. All of the isolates were evaluated for their in vitro inhibitory activity against PTP1B, VHR and PP1. The new compounds (1 and 2) inhibited PTP1B with IC₅₀ values ranging from 9.2 ± 1.4 to 12.6 ± 1.2 μM.     

Magmenthanes A-H: Eight new meroterpenoids from the bark of Magnolia officinalis var. Biloba

Eight new meroterpenoids with different types of monoterpene units, namely, magmenthanes A-H (1–8), were identified from the bark of Magnolia officinalis var. biloba. Magmenthane A (1) possesses a 1,3-dioxabicyclo [4.3.0^1,5] nonane skeleton, 1–5 possess five pairs of enantiomers and 6 possesses a 1,1′-diallyl-biphenyl fragment. The structures of 1–8 were elucidated on the basis of 1D and 2D NMR, HRESIMS and electronic circular dichroism (ECD) calculations. Compounds 5 and 8 displayed significant PTP1B inhibitory activities with IC₅₀ values of 4.38 and 3.88 μM, respectively.     

Polycyclic phloroglucinols as PTP1B inhibitors from Hypericum longistylum: Structures,PTP1B inhibitory activities,and interactions with PTP1B

Protein tyrosine phosphatase 1B (PTP1B) has been regarded as a target for the research and development of new drugs to treat type II diabetes and PTP1B inhibitors are potential lead compounds for this type of new drugs. A phytochemical investigation to obtain new PTP1B inhibitors resulted in the isolation of four new phloroglucinols, longistyliones A–D (1–4) from the aerial parts of Hypericum longistylum. The structures of 1–4 were elucidated on the basis of extensive 1D and 2D NMR spectroscopic data analysis, and the absolute configurations of these compounds were established by comparing their experimental electronic circular dichroism (ECD) spectra with those calculated by the time-dependent density functional theory method. Compounds 1–4 possess a rare polycyclic phloroglucinol skeleton. The following biological evaluation revealed that all of the compounds showed PTP1B inhibitory effects. The further molecular docking studies indicated the strong interactions between these bioactive compounds with the PTP1B protein, which revealed the possible mechanism of PTP1B inhibition of bioactive compounds. All of the results implied that these compounds are potentially useful for the treatment of type II diabetes.     

PTP1B inhibitors from Selaginella tamariscina (Beauv.) Spring and their kinetic properties and molecular docking simulation

Diabetes is one of the most popular worldwide diseases, regulated by the defects in insulin secretion, insulin action, or both. The overexpression of protein tyrosine phosphatase 1B (PTP1B) was found to down-regulate the insulin-receptor activation. PTP1B has been known as a strategy for the treatment of diabetes via the regulation of insulin signal transduction pathway. Herein, we investigated the PTP1B inhibitors isolated from natural sources. The chemical investigation of Selaginella tamariscina (Beauv.) Spring revealed seven unsaturated alkynyl phenols 1–7, four new selaginellins T–W 1–4 together with three known compounds 5–7 isolated from the aerial parts. The structures of the isolates were determined by spectroscopic techniques (1D/2D-NMR, MS, and CD). The inhibitory effects of these isolates on the PTP1B enzyme activity were investigated. Among them, compounds 2–7 significantly exhibited the inhibitory effects with the IC₅₀ values ranging from 4.8 to 15.9 μM. Compound 1 moderately displayed the inhibitory activity with an IC₅₀ of 57.9 μM. Furthermore, active compounds were discovered from their kinetic and molecular docking analysis. The results revealed that compounds 2 and 4–7 were mixed-competitive inhibitors, whereas compound 3 was a non-competitive inhibitor. This data confirm that these compounds exhibited potential inhibitory effect on the PTP1B enzyme activity.     

Pyranocoumarins: A new class of anti-hyperglycemic and anti-dyslipidemic agents

A series of pyranocoumarin derivatives were synthesized and evaluated in vivo for their anti-hyperglycemic as well as anti-dyslipidemic activities. Compounds 7a, 7c, 8a, 8b, 8c, 8e and 8f have shown promising anti-hyperglycemic activities in sucrose loaded model (SLM) as well as sucrose challenged streptozotocin induced diabetic rat model (STZ). Compounds 8a and 8b were showing 38.0% and 42.0% blood glucose lowering activity in db/db mice model. In vitro anti-hyperglycemic activity evaluation exhibited that compounds 8a (IC₅₀ = 24.5 μM) and 8b (IC₅₀ = 36.2 μM) are potential PTP-1B inhibitors thereby revealing their possible mechanism of anti-diabetic action. Compounds 7a, 7b, 8a, 8b, 8d, 8e and 8f have shown significant anti-dyslipidemic activity in triton induced dyslipidemia in rats.     

Tanzawaic acid derivatives from a marine isolate of Penicillium sp. (SF-6013) with anti-inflammatory and PTP1B inhibitory activities

Chemical investigation of a marine-derived fungus Penicillium sp. SF-6013 resulted in the discovery of a new tanzawaic acid derivative, 2E,4Z-tanzawaic acid D (1), together with four known analogues, tanzawaic acids A (2) and D (3), a salt form of tanzawaic acid E (4), and tanzawaic acid B (5). Their structures were mainly determined by analysis of NMR and MS data, along with chemical methods. Preliminary screening for anti-inflammatory effects in lipopolysaccharide (LPS)-activated microglial BV-2 cells showed that compounds 1, 2, and 5 inhibited the production of nitric oxide (NO) with IC₅₀ values of 37.8, 7.1, and 42.5 μM, respectively. Compound 2 also inhibited NO production in LPS-stimulated RAW264.7 murine macrophages with an IC₅₀ value of 27.0 μM. Moreover, these inhibitory effects correlated with the suppressive effect of compound 2 on inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression in LPS-stimulated RAW264.7 and BV2 cells. In addition, compounds 2 and 5 significantly inhibited the activity of protein tyrosine phosphatase 1B (PTP1B) with the same IC₅₀ value (8.2 μM).     

Cembrane diterpenoids from the soft coral Sarcophyton trocheliophorum Marenzeller as a new class of PTP1B inhibitors

A detailed investigation of the South China Sea soft coral Sarcophyton trocheliophorum Marenzeller yielded, along with six known terpenes (6?11), the new sarcophytonolides N?R (1?5), whose structures have been elucidated by detailed spectroscopic analysis. Sarcophytonolides N–R are mono- or bicyclic cembranoids characterized by the presence of three/four double bonds and oxidized methyl groups. Some of the isolated compounds showed significant inhibitory activity against human protein tyrosine phosphatase 1B (PTP1B) enzyme, a key target for the treatment of type-II diabetes and obesity, and some preliminary structure–activity relationships have been drawn. This is the first report on the anti-PTP1B activity of cembrane diterpenoids.     

Four new C-glycosylflavones from the leaves of Iris lactea Pall. var. chinensis (Fisch.) Koidz.

Four new acylated C-glycosylflavones, termed embinins A–C and irislactin C, were isolated from the leaves of Iris lactea and their structures were elucidated by extensive NMR experiments and mass spectrometry studies. Embinin A and irislactin C showed weak cytotoxicity against A549 (human lung cancer) cells.     

Three new terpenoids from Trigonostemon xyphophylloides (Croiz.) L.K. Dai and T.L. Wu

Two new daphnane diterpenoids, trigoxyphins J and K (1 and 2), and one new friedelane triterpene derivative, 3-O-benzoylpluricostatic acid (3), together with thirteen known terpenoids (4–16) were isolated from Trigonostemon xyphophylloides (Croiz.) L.K. Dai and T.L. Wu. Their structures were identified on the basis of physicochemical properties and spectroscopic data. All compounds were evaluated for their cytotoxicity against K562, SGC-7901, and BEL-7402 tumor cell lines, respectively.     

Eight new biflavonoids with lavandulyl units from the roots of Sophora flavescens and their inhibitory effect on PTP1B

In the course of studying the components from the roots of Sophora flavescens, eight new unusual biflavonoids consisting of a flavanone fused with a dihydrochalcone skeleton were isolated. These new chemical structures were elucidated by means of UV, IR, HRESIMS, NMR and ECD spectroscopic data and a comparison of experimental ECD spectra with calculated ECD spectra. Some compounds were subjected to an antidiabetic bioassay on human recombinant PTP1B inhibition, and showed strong inhibitory activity.     

The insulin-mimetic effect of Morin: A promising molecule in diabetes treatment

Background

Type-2 diabetes is a worldwidely diffuse disease characterized by insulin resistance that arises from alterations of receptor and/or post-receptor events of insulin signalling. Studies performed with PTP1B-deficent mice demonstrated that PTP1B is the main negative regulator of insulin signalling. Inhibition or down regulation of this enzyme causes enhanced insulin sensitivity. Hence this enzyme represents the most attractive target for development of innovative anti-diabetic drugs.

Methods

Selection of new PTP1B inhibitors among an in house library of polyphenolic compounds was carried out screening their activity. The inhibition mechanism of Morin was determined by kinetic analyses. The cellular action of Morin was assayed on HepG2 cells. Analyses of the insulin signalling pathways was carried out by Western blot methods, glycogen synthesis was estimated by measuring the incorporation of [³H]-glucose, gluconeogenesis rate was assayed by measuring the glucose release in the cell medium. Cell growth was estimated by cell count. Docking analysis was conducted with SwissDock program.

Results

We demonstrated that Morin: i) is a non-competitive inhibitor of PTP1B displaying a K_i in the μM range; ii) increases the phosphorylation of the insulin receptor and Akt; iii) inhibits gluconeogenesis and enhances glycogen synthesis. Morin does not enhance cell growth.

Conclusions

We have identified Morin as a new small molecular non-competitive inhibitor of PTP1B, which behaves as an activator and sensitizer of the insulin receptor stimulating the metabolic pathways only.

General significance

Our study suggests that Morin is a useful lead for development of new low Mr compounds potentially active as antidiabetic drugs.     

Chemical constituents from Stenosolenium saxatile (Pall.) Turcz. (Boraginaceae)

Chemical investigation on the whole plants of Stenosolenium saxatile led to the isolation of three naphthoquinones (1–3), five pyrrolizidine alkaloids (PAs) (4–8), and six phenolic acids (9–14). The structure of the isolated compounds was elucidated by different spectrometric methods (¹H NMR, ¹³C NMR and ESI-MS). These results are the first chemical data on constituents of this genus. The chemotaxonomic relationships between the genera Stenosolenium, Onosma, Arnebia, Echium and Lithospermum are also discussed.     

Four new limonoids from the seeds of Chukrasia tabularis A. Juss.

Two new C-15 enolic acyl phragmalin-type limonoid orthoesters (1-2) which possessed a C-15-propionyl phragmalin skeleton and two new mexicanolide-type limonoids (3-4) were isolated from the ethanol extract of seeds of Chukrasia tabularis A. Juss. Their structures were established on the basis of spectroscopic analyses and electronic circular dichroism (ECD) exciton chirality method. Additionally, all of the compounds were screened against three human tumor cell lines MCF-7, SMMC-7721, and U2OS.     

Benzo[c][1,2,5]thiadiazole derivatives: A new class of potent Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) inhibitors

The Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) is an oncogenic phosphatase linked to various kinds of cancers. Consequently, SHP2 has emerged as a promising target for novel anti-cancer agents. Using scaffold-hopping strategy, a series of benzo[c][1,2,5]thiadiazole derivatives was designed from PTP1B inhibitors with 1H-2,3-Dihydroperimidine motif, synthesized and evaluated their biological activities against PTP1B and SHP2. Among them, the representative compound 11g displayed SHP2 inhibitory activity with IC₅₀ of 2.11?±?0.99?μM, exhibited 2.02-fold and 25-fold selectivity for SHP2 over SHP1 and PTP1B respectively and had no visible activity against TCPTP. These preliminary results could provide a possible opportunity for the development of novel SHP2 inhibitors with optimal potency and improved pharmacological properties.     

Phosphorylation and activation of protein tyrosine phosphatase (PTP) 1B by insulin receptor

We have previously reported a direct in vivo interaction between the activated insulin receptor and protein-tyrosine phosphatase-1B (PTP1B), which leads to an increase in PTP1B tyrosine phosphorylation. In order to determine if PTP1B is a substrate for the insulin receptor tyrosine kinase, the phosphorylation of the Cys 215 Ser, catalytically inactive mutant PTP1B (CS-PTP1B) was measured in the presence of partially purified and activated insulin receptor. In vitro, the insulin receptor tyrosine kinase catalyzed the tyrosine phosphorylation of PTP1B. 53% of the total cellular PTP1B became tyrosine phosphorylated in response to insulin in vivo. Tyrosine phosphorylation of PTP1B by the insulin receptor was absolutely dependent upon insulin-stimulated receptor autophosphorylation and required an intact kinase domain, containing insulin receptor tyrosines 1146, 1150 and 1151. Tyrosine phosphorylation of wild type PTP1B by the insulin receptor kinase increased phosphatase activity of the protein. Intermolecular transdephosphorylation was demonstrated both in vitro and in vivo, by dephosphorylation of phosphorylated CS-PTP1B by the active wild type enzyme either in a cell-free system or via expression of the wild type PTP1B into Hirc-M cell line, which constitutively overexpress the human insulin receptor and CS-PTP1B. These results suggest that PTP1B is a target protein for the insulin receptor tyrosine kinase and PTP1B can regulate its own phosphatase activity by maintaining the balance between its phosphorylated (the active form) and dephosphorylated (the inactive form) state.