•This paper provide attractive visualizations from active natural products to potent PTP1B inhibitors.•Two challenging aspects, cellular activity and selectivity over TCPTP, were break through.•Entropy-driven optimization was employed to improve inhibitory activity without massive restructuring.•As an efficient insulin-independent agent, 22 increased the phosphorylation levels of IRβ, Akt and IRS1.Protein tyrosine phosphatases 1B (PTP1B) is a promising and validated therapeutic target to effectively treat T2DM and obesity. However, the development of charged PTP1B inhibitors was restricted due to their low cell permeability and poor bioavailability. Based on active natural products, two series of uncharged catechol derivatives were identified as PTP1B inhibitors by targeting a secondary aryl phosphate-binding site as well as the catalytic site. The most potent inhibitor 22 showed an IC50 of 0.487 μM against PTP1B and strong selectivity (27-fold) over TCPTP. Kinetic studies were also performed that 22 act as a competitive PTP1B inhibitor. The treatment of C2C12 myotubes with 22 markedly increased the phosphorylation levels of IRβ, Akt and IRS1 phosphorylation. The similarity of its action profiling with that produced by insulin suggested its potential as a new non-insulin-dependent drug candidate.Download high-res image (223KB)Download full-size image

A series of novel carbohydrate-modified antitumor compounds were designed based on glucose transporter 1 (GLUT1), and evaluated for their anticancer activities against four cancer cell lines. The ribose derivatives (compound 9 and 10) exhibited modest inhibitory activity. The compound 9 significantly inhibited the migration of A549 cell and induced A549 cell apoptosis in a concentration-dependent manner. Moreover, compound 9 blocked A549 cells at the G0/G1 phase. The cellular uptake studies suggested that ribose-modified compound 9 could be taken through GLUT1 in A549 cell line.Download high-res image (84KB)Download full-size image

•The hybrid of bromophenol and saccharide was prepared.•Compound 10a exhibited remarkable selectivity for PTP1B over TCPTP.•Molecule docking and molecular dynamics studies reveal the reason of selectivity.•The cell permeability and cellular activity of compound 10a were demonstrated.Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin signaling pathway. Inhibition of PTP1B is expected to improve insulin action. Appropriate selectivity and permeability are the gold standard for excellent PTP1B inhibitors. In this work, molecular hybridization-based screening identified a selective competitive PTP1B inhibitor. Compound 10a has IC50 values of 199 nM against PTP1B, and shows 32-fold selectivity for PTP1B over the closely related phosphatase TCPTP. Molecule docking and molecular dynamics studies reveal the reason of selectivity for PTP1B over TCPTP. Moreover, the cell permeability and cellular activity of compound 10a are demonstrated respectively.Download high-res image (433KB)Download full-size image

•Compound 1 induced apoptosis in lung cancer cells.•Compound 1 induced G0/G1 phase arrest in lung cancer cells.•ROS-mitochondria pathway plays a vital role in compound 1-induced apoptosis.Thiosemicarbazone, a class of compounds with excellent biological activity, especially antitumor activity, have attracted wide attention. In this study, a novel fluorinated thiosemicarbazone derivative, 2-(3,4-difluorobenzylidene) hydrazinecarbothioamide (compound 1) was synthesized and its antitumor activities were further investigated on a non-small cell lung cancer cell line (A549) along with its underlying mechanisms. Compound 1 showed significant anti-proliferative activity on A549 cells, which was further proved by colony formation experiment. Compound 1 also inhibits the invasion of A549 cells in a trans-well culture system. Moreover, compound 1 markedly induced apoptosis on A549 cells, and the ratio of Bcl-2/Bax was decreased while the amount of p53, Cleaved-Caspase 3 and Cleaved-PARP expression were increased significantly. Compound 1 decreased the mitochondrial membrane potential, while the content of reactive oxygen was increased obviously. It is revealed that compound 1 mediated cell cycle arrest in G0/G1 phase by reducing G1 phase dependent proteins, CDK4 and Cyclin D1. As a result, it is indicated that compound 1 induced apoptosis on A549 cells was realized by regulating ROS-mediated mitochondria-dependent signaling pathway.

Finding novel anticancer agents is very important for the treatment of cancer, and marine organisms are a valuable source for developing novel agents for clinical application. Therefore, the isolation and identification of novel anticancer components from brown seaweeds and a study of their mode of action is very attractive in current scenarios to assess their potential as an unexplored source for pharmacological applications. This review will reveal the active components of brown algae, together with their antitumor potential toward cancer treatment according to their structure. This should provide useful information for medicinal chemists in their attempts to develop potent anticancer agents.

Protein tyrosine phosphatase 1B (PTP1B) has already been well studied as a highly validated therapeutic target for diabetes and obesity. However, the lack of selectivity limited further studies and clinical applications of PTP1B inhibitors, especially over T-cell protein tyrosine phosphatase (TCPTP). In this review, we enumerate the published specific inhibitors of PTP1B, discuss the structure–activity relationships by analysis of their X-ray structures or docking results, and summarize the characteristic of selectivity related residues and groups. Furthermore, the design strategy of selective PTP1B inhibitors over TCPTP is also proposed. We hope our work could provide an effective way to gain specific PTP1B inhibitors.

A series of novel fluorinated anticancer agents containing the indolin-2-one moiety were designed, synthesized and evaluated for their anticancer activities in vitro. Among them, compounds 6, 7, 9, 12 and 13 showed potent activities against the tested human cancer cell lines. Notably, compound 6 showed significant activities against A549, Bel7402, HepG2, HCT116 and HeLa cancer cell lines, which were comparable to those of sunitinib. Further study on its mechanisms demonstrated that compound 6 can be used as a potential anticancer agent for inhibiting proliferation and inducing apoptosis of HepG2 cells, along with inhibiting angiogenesis of HUVECs.

Diabetes mellitus, which includes both type 1 and type 2 diabetes mellitus (T2DM), is a major disease that threatens human health worldwide. Protein tyrosine phosphatase 1B (PTP1B) is a promising molecular-level therapeutic target that is effective in the management of T2DM. Natural products with various skeletons and diverse bioactivities offer opportunities for the development of new drugs and lead compounds with potent inhibitory activity against PTP1B in vitro and in vivo. Recently, a number of potent PTP1B inhibitors have been obtained from natural sources or prepared by synthesis/semi-synthesis, and they exhibit potential for the treatment of T2DM. In this review, we discuss the development of potent natural and semisynthetic PTP1B inhibitors with IC50 values under 10 μM over the past six years (2009–2014), including their structural features, biological features, structure–activity relationships (SARs). We also discuss strategies for identifying potent PTP1B inhibitors from natural products to provide useful information for use by medicinal chemists in developing potent PTP1B inhibitors as T2DM treatments.

•Bromophenol BDDPM was isolated from red alga Rhodomela confervoides.•Novel bromophenol derivatives were designed based on BDDPM.•The synthetic derivatives showed varying PTP1B inhibitory activities in vitro.•Compound 9 exhibits potent PTP1B inhibitory activity and high selectivity against other PTPs.•Compound 9 exhibits promising antidiabetic activities in db/db mouse model.In an effort to develop novel small molecule PTP1B inhibitors, a series of bromophenol derivatives were designed, synthesized and evaluated in vitro and in vivo. All of the synthesized compounds displayed weak to potent PTP1B inhibitory activities (5.62–96.25%) at 20 μg/mL. Among these compounds, 3,4-dibromo-5-(2-bromo-3,4-dihydroxy-6-(isobutoxymethyl)benzyl)benzene-1,2-diol (9) exhibited enhanced PTP1B inhibitory activity (IC50 = 1.50 μM) than the lead compound BDDPM (IC50 = 2.42 μM) and high selectivity against other PTPs (TCPTP, LAR, SHP-1 and SHP-2). Results of anti-diabetic assay using C57BL/KsJ-db/db mouse model demonstrated that compound 9 was effective at lowering blood glucose, total cholesterol and HbA1c (P < 0.01).Novel bromophenol derivatives were designed, synthesized and evaluated as PTP1B inhibitors.

A series of bromophenol derivatives were synthesized and evaluated as protein tyrosine phosphatase 1B (PTP1B) inhibitors in vitro and in vivo based on bromophenol 4e (IC50 = 2.42 μmol/L), which was isolated from red algae Rhodomela confervoides. The results showed that all of the synthesized compounds displayed weak to good PTP1B inhibition at tested concentration. Among them, highly brominated compound 4g exhibited promising inhibitory activity against PTP1B with IC50 0.68 μmol/L, which was approximately fourfold more potent than lead compound 4e. Further, compound 4g demonstrated high selectivity against other PTPs (TCPTP, LAR, SHP-1 and SHP-2). More importantly, in vivo antidiabetic activities investigations of compound 4g also demonstrated inspiring results.