OBJECTIVETo synthesize (2'-bromo-4',5'-dimethoxy-phenyl)-( 2,3- dibromo-4,5-dimethoxy-phenyl)-methane (6) as protein tyrosine phosphatase 1B (PTP1B) inhibitor.

METHODCompound 6 was synthesized by Friedel-Crafts reaction, bromination and decarbonylation and screened inhibitory activity against PTP1B by the colorimetric assay. The structure of synthetic intermediates and target product were identified on the basis of spectral analysis.

RESULTCompound 6 was synthesized successfully in four steps and evaluated for its PTP1B inhibitory activity, the screening result shown that compound 6 displayed good inhibitory activity against PTP1B.

CONCLUSIONThe target compound 6 was synthesized with the overall yield of 20%, which was a new compound and shown good inhibitory activity against PTP1B (inhibition 40.16% at 5 mg x L(-1)).

Enzyme Inhibitors ; chemical synthesis ; chemistry ; Kinetics ; Protein Tyrosine Phosphatase, Non-Receptor Type 1 ; antagonists & inhibitors

Drug Evaluation, Preclinical ; methods ; Magnetic Resonance Spectroscopy ; methods ; Protein Synthesis Inhibitors ; isolation & purification ; Structure-Activity Relationship

Small molecule covalent inhibitors, or called as irreversible inhibitors, are a type of inhibitors that exert their biological functions by irreversibly binding to target through covalent bonds. Compared with non-covalent inhibitors, covalent inhibitors have obvious advantages in bioactivity. Nevertheless, these agents may also exhibit larger toxicity once off-target effects arise. This "double-edged swords" property often leads drug researchers to avoid attaching them. In recent years, some problems such as drug resistance are difficult to be solved with reversible inhibitors leading researchers to pay more attention on the covalent inhibitors. In this review, we shall make a short summary to the recent research progress of covalent inhibitors and the interaction modes between covalent inhibitors and their target protein residues.
Amino Acids ; chemistry ; Antineoplastic Agents ; chemical synthesis ; chemistry ; therapeutic use ; Antiviral Agents ; chemical synthesis ; chemistry ; therapeutic use ; Drug Discovery ; Drug Resistance ; Enzyme Inhibitors ; chemical synthesis ; chemistry ; therapeutic use ; Hepatitis C ; drug therapy ; Humans ; Molecular Structure ; Neoplasms ; drug therapy ; Protein Binding ; Protein Kinase Inhibitors ; chemical synthesis ; chemistry ; therapeutic use ; Receptor, Epidermal Growth Factor ; antagonists & inhibitors ; Serine Proteinase Inhibitors ; chemical synthesis ; chemistry ; therapeutic use

To obtain higher potency and specificity, a series of 7-alkoxy analogues of illudalic acid was synthesized on the base of structure-activity relationship (SAR). All of these compounds exhibited submicromolar inhibition of the enzyme when tested against human leukocyte common antigen-related phosphatase (LAR) (for example, for 15e, IC50 = 180 nmol x L(-1)). They represent the most potent small-molecule inhibitors of LAR so far. These analogues also display excellent selectivity for LAR over other protein tyrosine phosphatases (PTPs) except for the highly homologous PTPsigma. The compound 15f is of 120-fold selectivity for LAR versus PTP-1B inhibition. The development of potent enzyme-specific inhibitors is so important that they may serve both as tools to study the role of LAR and as therapeutic agents for treatment of type II diabetes.
Coumarins ; chemical synthesis ; chemistry ; pharmacology ; Enzyme Inhibitors ; chemical synthesis ; chemistry ; pharmacology ; Inhibitory Concentration 50 ; Molecular Structure ; Receptor-Like Protein Tyrosine Phosphatases, Class 2 ; antagonists & inhibitors ; Structure-Activity Relationship

Kinases play crucial roles in the life of cell. Their functional abnormity usually leads to many human major diseases including tumors. The prospecting of ATP-competitive small-molecule kinase inhibitors targeting kinases of therapeutic interest has become the focus of researches. Due to the high conservation of the catalytic domain of kinases, the selectivity of kinase inhibitors is poor in general. However, along with the development of structural biology and computer-aided drug design, great progress in the research of selective, ATP-competitive kinase inhibitors has been achieved in recent years. In this account, the review has been made on the development of the design of selective kinase inhibitors.
Adenosine Triphosphate ; chemistry ; Binding, Competitive ; Drug Design ; Molecular Structure ; Protein Binding ; Protein Kinase Inhibitors ; chemical synthesis ; chemistry ; pharmacology

Sorafenib, the first oral multikinase inhibitor, can inhibit several kinases involved in tumor proliferation and angiogenesis including Raf, VEGFR, PDGFR, kit and so on. Due to the advantages of multi-mechanisms, broad-spectrum anticancer potency, and well-tolerated results in combination trials, more and more researchers have focused on the optimization of sorafenib in order to develop novel multi-targeted anticancer drugs. The present paper reviews the development of modification of sorafenib in recent years from two aspects: bio-isosterism and scaffold hopping. The structure-activity relationship (SAR) of these compounds is also summarized.
Animals ; Antineoplastic Agents ; chemical synthesis ; chemistry ; Cell Line, Tumor ; Humans ; Molecular Structure ; Neoplasms ; drug therapy ; pathology ; Neovascularization, Pathologic ; prevention & control ; Niacinamide ; analogs & derivatives ; chemical synthesis ; chemistry ; Phenylurea Compounds ; chemical synthesis ; chemistry ; Protein Kinase Inhibitors ; chemical synthesis ; chemistry ; Structure-Activity Relationship

HIV-1 fusion inhibitors are a new class of anti-HIV compounds, which block the entry of HIV into target cells through preventing the fusion between viral and cell plasma membrane and thus interrupt the initial steps of viral replication. T-20 (enfuvirtide), which has been clinically approved as the first fusion inhibitor of HIV-1 by U.S. FDA in 2003, can suppress replication of HIV variants with multi-drug resistance to reverse transcriptase and protease inhibitors. Peptides and small molecules display potent anti-HIV fusion activities by targeting gp41 thus inhibit its fusogenic function. In recent years, with the development of studies on the molecular mechanism of HIV membrane fusion process and the function of gp41, many new fusion inhibitors are found and some have been in advanced clinical trials. This review discusses recent progress in the development of HIV-1 fusion inhibitors targeting the gp41.
Anti-HIV Agents ; chemical synthesis ; chemistry ; pharmacology ; Drug Resistance, Multiple ; HIV Envelope Protein gp41 ; chemical synthesis ; chemistry ; pharmacology ; HIV Fusion Inhibitors ; chemical synthesis ; chemistry ; pharmacology ; HIV Infections ; drug therapy ; HIV-1 ; drug effects ; physiology ; Humans ; Peptide Fragments ; chemical synthesis ; chemistry ; pharmacology ; Peptides ; chemical synthesis ; chemistry ; pharmacology ; Recombinant Fusion Proteins ; chemical synthesis ; chemistry ; pharmacology ; Virus Replication ; drug effects ; alpha 1-Antitrypsin ; chemical synthesis ; chemistry ; pharmacology

OBJECTIVETo study the roles of protein synthesis inhibitors in long-term potentiation(LTP) and depotentiation(DP) in hippocampal CA1 region of adult rats.

METHODSStandard extracellular recording technique was used to record field EPSP(fEPSP) evoked by Schaffer collateral stimulation from the CA1 subfield of adult rat hippocampal slices. Paired-pulse low-frequency stimulation(PP-LFS) or high-intensity paired-pulse low-frequency stimulation(HI-PP-LFS) was delivered to induce depotentiation 2 h after LTP induction induced by six theta-burst stimulations. Protein synthesis inhibitors were applied before and after LTP induction to study their roles in LTP and DP in hippocampal CA1 region of adult rats.

RESULTSWhen HI-PP-LFS was applied at 2 h after LTP induction, the depotentiation was induced. The mean fEPSP slopes reduced from 346.2%±26.3% to 207.1%±21.6%. This depotentiation was named as partial LTP depotentiation and maintained at least for 30 min. The percentage of depotentiation was 59.81%. Application of protein synthesis inhibitors, anisomycin and cycloheximide prior to tetanus resulted in smaller LTP compared to control group, and almost complete depotentiation was induced by HI-PP-LFS. With application of protein synthesis inhibitors anisomycin and cycloheximide 90 min after LTP induction, HI-PP-LFS still induced partial LTP depotentiation. However, there was no significant difference in the percentage of depotentiation between this group and control group.

CONCLUSIONHI-PP-LFS partially reverses late phase LTP. When protein synthesis inhibitors are applied prior to tetanus, LTP amplitude is markedly reduced, and HI-PP-LFS completely reverses late-phase LTP. Application of protein synthesis inhibitors after LTP induction does not significantly affect either the amplitude or depotentiation of LTP.

Animals ; CA1 Region, Hippocampal ; drug effects ; In Vitro Techniques ; Long-Term Potentiation ; Long-Term Synaptic Depression ; Protein Synthesis Inhibitors ; pharmacology ; Rats

OBJECTIVETo discover BCR-ABL tyrosine kinase inhibitors through structure based virtual screening.

METHODSDocking screening against the distinctive inactive conformation of the catalytic domain of BCR-ABL tyrosine kinase was performed on 3D database. The MTT assay was performed to assess the viability of the tumor cells treated with selected compounds. The amount and kinase activity of BCR-ABL protein were detected in the presence of compounds by Western blot analysis and immunoprecipitation.

RESULTSFrom the top 1,000 compounds with the best DOCK energy score, 15 compounds were selected for biological assay. Eight out of 15 compounds showed notable inhibitory activity against Ph+ human K562 cells with IC50 values ranging from 10 to 200 micromol/L. In cell-based assays of ABL tyrosine phosphorylation, the ability of two kinds of novel, structurally diverse, lead compounds to inhibit ABL kinase activity was observed. However, no significant differences in the amount of BCR-ABL protein were noted on the ABL immunoblot in the presence of these lead compounds.

CONCLUSIONSTwo promising lead compounds were discovered to inhibit BCR-ABL tyrosine kinase activity. Virtual screening technique has been proven to narrow down the size of screening compound libraries to the most prospective drug candidates with high success rates.

Computer Simulation ; Drug Evaluation, Preclinical ; Enzyme Inhibitors ; chemical synthesis ; Fusion Proteins, bcr-abl ; Humans ; K562 Cells ; Models, Molecular ; Molecular Conformation ; Phosphorylation ; Protein-Tyrosine Kinases ; antagonists & inhibitors ; chemistry ; genetics

The enzyme leukotriene A4 (LTA4) plays an important role as precursor of slow reactive substances as LTC4, LTD4, and LTE4. It is an attractive target for molecular modeling and QSAR study. Our effort is mainly focused on exploring the SAR for inhibitors of the LTA4 hydrolase through docking study, pharmacophore modeling and molecular descriptor study. The binding of these small molecules on LTA4 hydrolase enzyme was described by the models developed on 2D molecular descriptors, with good predictive power (39 compounds, 6 descriptors, r2 0.98, SEE 0.167, F-value 268.53, q2 0.90, r2 adj 0.97, P-value < 0.0001, SD of residuals 0.15). Docking studies were employed to presume the probable binding conformation of these analogues and exploring the SAR for the compounds. The novel pharmacophore represents the ligand features that are involved in interactions with the target protein, as well as the space around the ligand occupied by the protein. The efforts are aimed to discover the SAR for the inhibitors of LTA4 hydrolase through techniques of QSAR, docking and pharmacophore.
Catalytic Domain ; Databases, Factual ; Enzyme Inhibitors ; chemical synthesis ; chemistry ; Epoxide Hydrolases ; antagonists & inhibitors ; Models, Molecular ; Molecular Structure ; Protein Binding ; Quantitative Structure-Activity Relationship ; Software ; beta-Alanine ; analogs & derivatives ; chemical synthesis ; chemistry