Search

Oestrogen related receptor α participated in the regulation of oxidative metabolism and mitochondrial biogenesis, and was overexpressed in many cancers including triple-negative breast cancer. A set of new ERRα inverse agonists based on p-nitrobenzenesulfonamide template were discovered and compound 11 with high potent activity (IC50 = 0.80 &#191'M) could significantly inhibit the transcription of ERRα-regulated target genes. By regulating the downstream signalling pathway, compound 11 could suppress the migration and invasion of the ER-negative MDA-MB-231 cell line. Furthermore, compound 11 demonstrated a significant growth suppression of breast cancer xenograft tumours in vivo (inhibition rate 23.58%). The docking results showed that compound 11 could form hydrogen bonds with Glu331 and Arg372 in addition to its hydrophobic interaction with ligand-binding domain. Our data implied that compound 11 represented a novel and effective ERRα inverse agonist, which had broad application prospects in the treatment of triple-negative breast cancer. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is the second common rheumatic immune disease with chronic, invasive inflammatory characteristics. Non-steroidal anti-inflammatory drugs (NSAIDs), slow-acting anti-rheumatic drugs (SAARDs), or glucocorticoid drugs can improve RA patients' symptoms, but fail to cure. Broton's tyrosine kinase (BTK) inhibitors have been proven to be an efficacious target against autoimmune indications and B-cell malignancies. Among the current 11 clinical drugs, only BMS-986142, classified as a carbazole derivative, is used for treating RA. To design novel and highly potent carbazole inhibitors, molecular docking and three dimensional quantitative structure-activity relationship (3D-QSAR) were applied to explore a dataset of 132 new carbazole carboxamide derivatives. The established comparative molecular field analysis (CoMFA) (q² = 0.761, r² = 0.933) and comparative molecular similarity indices analysis (CoMSIA) (q² = 0.891, r² = 0.988) models obtained high predictive and satisfactory values. CoMFA/CoMSIA contour maps demonstrated that bulky substitutions and hydrogen-bond donors were preferred at R1 and 1-position, respectively, and introducing hydrophilic substitutions at R1 and R4 was important for improving BTK inhibitory activities. These results will contribute to the design of novel and highly potent BTK inhibitors. [ABSTRACT FROM AUTHOR]

Abnormality of fibroblast growth factor receptor (FGFR)-mediated signaling pathways were frequently found in various human malignancies, making FGFRs hot targets for cancer treatment. To address the consistent need for a new chemotype of FGFR inhibitors, here, we started with a hit structure identified from our internal hepatocyte growth factor receptor (also called c-Met) inhibitor projecţ and conducted a chemical optimization. After exploring three parts of the hit compound, we finally discovered a new series of pyrrolo[2,3-b]pyrazine FGFR inhibitors, which contain a novel scaffold and unique molecular shape. We believe that our findings can help others to further develop selective FGFR inhibitors. [ABSTRACT FROM AUTHOR]

Tyrosine kinase fibroblast growth factor receptor (FGFR), which is aberrant in various cancer types, is a promising target for cancer therapy. Here we reported the design, synthesis, and biological evaluation of a new series of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-4-substituted-1H-indazole derivatives as potent FGFR inhibitors. The compound 6-(2,6-dichloro-3,5-dimethoxyphenyl)-N-phenyl-1H-indazole-4-carboxamide (10a) was identified as a potent FGFR1 inhibitor, with good enzymatic inhibition. Further structure-based optimization revealed that 6-(2,6-dichloro-3,5-dimethoxyphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1H-indazole-4-carboxamide (13a) is the most potent FGFR1 inhibitor in this series, with an enzyme inhibitory activity IC50 value of about 30.2 nM. [ABSTRACT FROM AUTHOR]

c-Met has emerged as an attractive target for targeted cancer therapy because of its abnormal activation in many cancer cells. To identify high potent and selective c-Met inhibitors, we started with profiling the potency and in vitro metabolic stability of a reported hit 7. By rational design, a novel sulfonylpyrazolo[4,3-b]pyridine 9 with improved DMPK properties was discovered. Further elaboration of p-p stacking interactions and solvent accessible polar moieties led to a series of highly potent and selective type I c-Met inhibitors. On the basis of in vitro and in vivo pharmacological and pharmacokinetics studies, compound 46 was selected as a preclinical candidate for further anticancer drug development. [ABSTRACT FROM AUTHOR]

A new strategy for diversity-oriented direct glycosylation of bioactive small molecules was developed. This reaction features (-)-β-pinene as acid scavenger and work with glycosyl iodides under mild conditions. With the aid of RP-HPLC and chiral SFC separation techniques, the new direct glycosylation proved effective at gram scale on bioactive small molecules including AZD6244, podophyllotoxin, paclitaxel, and docetaxel. Interesting glycoside derivatives were efficiently created with good yields and 1,2-cis selectivity. [ABSTRACT FROM AUTHOR]

The natural product Laetispicine (N-isobutyl-(3,4-methylendioxyphenyl)-2E, 4E, 9E-undecatrienoamide), was isolated from the Piper laetispicum C. DC and screened, for its antidepressant activity and antinociceptive effects. Structure-functional activities of five natural products indicated that biological activity is dependent on double bonds present within the benzene ring and a conjugated double bond located at positions 2-3 and 4-5 in the molecular structure. To further understand the structural-activity relationship of Laetispicine as a new potent and safe antidepressant, the structural-activity relationship of 39 analogs of Laetispicine were synthetized and tested in forced swimming tests in mice whilst also in protective effects against glutamate or H2O2 induced apoptosis in PC12 cells. The results show that the compound 30 — N-isobutyl-11-(4-chlorophenyl) undeca-2E,4E,9E-trienamide exhibited the same activity as the parental compound Laetispicine, and furthermore, the effective dose of this compound is lower than Laetispicine. Therefore, the compound 30 might be a potentially useful therapy in the treatment of depression. For structure, the conjugated double bonds located at 2-3, 4-5 and isolated double bonds from benzene ring are necessary for the antidepressant activities no matter the different length of carbon chain; the isobutyl connected with acylamino also are necessary; and the benzodioxole moiety is replaceable, the halogen atom in phenyl ring at the para-position could enhance this kind of activity. [ABSTRACT FROM AUTHOR]

Proteolytic cleavage of amyloid precursor protein by β-secretase (BACE1) is a key step in generating the N-terminal of β-amyloid (Aβ), which further forms into amyloid plaques that are considered as the hallmark of Alzheimer's disease. Inhibitors of BACE1 can reduce the levels of Aβ and thus have a therapeutic potential for treating the disease. We report here the identification of a series of small molecules bearing an indole acylguanidine core structure as potent BACE1 inhibitors. The initial weak fragment was discovered by virtual screening, and followed with a hit-to-lead optimization. With the aid of co-crystal structures of two discovered inhibitors (compounds 19 and 25) with BACE1, we explored the SAR around the indole and aryl groups, and obtained several BACE1 inhibitors about 1,000-fold more potent than the initial fragment hit. Accompanying the lead optimization, a previously under-explored sub-site opposite the flap loop was redefined as a potential binding site for later BACE1 inhibitor design. [ABSTRACT FROM AUTHOR]

Microwave-promoted efficient synthesis of a (Z)-3-methyleneisoindolin-1-one library from 2-bromobenzamides and terminal alkynes using Cu(OAc)2•H2O/DBU is described. Various benzamide substituents, ring substitutions, including heteroaryl, aryl acetylenes and aliphatic alkynes, could be applied to afford the desired products in good to moderate yield with high stereoselectivity. It is noteworthy that DBU maybe play a dual role as not only the base, but also as a ligand for copper. The reaction is catalyzed by the complex of Cu(OAc)2•H2O and DBU without other additives. [ABSTRACT FROM AUTHOR]

An efficient tandem route to the synthesis of 3H-1,2a¹,3-triazaacenaphthylene derivatives of the cyclazine family has been developed. Target compounds were obtained in moderate to good yields by a Yb(0Tf)3/Ag2CO3-catalyzed, three-component domino reaction. This in turn will set the stage for a wide application of this useful reaction for the synthesis of structurally diverse polyheterocydic skeletons containing the imidazo[1,2-a]pyridine privileged structure. [ABSTRACT FROM AUTHOR]

AMP-activated protein kinase (AMPK) plays an important role in mediating energy metabolism and is controlled mainly by two upstream kinases, LKB1 or Ca2+ /calmodulin-dependent protein kinase kinase-β (CaMKKβ). Previously, we found that baicalin, one of the major flavonoids in a traditional Chinese herb medicine, Scutellaria baicalensis, protects against the development of hepatic steatosis in rats feeding with a high-fat diet by the activation of AMPK, but, the underlying mechanism for AMPK activation is unknown. Here we show that in two LKB1-deficient cells, HeLa and A549 cells, baicalin activates AMPK by α Thr-172 phosphorylation and subsequent phosphorylation of its downstream target, acetyl CoA carboxylase, at Ser-79, to a similar degree as does in HepG2 cells (that express LKB1). Pharmacologic inhibition of CaMKKβ by its selective inhibitor STO-609 markedly inhibits baicalin-induced AMPK activation in both HeLa and HepG2 cells, indicating that CaMKKβ is the responsible AMPK kinase. We also show that treatment of baicalin causes a larger increase in intracellular Ca concentration ([Ca2+]i), although the maximal level of [Ca 2+]i is lower in HepG2 cells compared to HeLa cells. Chelation of intracellular free Ca2+ by EDTA and EGTA, or depletion of intracellular Ca2+ stores by the endoplasmic reticulum Ca2+ -ATPase inhibitor thapsigargin abrogates baicalin-induced activation of AMPK in HeLa cells. Neither cellular ATP nor the production of reactive oxygen species is altered by baicalin. Finally, in HeLa cells, baicalin treatment no longer decreases intracellular lipid accumulation caused by oleic acid after inhibition of CaMKKβ by STO-609. These results demonstrate that a potential Caβ /CaMKKβ dependent pathway is involved in the activation of AMPK by baicalin and suggest that CaMKKβ likely acts as an upstream kinase of AMPK in response to baicalin. [ABSTRACT FROM AUTHOR]

The first total synthesis of laetispicine (1a), an amide alkaloid isolated from the stems of Piper laetispicum C.DC (Piperaceae), and the synthesis of some of its derivatives were described. Based on the evaluation of antidepressant activities in the forced swimming test, compounds 1h and 1i were identified as potent and safe antidepressant lead compounds. [ABSTRACT FROM AUTHOR]

Background: Genome sequencing and post-genomics projects such as structural genomics are extending the frontier of the study of sequence-structure-function relationship of genes and their products. Although many sequence/structure-based methods have been devised with the aim of deciphering this delicate relationship, there still remain large gaps in this fundamental problem, which continuously drives researchers to develop novel methods to extract relevant information from sequences and structures and to infer the functions of newly identified genes by genomics technology. Results: Here we present an ultrafast method, named BSSF(Binding Site Similarity & Function), which enables researchers to conduct similarity searches in a comprehensive three-dimensional binding site database extracted from PDB structures. This method utilizes a fingerprint representation of the binding site and a validated statistical Z-score function scheme to judge the similarity between the query and database items, even if their similarities are only constrained in a sub-pocket. This fingerprint based similarity measurement was also validated on a known binding site dataset by comparing with geometric hashing, which is a standard 3D similarity method. The comparison clearly demonstrated the utility of this ultrafast method. After conducting the database searching, the hit list is further analyzed to provide basic statistical information about the occurrences of Gene Ontology terms and Enzyme Commission numbers, which may benefit researchers by helping them to design further experiments to study the query proteins. Conclusions: This ultrafast web-based system will not only help researchers interested in drug design and structural genomics to identify similar binding sites, but also assist them by providing further analysis of hit list from database searching. [ABSTRACT FROM AUTHOR]

An efficient method for the soluble polymer-supported synthesis of 5-arylidene thiazolidinones and pyrimidinones using aniline as a traceless linker was described. Aldehyde substrates were attached to the polyethylene glycol (PEG)-bound aniline via an imine linkage, and after the subsequent PEG-promoted Suzuki coupling reaction for the diversification, Knoevenagel condensation was readily employed as the cleavage strategy. [ABSTRACT FROM AUTHOR]

Summary: DrugViz is a Cytoscape plugin that is designed to visualize and analyze small molecules within the framework of the interactome. DrugViz can import drug–target network information in an extended SIF file format to Cytoscape and display the two-dimensional (2D) structures of small molecule nodes in a unified visualization environment. It also can identify small molecule nodes by means of three different 2D structure searching methods, namely isomorphism, substructure and fingerprint-based similarity searches. After selections, users can furthermore conduct a two-side clustering analysis on drugs and targets, which allows for a detailed analysis of the active compounds in the network, and elucidate relationships between these drugs and targets. DrugViz represents a new tool for the analysis of data from chemogenomics, metabolomics and systems biology. Availability: DrugViz and data set used in Application are freely available for download at http://202.127.30.184:8080/software.html Contact: jkshen@mail.shcnc.ac.cn [ABSTRACT FROM AUTHOR]