Nano-​cuprous oxide catalyzed one-​pot synthesis of a carbazole-​based STAT3 inhibitor: a facile approach via intramolecular C-​N bond formation reactions

In this study, we report the one-​pot synthesis of substituted carbazole derivs. using nano cuprous oxide as a catalyst via intramol. C-​N bond forming reactions. Among the synthesized carbazoles, 3'-​((3-​acetyl-​6-​chloro-​9H-​carbazol-​9-​yl)​methyl)​-​[1,​1'-​biphenyl]​-​2-​carbonitrile (ACB) was identified as a lead antiproliferative agent against lung cancer cell lines A549 and LLC with an IC50 of 13.6 and 16.4 μM resp. Furthermore, we found that the lead compd. suppresses the constitutive phosphorylation of STAT3 (Tyr-​705) in A549, HCC-​2279 and H1975 cells. We analyzed the levels of phospho-​STAT3 and LSD1 in the nuclear ext. of ACB treated HCC-​2279 cells to evaluate the transcriptional activity of STAT3. We found the downregulation of phospho-​STAT3 without any change in the expression of LSD1 indicating that ACB downregulates the transcriptional activity of STAT3. Mol. docking anal. revealed that ACB makes a favorable interaction with Arg-​609 and Ser-​613 in the pTyr site of the SH2 domain of STAT3

Anticancer Functions of Pyridine Heterocycles

Pyridine is a heterocyclic molecule with a nitrogen atom that is often found in nature. As a prosthetic group taking part in redox processes in the biological system, it plays an important function in many enzymes of the living system. Pyridine is an important pharmacophore, a privileged scaffold, and a superior heterocyclic system in drug development, with various applications in anticancer research because of its ability to work on significant receptors. Typically, it is the core of several currently available medicines. In the fight against cancer, many pyridine derivatives have been shown to inhibit kinases, androgen receptors, tubulin polymerization, topoisomerase enzyme, human carbonic anhydrase, and several other targets. Researchers are now concentrating on developing pyridine novel entities with other moieties for cancer therapy. This section presents pyridine derivative synthesis and biological expansions, as well as their target receptor sites

The crystal structure of (RS)-7-chloro-2-(2,5-dimethoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one : two hydrogen bonds generate an elegant three-dimensional framework structure

KHN is grateful to UGC, RFSMS, Government of India for a Research Fellowship. BKS thanks the University of Mysore, for research facilities.In the title compound, C61H15ClN2O3, the heterocyclic ring adopts an envelope conformation, folded across the N⋯N line, with the 2,5-di­meth­oxy­phenyl unit occupying a quasi-axial site. There are two N—H⋯O hydrogen bonds in the structure: one hydrogen bond links mol­ecules related by a 41 screw axis to form a C(6) chain, and the other links inversion-related pairs of mol­ecules to form an R22(8) ring. The ring motif links all of the chains into a continuous three-dimensional framework structure. Comparisons are made with the structures of some related compounds.Publisher PDFPeer reviewe

Identification of Novel Class of Triazolo-Thiadiazoles as Potent Inhibitors of Human Heparanase and their Anticancer Activity.

BACKGROUND: Expression and activity of heparanase, an endoglycosidase that cleaves heparan sulfate (HS) side chains of proteoglycans, is associated with progression and poor prognosis of many cancers which makes it an attractive drug target in cancer therapeutics. METHODS: In the present work, we report the in vitro screening of a library of 150 small molecules with the scaffold bearing quinolones, oxazines, benzoxazines, isoxazoli(di)nes, pyrimidinones, quinolines, benzoxazines, and 4-thiazolidinones, thiadiazolo[3,2-a]pyrimidin-5-one, 1,2,4-triazolo-1,3,4-thiadiazoles, and azaspiranes against the enzymatic activity of human heparanase. The identified lead compounds were evaluated for their heparanase-inhibiting activity using sulfate [35S] labeled extracellular matrix (ECM) deposited by cultured endothelial cells. Further, anti-invasive efficacy of lead compound was evaluated against hepatocellular carcinoma (HepG2) and Lewis lung carcinoma (LLC) cells. RESULTS: Among the 150 compounds screened, we identified 1,2,4-triazolo-1,3,4-thiadiazoles bearing compounds to possess human heparanase inhibitory activity. Further analysis revealed 2,4-Diiodo-6-(3-phenyl-[1, 2, 4]triazolo[3,4-b][1, 3, 4]thiadiazol-6yl)phenol (DTP) as the most potent inhibitor of heparanase enzymatic activity among the tested compounds. The inhibitory efficacy was demonstrated by a colorimetric assay and further validated by measuring the release of radioactive heparan sulfate degradation fragments from [35S] labeled extracellular matrix. Additionally, lead compound significantly suppressed migration and invasion of LLC and HepG2 cells with IC50 value of ~5 μM. Furthermore, molecular docking analysis revealed a favourable interaction of triazolo-thiadiazole backbone with Asn-224 and Asp-62 of the enzyme. CONCLUSIONS: Overall, we identified biologically active heparanase inhibitor which could serve as a lead structure in developing compounds that target heparanase in cancer

Resultative Compound Verb in Modern Chinese : A Comment on Imai(1985) and Lu(1986)

<p>A. API and DMO suppresses NF-κB DNA binding ability in HCT116 cells. HCT116 cells were treated with DMO and API at indicated doses, nuclear extracts were prepared, and 20 μg of the nuclear extract protein was used for the ELISA-based DNA-binding assay *p<0.05; **p<0.005). B & C. NF-κB responsive elements linked to a luciferase reporter gene were transfected with wild-type or dominant-negative IκB and transfected cancer cells were treated at indicated doses for 6 h and luciferase activity was measured as described in Materials and Methods section. All luciferase experiments were done in triplicate and repeated twice (*p<0.05; **p<0.005). D. API abrogates constitutive IκBα phosphorylation in dose-dependent manner in HCT116 cells. HCT116 cells were treated with different concentrations of API (0, 5, 10 and 20 μM) for 6 h and cytoplasmic extract was prepared. Lysates were resolved on SDS gel and electrotransferred to a nitrocellulose membrane and probed with anti-phospho-IκBα/IκBα. The blot was washed, exposed to HRP-conjugated secondary antibodies for 1 h, and finally examined by chemiluminescence. GAPDH was used as loading control.</p