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

Novel 1,3,4-oxadiazole induces anticancer activity by targeting NF-κB in hepatocellular carcinoma cells

Aberrant activation of NF-κB is linked with the progression of human malignancies including hepatocellular carcinoma (HCC), and blockade of NF-κB signaling could be a potential target in the treatment of several cancers. Therefore, designing of novel small molecule inhibitors that target NF-κB activation is of prime importance in the treatment of several cancers. In the present work, we report the synthesis of series of 1,3,4-oxadiazoles, investigated their anticancer potential against HCC cells, and identified 2-(3-chlorobenzo[b]thiophen-2-yl)-5-(3-methoxyphenyl)-1,3,4-oxadiazole (CMO) as the lead compound. Further, we examined the effect of CMO on cell cycle distribution (flow cytometry), apoptosis (annexin V-propidium iodide-FITC staining), and phosphorylation of NF-κB signaling pathway proteins (IκB and p65) in HCC cells. We found that CMO induced antiproliferative effect in dose- and time-dependent manner. Also, CMO significantly increased the percentage of sub-G1 cell population and induced apoptosis. Furthermore, CMO found to decrease the phosphorylation of IκB (Ser 32) in the cytoplasmic extract and p65 (Ser 536) in the nuclear extract of HCC cells. It also abrogated the DNA binding ability and transcriptional activity of NF-κB. CMO induced the cleavage of PARP and caspase-3 in a time-dependent manner. In addition, transfection with p65 small interfering RNA blocks CMO-induced caspase-3/7 activation. Molecular docking analysis revealed that CMO interacts with the hydrophobic region of p65 protein. Thus, we are reporting CMO as an inhibitor of NF-κB signaling pathway

Investigation of the Role of Protein Kinase D in Human Rhinovirus Replication

Picornavirus replication is known to cause extensive remodeling of Golgi and endoplasmic reticulum membranes, and a number of the host proteins involved in the viral replication complex have been identified, including oxysterol binding protein (OSBP) and phosphatidylinositol 4-kinase III beta (PI4KB). Since both OSBP and PI4KB are substrates for protein kinase D (PKD) and PKD is known to be involved in the control of Golgi membrane vesicular and lipid transport, we hypothesized that PKD played a role in viral replication. We present multiple lines of evidence in support of this hypothesis. First, infection of HeLa cells with human rhinovirus (HRV) induced the phosphorylation of PKD. Second, PKD inhibitors reduced HRV genome replication, protein expression, and titers in a concentration-dependent fashion and also blocked the replication of poliovirus (PV) and foot-and-mouth disease virus (FMDV) in a variety of cells. Third, HRV replication was significantly reduced in HeLa cells overexpressing wild-type and mutant forms of PKD1. Fourth, HRV genome replication was reduced in HAP1 cells in which the PKD1 gene was knocked out by clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9. Although we have not identified the molecular mechanism through which PKD regulates viral replication, our data suggest that this is not due to enhanced interferon signaling or an inhibition of clathrin-mediated endocytosis, and PKD inhibitors do not need to be present during viral uptake. Our data show for the first time that targeting PKD with small molecules can inhibit the replication of HRV, PV, and FMDV, and therefore, PKD may represent a novel antiviral target for drug discovery. IMPORTANCE Picornaviruses remain an important family of human and animal pathogens for which we have a very limited arsenal of antiviral agents. HRV is the causative agent of the common cold, which in itself is a relatively trivial infection; however, in asthma and chronic obstructive pulmonary disease (COPD) patients, this virus is a major cause of exacerbations resulting in an increased use of medication, worsening symptoms, and, frequently, hospital admission. Thus, HRV represents a substantial health care and economic burden for which there are no approved therapies. We sought to identify a novel host target as a potential anti-HRV therapy. HRV infection induces the phosphorylation of PKD, and inhibitors of this kinase effectively block HRV replication at an early stage of the viral life cycle. Moreover, PKD inhibitors also block PV and FMDV replication. This is the first description that PKD may represent a target for antiviral drug discovery

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 derivatives using nano cuprous oxide as a catalyst via intramolecular 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 respectively. Furthermore{,} we found that the lead compound 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 extract 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. Molecular docking analysis revealed that ACB makes a favorable interaction with Arg-609 and Ser-613 in the pTyr site of the SH2 domain of STAT3

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 derivatives using nano cuprous oxide as a catalyst via intramolecular 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 respectively. Furthermore{,} we found that the lead compound 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 extract 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. Molecular docking analysis revealed that ACB makes a favorable interaction with Arg-609 and Ser-613 in the pTyr site of the SH2 domain of STAT3

Pulsed stimulated Brillouin microscopy enables high-sensitivity mechanical imaging of live and fragile biological specimens

This repository contains the raw data files for Fig. 1, 2, 3 and Extended Data Fig. 1, 2, 3, 8 of the publication Yang et al. "Pulsed stimulated Brillouin microscopy enables high-sensitivity mechanical imaging of live and fragile biological specimens" (2023

Synthesis and in vitro evaluation of hydrazinyl phthalazines against malaria parasite, Plasmodium falciparum

In this report, we describe the synthesis of 1-(Phthalazin-4-yl)-hydrazine using bronsted acidic ionic liquids and demonstrate their ability to inhibit asexual stage development of human malaria parasite, Plasmodium falciparum. Through computational studies, we short-listed chemical scaffolds with potential binding affinity to an essential parasite protein, dihydroorotate dehydrogenase (DHODH). Further, these compounds were synthesized in the lab and tested against P. falciparum. Several compounds from our library showed inhibitory activity at low micro-molar concentrations with minimal cytotoxic effects. These results indicate the potential of hydralazine derivatives as reference scaffolds to develop novel antimalarials