2058 research outputs found
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Synthesis of Bis-pyrrolizidine-Fused Dispiro-oxindole Analogues of Curcumin via One-Pot Azomethine Ylide Cycloaddition: Experimental and Computational Approach toward Regio- and Diastereoselection
No full textCurcumin has been transformed to racemic curcuminoids
via an azomethine ylide cycloaddition reaction using isatin/
acenaphthoquinone and proline as the reagents. The products were characterized by extensive 1D/2D NMR analysis and single-crystal X-ray crystallographic studies. The enantiomers of one racemic product were separated by HPLC on a Chiralcel OD-H column and were indeed confirmed by the CD spectra of the separated enantiomers
Through-Space 1,4-Palladium Migration and 1,2-Aryl Shift: Direct Access to Dibenzo[a,c]carbazoles through a Triple C¢H Functionalization Cascade
No full textA palladium-catalyzed expeditious synthesis of
dibenzofused carbazoles from readily available 2-arylindoles
and diaryliodonium salts is reported. Interestingly,
after the electrophilic C3 palladation of indole, an unexpected “through-space” 1,4-palladium migration to the 2-
aryl moiety, by remote C¢H bond activation followed by
C¢H arylation with diaryliodonium salt, and an unprecedented
1,2-aryl shift take place. Finally, an intramolecular
cross-dehydrogenative coupling (CDC) at the C2 position
affords dibenzo[a,c]carbazoles in high yields. Remarkably,
the present migratory annulation occurs through three C¢
H bond activation one C¢C bond cleavage, and the simultaneous construction of three new C¢C bonds in a single
operation
Radiolabeling and Tumour Targeting Applications of Surface–Modified Solid Lipid Nanoparticles by Using Octreotide Analogues
No full text99mTc-paclitaxel was synthesized by using sodium borohydride as a reducing agent.Greater than 95 % labelling efficiency was achieved. Radiochemical purity of the synthesized 99mTc-paclitaxel was validated by Thin Layer Chromatography (TLC) scanner and High
Performance Liquid Chromatography (HPLC). 99mTc-paclitaxel passed in vitro stability tests.
Biodistribution and scintigraphy studies were performed in Sprague-Dawley rats. The biodistribution study results of 99mTc-paclitaxel were related mainly to the metabolism
and excretion routes followed by the parental drug, paclitaxel (PTX). Apart from that,biodistribution of 99mTc-paclitaxel was altered after pre-treatment with cold PTX. Hence,99mTc-paclitaxel may be used as a tracer for PTX.Nanoparticle biodistribution study is of great importance in bringing nanomedicine to patients. Solid lipid nanoparticle (SLN) with dimension less than 100 nm was successfully radiolabelled with 99mTc by using sodium borohydride as a reducing agent (instead of stannous salts). PTX was used as a model anticancer drug for the preparation of drug loaded SLN (PSLN). PSLN was characterized by standard methods. Encapsulation efficiency for PTX in PSLN was estimated by HPLC. Taxol formulation and PSLN were radiolabelled separately and subsequent characterizations of these complexes were performed. Greater than 95% radiolabelling efficiency was achieved and the labelling efficiency was calculated to be more than 90% up to 24 h. Interference of radiocolloids on the biodistribution can be avoided
by this method as both the radiolabelling efficiency and radiochemical purity of the complex was found to be > 95%. Radiolabelling by this method was found to be easy and effective. 99mTc-PSLN and 99mTc-Taxol passed the in vitro stability tests. 99mTc-PSLN achieved more
brain concentration than 99mTc-Taxol as determined by biodistribution studies. This study indicates prepared PSLN may effectively deliver more PTX in brain than the marketed formulation of PTX (i.e. Taxol). Apart from that, this type of radiolabelling technique can be
useful in preclinical evaluation of drug loaded SLN.
PSLN improved the apoptosis-induction activity of PTX in C6 rat glioma cell line (as compared to Taxol). SPECT imaging and biodistribution studies showed that 99mTc-PSLN has achieved considerable concentration within the orthotopic glioma-bearing rats. More importantly, PSLN exhibited powerful antitumor activity without observable accompanied toxicity. Survival experiment further confirmed the improved anti-glioma efficacy of PSLN
Recognition of human telomeric G-quadruplex DNA by berberine analogs: effect of substitution at the 9 and 13 positions of the isoquinoline moiety
No full textG-quadruplex forming sequences are widely distributed in human genome and serve as novel targets for regulating
gene expression and chromosomal maintenance. They offer unique targets for anticancer drug development. Here,
the interaction of berberine (BC) and two of its analogs bearing substitution at 9 and 13-position with human
telomeric G-quadruplex DNA sequence has been investigated by biophysical techniques. Both the analogs exhibited
several-fold higher binding affinity than berberine. The Scatchard binding isotherms revealed non-cooperative
binding. 9-ω-amino hexyl ether analog (BC1) showed highest affinity (1.8 × 106M�1) while the affinity of the 13-
phenylpropyl analog (BC2) was 1.09 × 106M�1. Comparative fluorescence quenching and polarization anisotropy
of the emission spectra gave evidence for a stronger stacking interaction of the analogs compared to berberine.
The thiazole orange displacement assay has clearly established that the analogs were more effective in displacing the end stacked dye in comparison to berberine. However, the binding of the analogs did not induce any major
structural perturbation in the G-quadruplex structure, but led to higher thermal stability. Energetics of the binding
indicated that the association of the analogs was exothermic and predominantly entropy driven phenomenon. Increasing the temperature resulted in weaker binding; the enthalpic contribution increased and the entropic contribution decreased. A small negative heat capacity change with significant enthalpy–entropy compensation
established the involvement of multiple weak noncovalent interactions in the binding process. The 9-ω-amino hexyl
ether analog stabilized the G-quadruplex structure better than the 13-phenyl alkyl analog
Blood Brain Barrier: A Challenge for Effectual Therapy of Brain Tumors
No full textBrain tumors are one of the most formidable diseases of mankind. They have only a fair to poor prognosis and high relapse rate. One of the major causes of extreme difficulty in brain tumor treatment is the presence of blood brain barrier (BBB). BBB comprises different molecular components and transport systems, which in turn create efflux machinery or hindrance for the entry of several drugs in brain.Thus, along with the conventional techniques, successful modification of drug delivery and novel
therapeutic strategies are needed to overcome this obstacle for treatment of brain tumors. In this review, we have elucidated some critical insights into the composition and function of BBB and along with it we have discussed the effective methods for delivery of drugs to the brain and therapeutic strategies overcoming the barrier
3D-QSAR studies and shape based virtual screening for identification of novel hits to inhibit MbtA in Mycobacterium tuberculosis
No full textMycobacterium tuberculosis, the pathogen responsible for tuberculosis, uses various strategies to survive in a variety of
host lesions. The re-emergence of multi-drug-resistant strains of M. tuberculosis underlines the necessity to discover new
molecules. Inhibitors of aryl acid adenylating enzyme, MbtA, involved in siderophore biosynthesis in M. tuberculosis,
are being explored as potential anti tubercular agents. In this study, we have used 3D-QSAR models and shape based
virtual screening to identify novel MbtA inhibitors. 3D-QSAR studies were carried out on nucleoside bisubstrate derivatives.
Both Comparative Molecular Field Analysis (r2 = .944 and r2
pred = .938) and Comparative Molecular Similarity
Indices Analysis (r2 = .892 and r2
pred = .842) models, developed using Gasteiger charges with all fields, predicted
efficiently. A total of 13 hits were identified as novel prospective inhibitors for MbtA by utilizing an insilico workflow.
Out of 13 hits, five top ranked hits were used for further molecular dynamics studies to gain more insights about the
stability of the complexes
Role of the Flagellar Hook-Length Control Protein FliK and σ28 in cagA Expression in Gastric Cell–Adhered Helicobacter pylori
No full textAdherence of Helicobacter pylori to the gastric epithelial cell line AGS strongly induces expression of fliK encoding
a flagellar hook-length control protein. FliK has a role in triggering dissociation of the alternate sigma actor, σ28, from a nonfunctional σ28-FlgM complex, releasing free, functional σ28. The σ28-RNA polymerase nitiates transcription of cagA, the major virulence gene, from a promoter identified in this study. Consequently,
significant up-regulation of cagA was observed in AGS-adhered H. pylori. Direct binding of σ28 to the cagA
promoter was demonstrated by chromatin immunoprecipitation and the transcription start site was identified y 5′ RACE (rapid amplification of complementary DNA ends). The σ28-dependent cagA promoter was active pecifically in AGS-adhered H. pylori, and this motif might be associated with high cagA expression and severity f disease. These results also indicate that H. pylori has evolved to integrate expression of the major virulence ene cagA with the flagellar regulatory circuit, essential for colonization of the human host
Polysome arrest restricts miRNA turnover by preventing exosomal export of miRNA in growth-retarded mammalian cells
No full textMicroRNAs (miRNAs) are tiny posttranscriptional regulators of gene expression in metazoan cells, where activity and abundance of miRNAs are tightly controlled. Regulated turnover of these regulatory RNAs is important to optimize cellular response to external stimuli. We report that the stability of mature miRNAs increases inversely with cell proliferation, and the increased number of microribonucleoproteins (miRNPs) in growth-restricted mammalian cells are in turn associated with polysomes. This heightened association of miRNA with polysomes also elicits reduced degradation of target mRNAs and impaired extracellular export of miRNA via exosomes. Overall polysome sequestration contributes to an increase of cellular miRNA levels but without an increase in miRNA activity. Therefore miRNA activity and turnover can be controlled by subcellular distribution of miRNPs that may get differentially regulated as a function of cell growth in mammalian cells
PALM-IST: Pathway Assembly from Literature Mining - an Information Search Tool
No full textManual curation of biomedical literature has become extremely tedious process due to its exponential growth in recent years. To extract meaningful information from such large and unstructured text, newer and more efficient mining tool is required. Here, we introduce PALM-IST,
a computational platform that not only allows users to explore biomedical abstracts using keyword based text mining but also extracts biological entity (e.g., gene/protein, drug, disease, biological processes, cellular component, etc.) information from the extracted text and subsequently mines various databases to provide their comprehensive inter-relation (e.g., interaction, expression, etc.). PALM-IST constructs protein interaction network and pathway information data relevant to the text
search using multiple data mining tools and assembles them to create a meta-interaction network. It also analyzes scientific collaboration by extraction and creation of “co-authorship network,” for a given search context. Hence, this useful combination of literature and data mining provided in PALMIST can be used to extract novel protein-protein interaction (PPI), to generate meta-pathways and
further to identify key crosstalk and bottleneck proteins. PALM-IST is available at www.hpppi.iicb. res.in/ctm
Identification Of Proteins Or Peptides For Development Of Biomarkers Of Heart Diseases
No full textHeart disease is one of the foremost reasons behind mortality and morbidity globally. It is a major economic burden especially in low and middle-income countries (LMICs). Different types of cardiovascular diseases may occur in the heart or blood vessels. Functionally, heart disease is the difficulty of the heart to pump sufficient blood to meet the metabolic needs of the body. It can occur quickly as with an AMI or progress gradually over years as with chronic HF. In each case, the heart is unable to efficiently or effectively contract making it more difficult to maintain cardiac output.Mortality resulting from cardiovascular diseases stood at about 17.1 million in
2004, representing 29% of all global deaths, and as estimated by WHO, about 23.6 million individuals will die each year from cardiovascular diseases by 2030. Hence, primary and secondary prevention of CVD are public health priorities (1). To prevent and control cardiovascular diseases, significant efforts have been made to understand the pathogenesis of such diseases. Generally, these diseases result from the crosstalk between lifestyle risk
factors, environmental cues and the inherent intracellular system. Therefore, the pathogenesis of cardiovascular diseases is complicated (2)