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Synthetic Studies on novel Chiral Heterocycles and Nucleosides from Carbohydrate Derivatives
No full textThe present work described in the dissertation has been divided into three chapters. Chapter describes “Application of intramolecular dipolar cycloaddition of sugar-based olefin keto-nitrones to the synthesis of chiral carbocycles, heterocycles and nucleoside analogues”. Chapter 2 deals with “Synthesis of carbohydrate-based macrocyclic nucleosides with polyether linkage by ring-closing metathesis and glycosylation reactions” and Chapter 3 describes “Synthesis of monoglycosides, bisglycosides and open-chain ketoacetals from sugar derived exocyclic enol ethers”
Evaluation of the health effects, genetic damage and dna methylation induced by arsenic through drinking water
No full textArsenic toxicity is a pandemic concern as addressed by the WHO to be one of the major natural calamities till date. More than 137 million individuals in nearly 70 nations are affected by arsenic mainly through drinking underground water. In the state of West Bengal, this scenario is
grim where nearly 26 million individuals in 9 out of 18 districts are affected by arsenic through drinking water. The arsenic content in these regions is nearly 10-20 times compared to the MPL of the WHO, i.e >10g/L. Although several preventive measures have been initiated by
installing arsenic filters in these regions, but still several regions are consuming arsenic lessened drinking water, that are still more than the WHO standard of 10g/L. Chronic exposure to arsenic leads to various types of patho-physiological end points like dermatological lesions, peripheral neuropathy, respiratory disorders and eye problems, etc in humans including several types of cancers.
Two epidemiological studies were conducted separately, to identify the ameliorative effect of reduction in arsenic through drinking water. In a two wave cross-sectional study, there were 189 arsenicosis patients and 171 unexposed individuals were recruited at two time points,
(2005–06 and 2010–11) with concomitant decrease in the level of arsenic exposure through drinking water for the arsenicosis group in 2010–11. Parameters evaluated in this study included dermatological, non-dermatological health status and cytogenetic damage. We identified that
reduction in arsenic through drinking water (190.1 g/l in 2005-06 to 37.94 g/l in 2010-11) had a positive effect on amelioration towards arsenic induced dermatological lesions (p<0.01) and cytogenetic damage (p<0.001). We also found that there was a significant (p<0.001) rise in the
incidence of each of the non-dermatological diseases, that is, peripheral neuropathy,conjunctivitis and respiratory distress over the period. This study was conducted in a study population who were consuming significantly higher amount of arsenic through drinking water;over the past 5 years the content was significantly reduced but still it was higher than the WHO recommendation. We considered another study group, where the drinking water arsenic was
below the WHO recommended limit. In this cohort study, we observed that the mean MN frequency in arsenic exposed individuals with skin lesions as well as no skin lesions reduced drastically (p<0.001) when compared between 2004-05 and 2010-11.Arsenic, is a xenobiotic substance and is biotransformed in the body to it’s methylated species by using the physiological S-Adenosyl Methionine (SAM). SAM determines methylation status of the genome and arsenic metabolism leads to depletion of this indigenous SAM leading
to an epigenetic disequilibrium. Since epigenetics is one of the major phenomenon at the interface between the environment and human health impact, it’s disequilibrium by arsenic induces alterations in the chromatin compaction, gene expression, genomic stability and a host of
biomolecular interactions, the interactome within the cell. Since arsenic is not mutagenic but is carcinogenic in nature; hence, arsenic induced epimutagenesis has come to the forefront since it determines the transcriptional and genomic integrity of the cell
Evaluation of the Anti-inflammatory Potential of Leishmanial Bioactive Lipid and its Role in Regulating the Growth of Cancer Cells
No full textTo be or not to be: The host genetic factor and beyond in Helicobacter pylori mediated gastro-duodenal diseases
No full textHelicobacter pylori (H. pylori ) have long been associated
with a spectrum of disease outcomes in the gastroduodenal
system. Heterogeneity in bacterial virulence
factors or strains is not enough to explain the divergent
disease phenotypes manifested by the infection.
This review focuses on host genetic factors that are
involved during infection and eventually are thought to
influence the disease phenotype. We have summarized the different host genes that have been investigated
for association studies in H. pylori mediated duodenal
ulcer or gastric cancer. We discuss that as the bacteria
co-evolved with the host; these host gene also show
much variation across different ethnic population.
We illustrate the allelic distribution of interleukin-1B,
across different population which is one of the most
popular candidate gene studied with respect to H.
pylori infections. Further, we highlight that several
polymorphisms in the pathway gene can by itself or
collectively affect the acid secretion pathway axis
(gastrin: somatostatin) thereby resulting in a spectrum
of disease phenotyp
Quercetin Improves the Activity of the Ubiquitin-Proteasomal System in 150Q Mutated Huntingtin-Expressing Cells but Exerts Detrimental Effects on Neuronal Survivability
No full textQuercetin, a strong free radical scavenger, is investigated
for neuroprotective effects in a Neuro 2a cell line conditionally transfected with 16Q huntingtin (Htt) and 150Q
Htt, which express the protein upon stimulation. Cells
were protected from death by a 20-mM dose of quercetin
on the second day of Htt induction, but 30–100-mM doses
of the drug caused further toxicity in both 16Q and 150Q
cells, as indicated by MTT assay and by significant reductions in the number of cells bearing neurites on the second day. A significant decrease in the number of cells
containing aggregate was seen in induced 150Q cells
treated with 20 mM but not for those treated with 40 or
50 mM quercetin up to 4 days of induction. Mutated Htt
(mHtt)-induced reduction in proteasomal activity of the
ubiquitin-proteasomal system (UPS) was significantly
attenuated by 20 mM quercetin. However, neither mitochondrial membrane potential loss nor colocalization of
20S proteasome with mHtt aggregate was corrected by
quercetin treatment. Our results imply that the neuroprotective effect of quercetin arises out of the upregulation of UPS activity, which causes a decrease in the number of mHtt aggregate-harboring cells. The increased neurotoxicity could result from the continued association of mHtt with 20S proteasome and the failure of quercetin to correct mitochondrial membrane potential loss. These results
suggest that, although quercetin at a low dose protects
against mHtt-mediated cell death, higher doses are toxic
to the cells, clearly demarcating a narrow therapeutic window for this dietary flavonoid
The DEAD box protein p68: a crucial regulator of AKT/FOXO3a signaling axis in oncogenesis
No full textIncreased abundance of proto-oncogene AKT and reduced expression of tumor suppressor Forkhead box O3 (FOXO3a), the
downstream target of AKT, is frequent in carcinogenesis. Mechanistic insights of AKT gene regulation are limited. DEAD box RNA helicase p68 is overexpressed in various cancers and acts as a transcriptional co-activator of several transcription factors, including β-catenin. Here, we report a novel mechanism of p68-mediated transcriptional activation of AKT, and its ensuing effect on FOXO3a,
in colon carcinogenesis. Interestingly, we found that the expression of p68 and AKT exhibits strong positive correlation in normal and colon carcinoma patient samples. In addition, p68 increased both AKT messenger RNA (mRNA) and protein, enhanced AKT promoter activity in multiple colon cancer cell lines. Conversely, p68 knockdown led to reduced AKT mRNA and protein, diminished AKT promoter activity. Here, we demonstrated that p68 occupies AKT promoter with β-catenin as well as nuclear factor-κB (NF-κB)
and cooperates with these in potentiating AKT transcription. Furthermore, p68 and FOXO3a expression followed inverse correlation in the same set of colon carcinoma samples. We observed that p68 significantly reduced FOXO3a protein level in an AKTdependent
manner. Studies in primary tumors and metastatic lung nodules generated in mice colorectal allograft model, using
syngeneic cells stably expressing p68, corroborated our in vitro findings. Hence, a new mechanism of oncogenesis is attributed to p68 by upregulation of AKT and consequent nuclear exclusion and degradation of tumor suppressor FOXO3
REGULATION OF EGFR SIGNALING NETWORK BY NOVEL MOLECULES FOR CANCER THERAPY
No full textThe thesis work is divided into two main sections, the first one emphasize on the
regulation of EGFR signaling in breast cancer by novel indole derivative and the
second one on the delivery of nanoencapsulated therapeutic indole derivative to
EGFR overexpressed brain tumors . In the first part of the work, by in vitro screening
we have selected a novel synthetic indole derivative 2,2‟-diphenyl-3,3‟-
diindolylmethane (DPDIM) as a potential anti- breast cancer agent. DPDIM induces
apoptosis both in vitro in breast cancer cells MCF7, MDA-MB 231 and MDA-MB
468 and in vivo in 7,12-dimethylbenz[a]anthracene (DMBA) induced Sprague-
Dawley (SD) rat mammary tumor. Our in vitro studies show that DPDIM exerts
apoptotic effect by negatively regulating the activity of EGFR and its downstream
molecules like STAT3, AKT and ERK1/2 which are involved in the proliferation and
survival of these cancer cells. In silico predictions also suggest that DPDIM may bind
to EGFR at its ATP binding site. DPDIM furthermore inhibits EGF induced increased
cell viability. We have also shown decreased expression of pro-survival factor Bcl-XL
as well as increase in the level of pro-apoptotic proteins like Bax, Bad, Bim in
DPDIM treated cells in vitro and in vivo. Our results further indicate that the DPDIM
induced apoptosis is mediated through mitochondrial apoptotic pathway involving the
caspase-cascade. Altogether this research work suggests that DPDIM could be an
effective therapeutic agent for breast cancer.
In the second part, in search of more effective therapeutic options for EGFR
pathway overexpressed glioma treatment we prepared a nanoparticle encapsulated
indole derivative (3,3‟diindolylmethane or DIM), tagged with a peptide against
Somatostatin receptor 2 (SSTR2) on the surface of the nanoparticles for effective
vi
glioma therapy. DIM was encapsulated by poly(lactic-co-glycolic acid). The
encapsulation was confirmed by TEM, FTIR, DLS etc. The effect of nanoparticle
encapsulated DIM was examined on C6 rat glioma cell line by MTT assay, FACS,
fluroscence microscopy, immunoblotting etc. To achieve the goal of target based
delivery, a peptide against SSTR2 (overexpressed in glioma) was designed,
synthesised and validated its target specificity in silico (by docking and simulation
study) and in vitro (by fluorescence microscopy, IP and FACS). After tagging it
chemically with the surface of DIM containing nanoparticles, passaging it through
blood brain barrier (BBB) was determined by both in vitro BBB model and in vivo rat
intracranial glioma model. Evaluation of the transportation of peptide coated
nanoparticle encapsulated DIM through the BBB showed prominent passaging of the
compound that induces apoptosis of glioma cells
Regulation of Egfr Signaling Network by Novel Molecules for Cancer Therapy
No full textThe thesis work is divided into two main sections, the first one emphasize on the regulation of EGFR signaling in breast cancer by novel indole derivative and the
second one on the delivery of nanoencapsulated therapeutic indole derivative to EGFR overexpressed brain tumors . In the first part of the work, by in vitro screening
we have selected a novel synthetic indole derivative 2,2‟-diphenyl-3,3‟- diindolylmethane (DPDIM) as a potential anti- breast cancer agent. DPDIM induces apoptosis both in vitro in breast cancer cells MCF7, MDA-MB 231 and MDA-MB
468 and in vivo in 7,12-dimethylbenz[a]anthracene (DMBA) induced Sprague- Dawley (SD) rat mammary tumor. Our in vitro studies show that DPDIM exerts apoptotic effect by negatively regulating the activity of EGFR and its downstream molecules like STAT3, AKT and ERK1/2 which are involved in the proliferation and survival of these cancer cells. In silico predictions also suggest that DPDIM may bind to EGFR at its ATP binding site. DPDIM furthermore inhibits EGF induced increased cell viability. We have also shown decreased expression of pro-survival factor Bcl-XL
as well as increase in the level of pro-apoptotic proteins like Bax, Bad, Bim in DPDIM treated cells in vitro and in vivo. Our results further indicate that the DPDIM
induced apoptosis is mediated through mitochondrial apoptotic pathway involving the caspase-cascade. Altogether this research work suggests that DPDIM could be an
effective therapeutic agent for breast cancer. In the second part, in search of more effective therapeutic options for EGFR pathway overexpressed glioma treatment we prepared a nanoparticle encapsulated indole derivative (3,3‟diindolylmethane or DIM), tagged with a peptide against
Somatostatin receptor 2 (SSTR2) on the surface of the nanoparticles for effective vi glioma therapy. DIM was encapsulated by poly(lactic-co-glycolic acid). The
encapsulation was confirmed by TEM, FTIR, DLS etc. The effect of nanoparticle encapsulated DIM was examined on C6 rat glioma cell line by MTT assay, FACS, fluroscence microscopy, immunoblotting etc. To achieve the goal of target based delivery, a peptide against SSTR2 (overexpressed in glioma) was designed,synthesised and validated its target specificity in silico (by docking and simulation study) and in vitro (by fluorescence microscopy, IP and FACS). After tagging it chemically with the surface of DIM containing nanoparticles, passaging it through
blood brain barrier (BBB) was determined by both in vitro BBB model and in vivo rat intracranial glioma model. Evaluation of the transportation of peptide coated
nanoparticle encapsulated DIM through the BBB showed prominent passaging of the compound that induces apoptosis of glioma cells
Structural and thermodynamic basis of interaction of the putative anticancer agent chelerythrine with single, double and triple-stranded RNAs
No full textcomparative study on the interaction of the natural plant alkaloid chelerythrine with triple helical poly(U)poly(U) and single stranded poly(U) (the dot and star representing the
Watson-Crick and Hoogsteen base pairing) has been performed using various biophysical and thermodynamic techniques. Chelerythrine binds to the duplex and triplexes in a cooperative manner with affinity of the order of 106 M�1. A weaker binding (�105 M�1) in a non-cooperative mode occurred
with poly(U). Chelerythrine is more selective towards RNA triplex than its parent duplex. The triplex was stabilized specifically without affecting the stability of the duplex. Fluorescence quenching, fluorescence polarization and energy transfer from the nucleotides to the alkaloid, and viscosity results gave convincing evidence for a true intercalative binding of chelerythrine to the triplex and the duplex structures, and partial base stacking with poly(U). The conformations of both double and triple helices
were perturbed on binding but no effect occurred to the single strand structure. The binding of the alkaloid to all three RNA helices was found to be exothermic; to the triplex it was entropy driven with favorable enthalpy change, to the duplex enthalpy driven and to the single strand it was enthalpy driven.These results provide new knowledge on the mode, mechanism and specificity, and energetics of binding of the natural alkaloid and putative anticancer agent chelerythrine to different RNA conformation
Synthetic Studies on Oligosaccharides, Carbohydrate Containing Triazoles and NBased Heterocycles of Biological Importance
No full textEfficient synthesis of 1,4-disubstituted triazolyl N-carboxamides via a simple and convenient MCR using basic alumina as solid support. Glucose-based inhibitors with
NHCO as linker between the sugar and the aromatics showed potent activity against glycogen phosphorylase which is a validated target against type 2 diabetes mellitus.
Successful bio-isosteric modification of the amide with different heteroaromatic compounds leading to compounds having better inhibition properties is also known. These
motivated us to synthesize a library of compounds where sugar moieties were linked to 1,2,3-triazoles by NHCO bonds and a long hydrophobic chain using a novel and an
environmentally benign chemical process. The long linking arm is likely to make the sugar moiety available for better binding with the appropriate receptor.
The synthesis of triazolyl N-carboxamides using traditional methods is a three-step process. Firstly, the aliphatic or aromatic azides are synthesized followed by the coppermediated azide–alkyne cyclization. Finally, the amide or ester linkages are formed. The traditional chemical synthesis requires extensive chromatographic purification of intermediates, which is tedious and time consuming. The new protocol developed by us allows domino Ullmann-type reaction, Click reaction and formation of ester or amidelinkages in a single reaction vessel using Cu(phen)(PPh3)Br as catalyst and chloro-phenylthio-
methylene-dimethylammonium chloride (CMPA) as coupling agent using basic alumina as solid support (Scheme 1)