Department of Biological Sciences
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Item Novel Spiro/non-Spiro Pyranopyrazoles: Eco-Friendly Synthesis, In-vitro Anticancer Activity, DNA Binding, and In-silico Docking Studies(Bentham Science, 2019) Chowdhury, Rajdeep; Shukla, Paritosh; Sharma, AshokBackground: Cancer being a deadly disease, many reports of new chemical entities are available. Pyranopyrazole (PPZ) compounds have also been disclosed as bioactive molecules but mainly as antimicrobial agents. Based on one previous report and our interest in anticancer drug design, we decided to explore PPZs as anticancer agents. To the best of our knowledge, we found that a comprehensive study, involving synthesis, in-vitro biological activity determination, exploration of the mechanism of inhibition and finally in-silico docking studies, was missing in earlier reports. This is what the present study intends to accomplish. Methods: Ten spiro and eleven non-spiro PPZ molecules were synthesized by environment-friendly multicomponent reaction (MCR) strategy. After subjecting each of the newly synthesized molecules to Hep3b hepatocellular carcinoma cell lines assay, we selectively measured the Optical Density (OD) of the most active ones. Then, the compound exhibiting the best activity was docked against human CHK- 1 protein to get an insight into the binding affinities and a quick structure activity relationship (SAR) of the PPZs. Results: The two series of spiro and non-spiro PPZs were easily synthesized in high yields using microwave assisted synthesis and other methods. Among the synthesized compounds, most compounds showed moderate to good anticancer activity against the MTT assay. After performing the absorbance studies we found that the non-spiro molecules showed better apoptosis results and appeared to bind to DNA causing disruption in their structures. Finally, the docking results of compound 5h (having N,Ndimethylamino substituted moiety) clearly showed good binding affinities as predicted by our experimental findings. Conclusion: The paper describes a comprehensive synthesis, in-vitro and docking studies done on new PPZs. The newly synthesized series of spiro and non-spiro PPZs were found to possess antineoplasmic activity as evinced by the studies on hep3b cells. Also, the UV visible absorbance study gave clues to the possible binding of these molecules to the DNA. Docking studies corroborated well with the experimental results. Thus, these new molecules appear to be potential anticancer agents, but further studies are required to substantiate and elaborate on these findings.Item Evaluation of novel platinum(ii) based AIE compound-encapsulated mesoporous silica nanoparticles for cancer theranostic application(RSC, 2018) Chowdhury, Rajdeep; Laskar, Inamur RahamanAdvanced biomedical research has established that cancer is a multifactorial disorder which is highly heterogeneous in nature and responds differently to different treatment modalities, due to which constant monitoring of therapy response is becoming extremely important. To accomplish this, different theranostic formulations have been evaluated. However, most of them are found to suffer from several limitations extending from poor resolution, radiation damage, to high costs. In order to develop a better theranostic modality, we have designed and synthesized a novel platinum(II)-based ‘aggregation induced emission’ (AIE) molecule (named BMPP-Pt) which showed strong intra-cellular fluorescence and also simultaneously exhibited potent cytotoxic activity. Due to this dual functionality, we wanted to explore the possibility of using this compound as a single molecule based theranostic modality. This compound was characterized using elemental analysis, NMR and IR spectroscopy, mass spectrometry and single crystal X-ray structure determination. BMPP-Pt was found to exhibit a high AIE property with emission maxima at 497 nm. For more efficient cancer cell targeting, BMPP-Pt was encapsulated into mesoporous silica nanoparticles (Pt-MSNPs) and the MSNPs were further surface modified with an anti-EpCAM aptamer (Pt-MSNP-E). Pt-MSNPs exhibited higher intracellular fluorescence compared to free BMPP-Pt, though both of them induced a similar degree of cell death via the apoptosis pathway, possibly via cell cycle arrest in the G1 phase. Anti-EpCAM aptamer modification was found to increase both cytotoxicity and intracellular fluorescence compared to unmodified MSNPs. Our study showed that EpCAM functionalized BMPP-Pt loaded MSNPs can efficiently internalize and induce apoptosis of cancer cells as well as show strong intracellular fluorescence. This study provides clues towards the development of a potential single compound based theranostic modality in future.Item Functional Autophagic Flux Regulates AgNP Uptake And The Internalized Nanoparticles Determine Tumor Cell Fate By Temporally Regulating Flux(Dove Press, 2019) Pande, Surojit; Chowdhury, RajdeepSilver nanoparticles (AgNPs) are known to induce the conserved, cellular, homeostatic process- autophagy in tumor cells. Previous studies primarily focus on the pro-survival role of autophagy post AgNP exposure in tumor cells, but seldom on its role in AgNP uptake, or on the functional significance of autophagy temporal dynamics. Our study sheds more light on the extensive crosstalk that exists between AgNP and autophagy, which can be critical to the improvement of AgNP-induced therapeutic effectsItem Hepatotoxicity of Microcystis aeruginosa Strains Growing as Blooms in Certain Eutrophic Ponds(TUD, 2006) Jha, Prabhat N.; Kumar, AnilCritical assessment of five eutrophicated ponds of Varanasi city (India) revealed the presence of heavy blooms of cyanobacteria consisting mainly of Microcystis aeruginosa. Crude aqueous extracts of blooms as well as laboratory grown M. aeruginosa isolated from three ponds, namely Lakshmikund, Durgakund and Adityanagar showed toxicity in mouse bioassay test. Crude aqueous extracts from these samples caused death of test mice within 1h of administration (i.p.) with a LD50 of 60 mg/kg body weight and the treated animals showed clinical signs of hepatotoxicity. However such an effect was not associated with the blooms from Laatbhairov and Surajkund ponds suggesting that not all strains of M. aeruginosa are toxic. Based on spectral properties (?max 230 nm), and comparison with standard microcystin-LR, the toxin is tentatively identified as microcystin-LR. The purified toxin caused death of test mice within 40 min of its administration with a LD50 of 100 µg/ kg body weight and induced gross morphological and functional changes in liver. A 1.55 fold increase in liver weight accompanied by deep red coloration most probably due to hemorrhage and blood pooling suggested the hepatotoxic properties of the toxin. Hepatotoxicity was also evident from the drastic increase (up to 2.5 fold) in activity of serum enzymes such as glutamate pyruvate transaminase/alanine aminotransferase (GPT/ALT), lactate dehydrogenase (LDH) and alkaline phosphatase (APase) following toxin treatment. ^14C-labelling experiments demonstrated maximum accumulation (~15%) of ^14C- toxin after 20 min. of toxin administration. Appreciable level of toxin was also detected in water of four ponds. In conclusion these results clearly demonstrate that microcystin-producing blooms of M. aeruginosa are common in eutrophicated ponds of Varanasi city but not all ponds harbour toxic blooms.Item ChemInform Abstract: Novel Grinding Synthesis of Pyranopyrazole Analogues and Their Evaluation as Antimicrobial Agents.(Wiley, 2016) Jha, Prabhat N.; Shukla, ParitoshCompounds are prepared and screened for their antibacterial and antifungal activitiesItem Biochemistry and genetics of ACC deaminase: a weapon to “stress ethylene” produced in plants(Frontiers, 2015-09) Jha, Prabhat N.; Kumar, Anil1-aminocyclopropane-1-carboxylate deaminase (ACCD), a pyridoxal phosphate-dependent enzyme, is widespread in diverse bacterial and fungal species. Owing to ACCD activity, certain plant associated bacteria help plant to grow under biotic and abiotic stresses by decreasing the level of “stress ethylene” which is inhibitory to plant growth. ACCD breaks down ACC, an immediate precursor of ethylene, to ammonia and α-ketobutyrate, which can be further metabolized by bacteria for their growth. ACC deaminase is an inducible enzyme whose synthesis is induced in the presence of its substrate ACC. This enzyme encoded by gene AcdS is under tight regulation and regulated differentially under different environmental conditions. Regulatory elements of gene AcdS are comprised of the regulatory gene encoding LRP protein and other regulatory elements which are activated differentially under aerobic and anaerobic conditions. The role of some additional regulatory genes such as AcdB or LysR may also be required for expression of AcdS. Phylogenetic analysis of AcdS has revealed that distribution of this gene among different bacteria might have resulted from vertical gene transfer with occasional horizontal gene transfer (HGT). Application of bacterial AcdS gene has been extended by developing transgenic plants with ACCD gene which showed increased tolerance to biotic and abiotic stresses in plants. Moreover, distribution of ACCD gene or its homolog's in a wide range of species belonging to all three domains indicate an alternative role of ACCD in the physiology of an organism. Therefore, this review is an attempt to explore current knowledge of bacterial ACC deaminase mediated physiological effects in plants, mode of enzyme action, genetics, distribution among different species, ecological role of ACCD and, future research avenues to develop transgenic plants expressing foreign AcdS gene to cope with biotic and abiotic stressors. Systemic identification of regulatory circuits would be highly valuable to express the gene under diverse environmental conditions.Item Synthesis and evaluation of bile acid amides of [Formula: see text]-cyanostilbenes as anticancer agents(Springer, 2017) Jha, Prabhat N.; Chowdhury, Rajdeep; Sakhuja, RajeevA series of amino-substituted α-cyanostilbene derivatives and their bile acid (cholic and deoxycholic acid) amides were designed and synthesized. A comparative study on the anticancer and antibacterial activity evaluation on the synthesized analogs was carried against the human osteosarcoma (HOS) cancer cell line, and two gram −ve (E. coli and S. typhi) and two gram +ve (B. subtilis and S. aureus) bacterial strains. All the cholic acid α-cyanostilbene amides showed an IC50 in the range 2–13 μM against human osteosarcoma cells (HOS) with the most active analog (6g) possessing an IC50 of 2μM. One of the amino-substituted α-cyanostilbene, 4e, was found to possess an IC50 of 3μM. An increase in the number of cells at the sub-G1 phase of the cell was observed in the in vitro cell cycle analysis of two most active compounds in the series (4e, 6g) suggesting a clear indication toward induction of apoptotic cascade. With respect to antibacterial screening, amino-substituted α-cyanostilbenes were found to be more active than their corresponding bile acid amides. The synthesized compounds were also subjected to in silico study to predict their physiochemical properties and drug-likeness score.Item Design and Synthesis of Imidazo/Benzimidazo[1,2-c]quinazoline Derivatives and Evaluation of Their Antimicrobial Activity(ACS, 2018) Jha, Prabhat N.; Kumar, AnilA new class of fused quinazolines has been designed and synthesized via copper-catalyzed Ullmann type C–N coupling followed by intramolecular cross-dehydrogenative coupling reaction in moderate to good yields. The synthesized compounds were tested for in vitro antibacterial activity against three Gram negative (Escherichia coli, Pseudomonas putida, and Salmonella typhi) and two Gram positive (Bacillus subtilis, and Staphylococcus aureus) bacteria. Among all tested compounds, 8ga, 8gc, and 8gd exhibited promising minimum inhibitory concentration (MIC) values (4–8 μg/mL) for all bacterial strains tested as compared to the positive control ciprofloxacin. The synthesized compounds were also evaluated for their in vitro antifungal activity against Aspergillus niger and Candida albicans and compounds 8ga, 8gc, and 8gd having potential antibacterial activity also showed pronounced antifungal activity (MIC values 8–16 μg/mL) against both strains. The bactericidal assay by propidium iodide and live–dead bacterial cell screening using a mixture of acridine orange/ethidium bromide (AO/Et·Br) showed considerable changes in the bacterial cell membrane, which might be the cause or consequence of cell death. Moreover, the hemolytic activity for most potent compounds (8ga, 8gc, and 8gd) showed their safety profile toward human blood cells.Item Synthesis, characterization and applications of imidazolium ionic liquid-tagged zinc(II) complex(Elsiever, 2018) Khungar, Bharti; Nehra, Pankaj; Sivasubramanian, S.C.; Jha, Prabhat N.A multi-functional zinc(II) complex of an imidazolium ionic liquid-tagged ligand was synthesized and characterized. The DSC and TGA analysis showed the thermal stability of the complex. The complex showed emission λmax at 368–467 nm with quantum yields up to 0.06. The time-resolved fluorescence study revealed enhancement in lifetime on complexation with zinc(II) ion indicating conformational rigidity. The complex showed good DNA cleavage, antifungal and antibacterial activities against Gram +ve and Gram −ve bacteria. The complex was found to be a good catalyst for the reaction of aromatic aldehydes and indole substrates in water to synthesize bis(indolyl)methanes.Item Green Synthesis, in-vitro Antimicrobial Evaluation, Docking, and SAR Studies of Potent Quinoline-4-Carboxylic Acids(Bentham Science, 2019) Jha, Prabhat N.; Murugesan, Sankaranarayanan; Shukla, ParitoshThe paper describes the synthesis of quinoline-4-carboxylic acid derivatives employing completely green methods such as the use of water as solvent and of microwave irradiation for heating. The prepared molecules were examined for bactericidal and antifungal behavior and two of the tested compounds showed reasonably good antimicrobial activity. The biological activity results were further corroborated by fluorescence microscopy and by evaluating their time-dependent bactericidal behavior. Two of the most potent compounds were then subjected to docking against DNA gyrase protein (PDB ID: 2XCT) showing possible interactions responsible for the potency of these compounds. Also, an SAR analysis was proposed based on the results obtained