Browsing by Author "Pankaj Pandey"

Now showing 1 - 4 of 4

Design, synthesis and biological evaluation of novel naturally-inspired multifunctional molecules for the management of Alzheimer's disease
(Elsevier Masson SAS, 2020) Yash Pal Singh; Gullanki Naga Venkata Charan Tej; Amruta Pandey; Khushbu Priya; Pankaj Pandey; Gauri Shankar; Prasanta Kumar Nayak; Geeta Rai; Amar G. Chittiboyina; Robert J. Doerksen; Swati Vishwakarma; Gyan Modi
In our overall goal to overcome the limitations associated with natural products for the management of Alzheimer's disease and to develop in-vivo active multifunctional cholinergic inhibitors, we embarked on the development of ferulic acid analogs. A systematic SAR study to improve upon the cholinesterase inhibition of ferulic acid with analogs that also had lower logP was carried out. Enzyme inhibition and kinetic studies identified compound 7a as a lead molecule with preferential acetylcholinesterase inhibition (AChE IC50 = 5.74 ± 0.13 μM; BChE IC50 = 14.05 ± 0.10 μM) compared to the parent molecule ferulic acid (% inhibition of AChE and BChE at 20 μM, 15.19 ± 0.59 and 19.73 ± 0.91, respectively). Molecular docking and dynamics studies revealed that 7a fits well into the active sites of AChE and BChE, forming stable and strong interactions with key residues Asp74, Trp286, and Tyr337 in AChE and with Tyr128, Trp231, Leu286, Ala328, Phe329, and Tyr341 in BChE. Compound 7a was found to be an efficacious antioxidant in a DPPH assay (IC50 = 57.35 ± 0.27 μM), and it also was able to chelate iron. Data from atomic force microscopy images demonstrated that 7a was able to modulate aggregation of amyloid β1-42. Upon oral administration, 7a exhibited promising in-vivo activity in the scopolamine-induced AD animal model and was able to improve spatial memory in cognitive deficit mice in the Y-maze model. Analog 7a could effectively reverse the increased levels of AChE and BChE in scopolamine-treated animals and exhibited potent ex-vivo antioxidant properties. These findings suggest that 7a can act as a lead molecule for the development of naturally-inspired multifunctional molecules for the management of Alzheimer's and other neurodegenerative disorders. © 2020 Elsevier Masson SAS
Fructose-2, 6-bisphosphate associated regulatory enzymes develop in concordance in mice brain during early postnatal life
(2005) Pankaj Pandey; Sanjay K. Singh; Surendra K. Trigun
Fructose-2, 6-bisphosphate (fru-2, 6P2), synthesized by 6-phosphofructo-2-kinase (PFK2), regulates glucose metabolism via modulating phosphofructokinase-1 (PFK1) and fructose-1, 6-bisphosphatase (FBPase1) reciprocally in mammalian tissues. How this control system develops in brain is poorly understood. This article presents the postnatal comparative profiles of fru-2, 6P2 and PFK2 & fru-2, 6P2 dependent regulation of PFK1 and FBPase1 in mice brain. Fru-2, 6P2 and PFK2 activity both attained their adult levels in concordance from day1 to 1wk age. Western blot analysis of mice liver and brain & rat liver PFK2 using anti rat liver PFK2/FBPase2 confirmed that both, mice liver and brain isoforms cross- react efficiently with this antibody. In addition, DEAE-eluted brain fractions from different postnatal ages revealed that 1day mice brain expresses a liver type enzyme (∼55 kDa) that is replaced by an adult brain type protein (∼110 kDa) from 1wk onward ages. As compared to 1day mice, significantly decreased Km values of PFK2 at 1wk-10wk ages also suggest the existence of a kinetically different isoform of this enzyme from 1wk onward ages. In vitro effects of fru-2, 6P2 on partially enriched brain PFK1 and FBPase1 suggest that fru-2, 6P2 dependent respective stimulatory and inhibitory responses of both these enzymes increase progressively from day1 to 3wk age. This is well corroborated with the postnatal age-dependent linear increase in PFK1 and decrease in FBPase1 activities in mice brain. The results suggest that fru-2, 6P2 associated regulatory components develop in concordance in mice brain during early postnatal life. © Universitätsverlag Ulm GmbH 2005.
Pepsin Assisted Doxorubicin Delivery from Mesoporous Silica Nanoparticles Downsizes Solid Tumor Volume and Enhances Therapeutic Efficacy in Experimental Murine Lymphoma
(American Chemical Society, 2018) Prateek Srivastava; Sumit Kumar Hira; Uttam Gupta; Vivek Kumar Singh; Ranjeet Singh; Pankaj Pandey; Divesh Narayan Srivastava; Ram Adhar Singh; Partha Pratim Manna
Pepsin, a digestive enzyme, plays an important role in the metabolism of protein products in the stomach. The pH is regarded as the most pivotal criteria in appraising the pepsin's enzymatic activity. Pepsin is idle at the physiological pH (7.4) but dynamic in the acidic environments of the stomach (pH 2.0-4.0). Inspired by such pH regulatory actions, we have used pepsin as an enhancer, which is attached to silica nanoparticles for the doxorubicin release in the acidic tumor environment. Pepsin enzyme is transitional between the doxorubicin loaded silica nanoparticles and the biotin-avidin cap system, which intercedes the pores. The formed nanoplatform is poised at the physiological pH. However, when switched to low pH simulated conditions, the pepsin become vibrant and cleaves the avidin, rendering the clearance of the path for the diffusion of the drug. This design strategy augmented the drug bioavailability deep inside the solid tumor with enhanced uptake and apoptosis of the tumor cells in experimental lymphoma. Copyright © 2018 American Chemical Society.
Ruthenium complex as enzyme modulator: Modulation of lactate dehydrogenase by a novel ruthenium(II) complex containing 4-carboxy N-ethylbenzamide as a ligand
(2007) Surendra K. Trigun; Raj K. Koiri; Lallan Mishra; Santosh K. Dubey; Santosh Singh; Pankaj Pandey
Ruthenium complex-protein interaction, particularly with respect to modulation of the enzymes associated to tumor development, is an evolving concept in understanding the mechanism of action of these complexes as anticancer agent. Lactate dehydrogenase (LDH; EC: 1.1.1.27) is critically implicated in maintaining tumor growth via 'Warburg effect' in cancerous cells. This article presents current status of Rucomplexes as enzyme inhibitors in general and a state of art on a novel ruthenium(II) complex containing 4-Carboxy-N-ethylbenzamide as an inhibitor of LDH. The 4-carboxy-N-ethylbenzamide (CNEB) was synthesized and characterized by single crystal X-ray measurement and complexed with cis-Ru(bpy)2Cl2.2H2O (bpy=2,2′bipyridine) resulting into synthesis of a [Ru(CNEB)2(bpy)2] 2PF6.0.5 NH4PF6] complex, Ru(II)-CNEB. The complex showed appreciable cytotoxicity on Dalton's lymphoma cells and a significant Ru(II)-CNEB-LDH interaction (Kc = 1.525 × 105 M-1). The later was further confirmed from luminescence quenching and gel retardation assays. The complex also caused a significant decline in the activities of purified LDH and LDH from mice liver extract. The complex was further characterized as a non-competitive inhibitor of LDH(Ki = 0.032 mM). Ru(II)-CNEB complex perfused mice liver also showed a significant decline in LDH activity coinciding with similar changes in the intensity of LDH bands on polyacrylamide gel electrophoresis. Thus, Ru(II)-CNEB complex, as a non-competitive inhibitor of LDH, seems to be a candidate for potential therapeutic applications. © 2007 Bentham Science Publishers Ltd.