RC Mishra
Publications
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4.25Impact points
Second generation benzofuranone ring substituted noscapine analogs: synthesis and biological evaluation.
Biochemical pharmacology. 07/2011; 82(2):110-21.
Microtubules, composed of α/β tubulin heterodimers, represent a validated target for cancer chemotherapy. Thus, tubulin- and microtubule-binding antimitotic drugs such as taxanes and vincas are widely employed for the chemotherapeutic management of various malignancies. Although quite successful in ... [more] Microtubules, composed of α/β tubulin heterodimers, represent a validated target for cancer chemotherapy. Thus, tubulin- and microtubule-binding antimitotic drugs such as taxanes and vincas are widely employed for the chemotherapeutic management of various malignancies. Although quite successful in the clinic, these drugs are associated with severe toxicity and drug resistance problems. Noscapinoids represent an emerging class of microtubule-modulating anticancer agents based upon the parent molecule noscapine, a naturally occurring non-toxic cough-suppressant opium alkaloid. Here we report in silico molecular modeling, chemical synthesis and biological evaluation of novel analogs derived by modification at position-7 of the benzofuranone ring system of noscapine. The synthesized analogs were evaluated for their tubulin polymerization activity and their biological activity was examined by their antiproliferative potential using representative cancer cell lines from varying tissue-origin [A549 (lung), CEM (lymphoma), MIA PaCa-2 (pancreatic), MCF-7 (breast) and PC-3 (prostate)]. Cell-cycle studies were performed to explore their ability to halt the cell-cycle and induce subsequent apoptosis. The varying biological activity of these analogs that differ in the nature and bulk of substituent at position-7 was rationalized utilizing predictive in silico molecular modeling.
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4.80Impact points
Adenine-Based Acyclic Nucleotides as Novel P2X(3) Receptor Ligands.
Journal of medicinal chemistry. 08/2009;
A new series of acyclic nucleotides based on the adenine skeleton and bearing in 9-position a phosphorylated four carbon chain has been synthesized. Various substituents were introduced in 2-position of the adenine core. The new compounds were evaluated on rat P2X(3) receptors, using patch clamp rec... [more] A new series of acyclic nucleotides based on the adenine skeleton and bearing in 9-position a phosphorylated four carbon chain has been synthesized. Various substituents were introduced in 2-position of the adenine core. The new compounds were evaluated on rat P2X(3) receptors, using patch clamp recording from HEK transfected cells and the full P2X(3) agonist alpha,beta-meATP as reference compound. The results suggest that certain acyclic nucleotides, in particular compounds 28 and 29, are endowed with modest partial agonism on P2X(3) receptors. This is an interesting property that can depress the function of P2X(3) receptors, whose activation is believed to be involved in a number of chronic pain conditions including neuropathic pain and migraine. In fact, the new acyclic nucleotides are able to persistently block (by desensitization) P2X(3) receptor activity after a brief, modest activation, yet leaving the ability of sensory neurons to mediate responses to standard painful stimuli via a lower level of signaling.
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3.23Impact points
Adenosine A(2A) Receptor Antagonists: New 8-Substituted 9-Ethyladenines as Tools for in vivo Rat Models of Parkinson's Disease.
ChemMedChem. 05/2009;
Clinical evidence has demonstrated that AA(2A)R antagonists could be an alternative approach to the treatment of Parkinson's disease. Recently, three 9-ethyladenine derivatives bearing a bromine atom, an ethoxy group, and a furyl ring, respectively, in the 8-position have been reported to amelio... [more] Clinical evidence has demonstrated that AA(2A)R antagonists could be an alternative approach to the treatment of Parkinson's disease. Recently, three 9-ethyladenine derivatives bearing a bromine atom, an ethoxy group, and a furyl ring, respectively, in the 8-position have been reported to ameliorate motor deficits in rat Parkinson's disease models, suggesting a potential therapeutic role for these compounds. Starting from these observations, a new series of 9-ethyladenine derivatives, bearing different substituents such as halogens, alkoxy groups, aromatic and heteroaromatic rings in the 8-position, were synthesized. Radioligand binding assays demonstrated that some of the new compounds bind rat AA(2A)R with higher affinity than the previously reported congeners and that there is a good correlation between binding to rat and human receptors. Hence, the new molecules could represent new tools suitable for the in vivo studies in rat models of Parkinson's disease. Finally, a molecular docking analysis of the compounds was performed using a homology model of rat AA(2A)R, built using the human crystal structure as the template, and results are in agreement with the binding data.
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0.77Impact points
Synthesis and biological activity of trisubstituted adenines as A 2A adenosine receptor antagonists.
Nucleosides, nucleotides & nucleic acids. 02/2007; 26(10-12):1443-6.
The discovery of new drugs for the treatment of neurodegenerative disorders, such as Parkinson's disease, has become an attractive field of research. Due to the regulation of D(2) receptor activity by A(2A) adenosine receptor, potent and selective ligands of A(2A) subtype could be useful tools t... [more] The discovery of new drugs for the treatment of neurodegenerative disorders, such as Parkinson's disease, has become an attractive field of research. Due to the regulation of D(2) receptor activity by A(2A) adenosine receptor, potent and selective ligands of A(2A) subtype could be useful tools to study neurodegenerative disorders. A series of 2,8-disubstituted-9-ethyladenine derivatives was synthesized and tested in binding affinity assay at human adenosine receptors. New compounds showed good affinity and selectivity at A(2A) receptor versus the other subtypes. The introduction of a bromine atom in 8-position increased the affinity of these compounds, leading to ligands with K(i) in the nanomolar range.
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0.77Impact points
Synthesis and stability studies of 2',3',5'-tri-O-acetyl-2-amino(-N6-cyclopentyl)-1-deazaadenosines.
Nucleosides, nucleotides & nucleic acids. 02/2007; 26(10-12):1439-42.
In this article, we report on the synthesis of 2',3',5'-tri-O-acetyl-2-amino-1-deazaadenosine and of 2',3',5'-tri-O-acetyl-2-amino-N(6)-cyclopentyl-1-deazaadenosine, which are very versatile intermediates for the preparation of 2-substituted 1-deazaadenosine derivatives. The ... [more] In this article, we report on the synthesis of 2',3',5'-tri-O-acetyl-2-amino-1-deazaadenosine and of 2',3',5'-tri-O-acetyl-2-amino-N(6)-cyclopentyl-1-deazaadenosine, which are very versatile intermediates for the preparation of 2-substituted 1-deazaadenosine derivatives. The two synthesized compounds showed to be quite unstable, with the N(6)-substituted derivatives being less stable than the N(6)-unsubstituted counterpart, according to the calculated HOMO-LUMO energy gap. Stability studies were performed through HPLC-MS analysis.
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4.71Impact points
Current status of malaria control.
Current medicinal chemistry. 02/2005; 12(22):2643-59.
Malaria caused by Plasmodium parasites kills approximately 1-3 million people and causes disease in 300-500 million people annually throughout the world. The current approaches to curtail this disease include vector control, vaccination, immunotherapy and chemotherapy. The vector control is achieved... [more] Malaria caused by Plasmodium parasites kills approximately 1-3 million people and causes disease in 300-500 million people annually throughout the world. The current approaches to curtail this disease include vector control, vaccination, immunotherapy and chemotherapy. The vector control is achieved by reducing vector density, interrupting their life cycle, and creating a barrier between the human host and mosquitoes. A number of vaccine candidates are being clinically tried and R&D effort in this direction is coming in a big way. Currently there are only limited safe drugs for the treatment of this disease, however, reports of emerging resistance against existing drugs warrant the introduction of new drugs, which are unlikely to come from pharmaceutical industries because of limited commercial opportunities. One of the most important current approaches to develop new drugs involves the synthesis of chemical libraries and evaluate them against most validated biochemical targets of malarial parasite. Although a number of such targets in antimalarial drug development are known today, yet only validated and selective biochemical targets including mitochondrial transport, glycolic pathway, folate pathway, proteases and heme metabolism, apicoplast metabolism, glycophospatidyl inositol, lipid metabolism (glycerophospholipids), peptidyl deformylase and oxidative stress in parasite-infected erythrocytes have been discussed here. The well known antimalarial drugs and different drug combinations for the treatment of malaria are also briefly reviewed. A survey of the recently discovered new molecules active against malaria has also been narrated. Lastly, the future of malaria chemotherapy and new directions emerging from literature has been elucidated.
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0.77Impact points
Synthesis and DNA topoisomerase-II inhibitory activity of unnatural nucleosides.
Nucleosides, nucleotides & nucleic acids. 02/2005; 24(1):15-35.
The synthesis and biological activities of a number of unnatural nucleosides (23-43) is described. Nucleosides have been synthesized by SnCl4-catalyzed condensation of amino sugar acetates and silylated modified pyrimidines. Few of the 2'-O-acetyl derivatives of the nucleosides were hydrolyzed t... [more] The synthesis and biological activities of a number of unnatural nucleosides (23-43) is described. Nucleosides have been synthesized by SnCl4-catalyzed condensation of amino sugar acetates and silylated modified pyrimidines. Few of the 2'-O-acetyl derivatives of the nucleosides were hydrolyzed to the respective hydroxy derivatives by treatment with methanol saturated with ammonia. The compounds were screened against Filarial DNA-topoisomerase-II but only one of the compounds (29) inhibited this enzyme at 40 microg/mL of reaction mixture.
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2.65Impact points
Leishmanicidal activity of phenylene bridged C2 symmetric glycosyl ureides.
Bioorganic & medicinal chemistry letters. 09/2004; 14(15):4055-9.
A number of phenylene bridged C2 symmetric glycosyl uerides with ester (3a-f), alcohol (4a-c) and acid (5a-d) functionalities were prepared by addition of glycosyl amino esters with phenyl diisocyanates and their further reaction with LiAlH(4) or hydrolysis with LiOH. All the compounds were screened... [more] A number of phenylene bridged C2 symmetric glycosyl uerides with ester (3a-f), alcohol (4a-c) and acid (5a-d) functionalities were prepared by addition of glycosyl amino esters with phenyl diisocyanates and their further reaction with LiAlH(4) or hydrolysis with LiOH. All the compounds were screened for their in vitro and in vivo antileishmanial activity. Most of the compounds exhibited good activity while two of the compounds 3e and 3f reduced the clinical dose of standard drug SSG.
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0.77Impact points
A versatile synthesis of dihydropyrimidinone C-nucleosides.
Nucleosides, nucleotides & nucleic acids. 02/2004; 23(3):531-44.
A versatile synthesis of N-substituted dihydropyrimidinone C-nucleosides (20-29) is described. Glycosyl amino esters (3-9), obtained by reductive alkylation of glycosyl amino esters 1 and 2, on condensation with different isocyanates afforded respective ureido derivatives (10-19) in good to quantita... [more] A versatile synthesis of N-substituted dihydropyrimidinone C-nucleosides (20-29) is described. Glycosyl amino esters (3-9), obtained by reductive alkylation of glycosyl amino esters 1 and 2, on condensation with different isocyanates afforded respective ureido derivatives (10-19) in good to quantitative yields. The latter on cyclative amidation with a combination of DBU/TBAB (tetrabutylammonium bromide)/4A molecular sieve gave the corresponding nucleosides (20-29) in good yields.
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2.82Impact points
Synthesis of glycosylated beta-amino hydroxamates as new class of antimalarials.
Bioorganic & medicinal chemistry. 01/2004; 11(24):5363-74.
Glycosylated beta-amino acids (3-18, 38, 39), obtained by hydrolysis of glycosylated beta-amino esters on reaction with hydroxylamine hydrochloride in presence of DIC/DCC afforded glycosyl beta-amino hydroxamates (19-34, 40, 41) in fair to good yields. Compounds (19-34, 40, 41) were screened against... [more] Glycosylated beta-amino acids (3-18, 38, 39), obtained by hydrolysis of glycosylated beta-amino esters on reaction with hydroxylamine hydrochloride in presence of DIC/DCC afforded glycosyl beta-amino hydroxamates (19-34, 40, 41) in fair to good yields. Compounds (19-34, 40, 41) were screened against human malarial parasite Plasmodium falciparum in vitro for their schizontocidal activity. Compounds (19, 24, 26, 28, 40 and 41) exhibited good activity at 2 microg/mL concentrations.
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2.82Impact points
Synthesis and bioevaluation of glycosyl ureas as alpha-glucosidase inhibitors and their effect on mycobacterium.
Bioorganic & medicinal chemistry. 08/2003; 11(13):2911-22.
Glycosyl amino esters (2-13) on reaction with different isocyanates resulted in quantitative conversion to glycosyl ureas (14--32). Few of the selected ureas (15-20, 22-28, 30 and 32) on cyclative amidation with DBU/TBAB/4 A MS gave respective dihydropyrimidinones in fair to good yields (33-47). The... [more] Glycosyl amino esters (2-13) on reaction with different isocyanates resulted in quantitative conversion to glycosyl ureas (14--32). Few of the selected ureas (15-20, 22-28, 30 and 32) on cyclative amidation with DBU/TBAB/4 A MS gave respective dihydropyrimidinones in fair to good yields (33-47). The compounds were screened for alpha-glucosidase inhibitory activity and two (19 and 23) of them showed strong inhibition against rat intestinal alpha-glucosidase. The compounds were also screened against Mycobacterium aurum, however, only one (19) of them exhibited marginal antitubercular activity.
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2.46Impact points
DBU-assisted cyclorelease elimination: combinatorial synthesis and gamma-glutamyl cysteine synthetase and glutathione-S-transeferase modulatory effect of C-nucleoside analogs.
Combinatorial chemistry & high throughput screening. 03/2003; 6(1):37-50.
A combinatorial library of 60C- nucleoside analogs was synthesized by sequential coupling of building blocks followed by cyclative cleavage with DBU in an efficient manner. Only DMSO soluble compounds were tested for their modulatory effect against filarial gamma-glutamyl cysteine synthetase (gamma-... [more] A combinatorial library of 60C- nucleoside analogs was synthesized by sequential coupling of building blocks followed by cyclative cleavage with DBU in an efficient manner. Only DMSO soluble compounds were tested for their modulatory effect against filarial gamma-glutamyl cysteine synthetase (gamma-GCase) and glutathione-S-transeferases (GSTs). Several compounds were found to be weak inhibitors of filarial gamma-GCase, whereas, most of them stimulated filarial GSTs.
Following (29)
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Anshuman Dixit
Institute of Life Sciences -
Biswajit Saha
The University of Arizona -
Ravindra Rawal
University of Georgia -
Sivakumar Palani
Hospira India private limited -
Manu Lopus
University of California, Santa Barbara
