The synthesis of dimethyl derivatives of 5.6.5 spiro bicyclic lactam Pro-Leu-Gly-NH(2) peptidomim... more The synthesis of dimethyl derivatives of 5.6.5 spiro bicyclic lactam Pro-Leu-Gly-NH(2) peptidomimetics was carried out to test the hypothesis that by placing methyl groups on the β-methylene carbon of the thiazolidine ring steric bulk would be introduced into the topological space that the β-methylene carbon is believed to occupy in the negative allosteric modulators of the dopamine D(2) receptor. With such a modification, a positive allosteric modulator would be converted into a negative allosteric modulator. This hypothesis was shown to be correct as 3a and 4a where found to be negative allosteric modulators, whereas their unmethylated derivatives were positive allosteric modulators of the dopamine D(2) receptor.
Conjugate addition of amines to olefinic esters derived from sugars leading to formation of glyco... more Conjugate addition of amines to olefinic esters derived from sugars leading to formation of glycosylated amino esters in a stereoselective manner is described. Some of the synthesized compounds possess DNA topoisomerase-II enzyme inhibitory activities at low concentrations.
In recent years, orotidine-5′-monophosphate decarboxylase (ODCase) has gained renewed attention a... more In recent years, orotidine-5′-monophosphate decarboxylase (ODCase) has gained renewed attention as a drug target. As a part of continuing efforts to design novel inhibitors of ODCase, we undertook a comprehensive study of potent, structurally diverse ligands of ODCase and analyzed their structural interactions in the active site of ODCase. These ligands comprise of pyrazole or pyrimidine nucleotides including the mononucleotide derivatives of pyrazofurin, barbiturate ribonucleoside, and 5-cyanouridine, as well as, in a computational approach, 1,4-dihydropyridinebased non-nucleoside inhibitors such as nifedipine and nimodipine. All these ligands bind in the active site of ODCase exhibiting distinct interactions paving the way to design novel inhibitors against this interesting enzyme. We propose an empirical model for the ligand structure for rational modifications in new drug design and potentially new lead structures.
The first click chemistry-inspired noscapine glycoconjugates have been developed in good to excel... more The first click chemistry-inspired noscapine glycoconjugates have been developed in good to excellent yields to increase the therapeutic efficacy of noscapine.
An efficient, high yielding one-pot synthesis of 4-substituted cyclopropyl phenyl methanones boun... more An efficient, high yielding one-pot synthesis of 4-substituted cyclopropyl phenyl methanones bound to RAM and WANG resins has been developed. The resin bound cyclopropyl phenyl methanone served as a combinatorial scaffold for the generation of structurally diverse alicyclic compounds.
In this article, we report on the synthesis of 2&... 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.
Nucleic acids U 0700 Synthesis and DNA Topoisomerase-II Inhibitory Activity of Unnatural Nucleosi... more Nucleic acids U 0700 Synthesis and DNA Topoisomerase-II Inhibitory Activity of Unnatural Nucleosides.-Among the nucleosides (I) (21 examples) synthesized, only compound (Ic) shows moderate topoisomerase-II inhibitory activity.
Nucleic acids Nucleic acids U 0700 A Versatile Synthesis of Dihydropyrimidinone C-Nucleosides.-A ... more Nucleic acids Nucleic acids U 0700 A Versatile Synthesis of Dihydropyrimidinone C-Nucleosides.-A versatile synthesis of dihydropyrimidinone C-nucleosides (VI) is described. Glycosyl amino esters (III), obtained by reductive alkylation of (I) on condensation with different isocyanates (IV), afford respective ureido derivatives (V) in good yields. The latter, on cyclative amidation with a combination of DBU, tetrabutylammonium bromide and molecular sieves, furnish the target compounds (VI).
In addition to being valuable source of energy, carbohydrates, one of the main dietary components... more In addition to being valuable source of energy, carbohydrates, one of the main dietary components, are integral parts of the cell. As extra- & intracellular molecules they act as cell surface receptor and also as signaling molecules playing predominant role in molecular recognition and many other cellular processes. The clear understanding of their role in the various important biological events has led to the demand for easy access of diverse glycoconjugates for their complete chemical and biological investigations. Several carbohydrate-based molecules both of synthetic and natural origin are known for their wide range of pharmacological activities and even many of them are clinically used to treat different ailments. Due to their structural diversity in terms of functional groups, ring size and linkages they are valuable scaffolds in drug discovery processes. Because of the hydrophilic nature of monosaccharides they offer good water solubility, optimum pharmacokinetics and decreased toxicity. These naturally occurring molecules have therefore been extensively used to access diverse library of compounds with great chemotherapeutic importance. This review highlights an overview of development of carbohydrate-based molecules from others and our lab which have shown promising biological activity against front line diseases.
2&amp... more 2'-Fluoro-6'-methylene carbocyclic adenosine (FMCA) is a potent and selective inhibitor of wild type as well as drug-resistant hepatitis B virus (HBV) mutants. FMCA demonstrated excellent anti-HBV activity against both adefovir-resistant and lamivudine-resistant double (rtL180M/rtM204V) mutants as well as in lamivudine/entecavir triple mutants (L180M+S202G+M204V) in vitro. Its monophosphate prodrug (FMCAP) demonstrated a greater than 12-fold increase of anti-HBV activity in comparison to that of the nucleoside without elevation of cellular toxicity. In the preliminary in vivo study in chimeric mice harboring the lamivudine/entecavir triple mutant, FMCAP effectively reduced HBV viral load, while entecavir was not effective. Therefore, it was of great interest to develop an efficient synthetic procedure to support the preclinical investigation. In this article, a new approach for the synthesis of FMCA from a readily available starting material (Vince lactam) in 16 steps is described. An efficient and practical methodology for stereospecific preparation of a versatile carbocyclic key intermediate,…
A new series of acyclic nucleotides based on the adenine skeleton and bearing in 9-position a pho... 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 R,β-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.
Abstract Reductive amination of glycosyl aldehydes (1a–c, 2) with glycosyl amino esters (3a–c, 4)... more Abstract Reductive amination of glycosyl aldehydes (1a–c, 2) with glycosyl amino esters (3a–c, 4) in the presence of sodium borohydride gave diglycosylated amino esters (5–15) in good yield. N‐Glycosyl‐glycosylated amino esters were reduced to the respective ...
Nucleic acids Nucleic acids U 0700 Diastereoselective Synthesis of Galactopyranosyl Amino Esters ... more Nucleic acids Nucleic acids U 0700 Diastereoselective Synthesis of Galactopyranosyl Amino Esters and Their Transformation into C-Nucleosides.-Galactopyranosylated olefinic esters of type (III) yield the corresponding amino esters (V) and (VI) on treatment with amines. Amino esters (V) give ureido amino esters (VIII) when reacted with isocyanates. Cyclization of (VIII) affords the corresponding dihydropyrimidine-2,4-diones of type (IX).
Glycosyl nitrile oxides, generated in situ by reaction of glycosyl oximes (3a, 3b, 4) with N-chlo... more Glycosyl nitrile oxides, generated in situ by reaction of glycosyl oximes (3a, 3b, 4) with N-chlorosuccinimide and DBU, on 1,3-dipolar cycloaddition with substituted alkenes resulted in glycosyl isoxazolines (5, 7-28) in diastereoselective manner. The extent of diastereoselection varies with the nature of substituents both in sugar and alkenes. The compounds synthesized were screened in vitro against many fungi wherein two of the compounds (12, 23) showed significant inhibition against Sporothrix schenckii, Trychophyton mentagrophytes, and Cryptococcus neoformans with MIC of 12.5 and 6.25 mg/mL, respectively.
Combinatorial Chemistry & High Throughput Screening, 2003
A combinatorial library of 60 C-nucleoside analogs was synthesized by sequential coupling of buil... more A combinatorial library of 60 C-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 γ-glutamyl cysteine synthetase (γ-GCase) and glutathione-S-transeferases (GSTs). Several compounds were found to be weak inhibitors of filarial γ-GCase, whereas, most of them stimulated filarial GSTs.
ABSTRACT Guanosine, released extracellularly from neurons and glial cells, plays important roles ... more ABSTRACT Guanosine, released extracellularly from neurons and glial cells, plays important roles in the central nervous system, including neuroprotection. The innovative DELFIA Eu-GTP binding assay was optimized for characterization of the putative guanosine receptor binding site at rat brain membranes by using a series of novel and known guanosine derivatives. These nucleosides were prepared by modifying the purine and sugar moieties of guanosine at the 6- and 5'-positions, respectively. Results of these experiments prove that guanosine, 6-thioguanosine, and their derivatives activate a G protein-coupled receptor that is different from the well-characterized adenosine receptors.
A new series of 8-substituted 9-ethyladenine derivatives has been synthesized and tested at rat a... more A new series of 8-substituted 9-ethyladenine derivatives has been synthesized and tested at rat and human adenosine receptors. Binding data demonstrates that some compounds could represent new tools suitable for in vivo studies in rat models of Parkinson's disease and for the design of new molecules with improved affinity and selectivity at human AA(2A)R.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.
A number of phenylene bridged C 2 symmetric glycosyl uerides with ester (3a-f), alcohol (4a-c) an... more A number of phenylene bridged C 2 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.
The synthesis of dimethyl derivatives of 5.6.5 spiro bicyclic lactam Pro-Leu-Gly-NH(2) peptidomim... more The synthesis of dimethyl derivatives of 5.6.5 spiro bicyclic lactam Pro-Leu-Gly-NH(2) peptidomimetics was carried out to test the hypothesis that by placing methyl groups on the β-methylene carbon of the thiazolidine ring steric bulk would be introduced into the topological space that the β-methylene carbon is believed to occupy in the negative allosteric modulators of the dopamine D(2) receptor. With such a modification, a positive allosteric modulator would be converted into a negative allosteric modulator. This hypothesis was shown to be correct as 3a and 4a where found to be negative allosteric modulators, whereas their unmethylated derivatives were positive allosteric modulators of the dopamine D(2) receptor.
Conjugate addition of amines to olefinic esters derived from sugars leading to formation of glyco... more Conjugate addition of amines to olefinic esters derived from sugars leading to formation of glycosylated amino esters in a stereoselective manner is described. Some of the synthesized compounds possess DNA topoisomerase-II enzyme inhibitory activities at low concentrations.
In recent years, orotidine-5′-monophosphate decarboxylase (ODCase) has gained renewed attention a... more In recent years, orotidine-5′-monophosphate decarboxylase (ODCase) has gained renewed attention as a drug target. As a part of continuing efforts to design novel inhibitors of ODCase, we undertook a comprehensive study of potent, structurally diverse ligands of ODCase and analyzed their structural interactions in the active site of ODCase. These ligands comprise of pyrazole or pyrimidine nucleotides including the mononucleotide derivatives of pyrazofurin, barbiturate ribonucleoside, and 5-cyanouridine, as well as, in a computational approach, 1,4-dihydropyridinebased non-nucleoside inhibitors such as nifedipine and nimodipine. All these ligands bind in the active site of ODCase exhibiting distinct interactions paving the way to design novel inhibitors against this interesting enzyme. We propose an empirical model for the ligand structure for rational modifications in new drug design and potentially new lead structures.
The first click chemistry-inspired noscapine glycoconjugates have been developed in good to excel... more The first click chemistry-inspired noscapine glycoconjugates have been developed in good to excellent yields to increase the therapeutic efficacy of noscapine.
An efficient, high yielding one-pot synthesis of 4-substituted cyclopropyl phenyl methanones boun... more An efficient, high yielding one-pot synthesis of 4-substituted cyclopropyl phenyl methanones bound to RAM and WANG resins has been developed. The resin bound cyclopropyl phenyl methanone served as a combinatorial scaffold for the generation of structurally diverse alicyclic compounds.
In this article, we report on the synthesis of 2&... 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.
Nucleic acids U 0700 Synthesis and DNA Topoisomerase-II Inhibitory Activity of Unnatural Nucleosi... more Nucleic acids U 0700 Synthesis and DNA Topoisomerase-II Inhibitory Activity of Unnatural Nucleosides.-Among the nucleosides (I) (21 examples) synthesized, only compound (Ic) shows moderate topoisomerase-II inhibitory activity.
Nucleic acids Nucleic acids U 0700 A Versatile Synthesis of Dihydropyrimidinone C-Nucleosides.-A ... more Nucleic acids Nucleic acids U 0700 A Versatile Synthesis of Dihydropyrimidinone C-Nucleosides.-A versatile synthesis of dihydropyrimidinone C-nucleosides (VI) is described. Glycosyl amino esters (III), obtained by reductive alkylation of (I) on condensation with different isocyanates (IV), afford respective ureido derivatives (V) in good yields. The latter, on cyclative amidation with a combination of DBU, tetrabutylammonium bromide and molecular sieves, furnish the target compounds (VI).
In addition to being valuable source of energy, carbohydrates, one of the main dietary components... more In addition to being valuable source of energy, carbohydrates, one of the main dietary components, are integral parts of the cell. As extra- & intracellular molecules they act as cell surface receptor and also as signaling molecules playing predominant role in molecular recognition and many other cellular processes. The clear understanding of their role in the various important biological events has led to the demand for easy access of diverse glycoconjugates for their complete chemical and biological investigations. Several carbohydrate-based molecules both of synthetic and natural origin are known for their wide range of pharmacological activities and even many of them are clinically used to treat different ailments. Due to their structural diversity in terms of functional groups, ring size and linkages they are valuable scaffolds in drug discovery processes. Because of the hydrophilic nature of monosaccharides they offer good water solubility, optimum pharmacokinetics and decreased toxicity. These naturally occurring molecules have therefore been extensively used to access diverse library of compounds with great chemotherapeutic importance. This review highlights an overview of development of carbohydrate-based molecules from others and our lab which have shown promising biological activity against front line diseases.
2&amp... more 2'-Fluoro-6'-methylene carbocyclic adenosine (FMCA) is a potent and selective inhibitor of wild type as well as drug-resistant hepatitis B virus (HBV) mutants. FMCA demonstrated excellent anti-HBV activity against both adefovir-resistant and lamivudine-resistant double (rtL180M/rtM204V) mutants as well as in lamivudine/entecavir triple mutants (L180M+S202G+M204V) in vitro. Its monophosphate prodrug (FMCAP) demonstrated a greater than 12-fold increase of anti-HBV activity in comparison to that of the nucleoside without elevation of cellular toxicity. In the preliminary in vivo study in chimeric mice harboring the lamivudine/entecavir triple mutant, FMCAP effectively reduced HBV viral load, while entecavir was not effective. Therefore, it was of great interest to develop an efficient synthetic procedure to support the preclinical investigation. In this article, a new approach for the synthesis of FMCA from a readily available starting material (Vince lactam) in 16 steps is described. An efficient and practical methodology for stereospecific preparation of a versatile carbocyclic key intermediate,…
A new series of acyclic nucleotides based on the adenine skeleton and bearing in 9-position a pho... 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 R,β-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.
Abstract Reductive amination of glycosyl aldehydes (1a–c, 2) with glycosyl amino esters (3a–c, 4)... more Abstract Reductive amination of glycosyl aldehydes (1a–c, 2) with glycosyl amino esters (3a–c, 4) in the presence of sodium borohydride gave diglycosylated amino esters (5–15) in good yield. N‐Glycosyl‐glycosylated amino esters were reduced to the respective ...
Nucleic acids Nucleic acids U 0700 Diastereoselective Synthesis of Galactopyranosyl Amino Esters ... more Nucleic acids Nucleic acids U 0700 Diastereoselective Synthesis of Galactopyranosyl Amino Esters and Their Transformation into C-Nucleosides.-Galactopyranosylated olefinic esters of type (III) yield the corresponding amino esters (V) and (VI) on treatment with amines. Amino esters (V) give ureido amino esters (VIII) when reacted with isocyanates. Cyclization of (VIII) affords the corresponding dihydropyrimidine-2,4-diones of type (IX).
Glycosyl nitrile oxides, generated in situ by reaction of glycosyl oximes (3a, 3b, 4) with N-chlo... more Glycosyl nitrile oxides, generated in situ by reaction of glycosyl oximes (3a, 3b, 4) with N-chlorosuccinimide and DBU, on 1,3-dipolar cycloaddition with substituted alkenes resulted in glycosyl isoxazolines (5, 7-28) in diastereoselective manner. The extent of diastereoselection varies with the nature of substituents both in sugar and alkenes. The compounds synthesized were screened in vitro against many fungi wherein two of the compounds (12, 23) showed significant inhibition against Sporothrix schenckii, Trychophyton mentagrophytes, and Cryptococcus neoformans with MIC of 12.5 and 6.25 mg/mL, respectively.
Combinatorial Chemistry & High Throughput Screening, 2003
A combinatorial library of 60 C-nucleoside analogs was synthesized by sequential coupling of buil... more A combinatorial library of 60 C-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 γ-glutamyl cysteine synthetase (γ-GCase) and glutathione-S-transeferases (GSTs). Several compounds were found to be weak inhibitors of filarial γ-GCase, whereas, most of them stimulated filarial GSTs.
ABSTRACT Guanosine, released extracellularly from neurons and glial cells, plays important roles ... more ABSTRACT Guanosine, released extracellularly from neurons and glial cells, plays important roles in the central nervous system, including neuroprotection. The innovative DELFIA Eu-GTP binding assay was optimized for characterization of the putative guanosine receptor binding site at rat brain membranes by using a series of novel and known guanosine derivatives. These nucleosides were prepared by modifying the purine and sugar moieties of guanosine at the 6- and 5'-positions, respectively. Results of these experiments prove that guanosine, 6-thioguanosine, and their derivatives activate a G protein-coupled receptor that is different from the well-characterized adenosine receptors.
A new series of 8-substituted 9-ethyladenine derivatives has been synthesized and tested at rat a... more A new series of 8-substituted 9-ethyladenine derivatives has been synthesized and tested at rat and human adenosine receptors. Binding data demonstrates that some compounds could represent new tools suitable for in vivo studies in rat models of Parkinson's disease and for the design of new molecules with improved affinity and selectivity at human AA(2A)R.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.
A number of phenylene bridged C 2 symmetric glycosyl uerides with ester (3a-f), alcohol (4a-c) an... more A number of phenylene bridged C 2 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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Papers by Ram C Mishra