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1.
Med Chem Res ; 25(5): 932-940, 2016.
Article in English | MEDLINE | ID: mdl-32214768

ABSTRACT

Novel classes of acetylated and fully deprotected N-acyl-ß-d-glucopyranosylamines and ureas have been synthesized and biologically evaluated. Acylation of the per-O-acetylated ß-d-glucopyranosylurea (5), easily prepared via its corresponding phosphinimine derivative, by zinc chloride catalyzed reaction of the corresponding acyl chlorides RCOCl (a-f) gave the protected N-acyl-ß-d-glucopyranosylureas (6a-f), in acceptable-to-moderate yields. Subsequent deacetylation of analogues 6a-f under Zemplén conditions afforded the fully deprotected derivatives 7a,b,d,e,f, while the desired urea 7c was formed after treatment of 6c with dibutyltin oxide. All protected and unprotected compounds were examined for their cytotoxic activity in different L1210, CEM and HeLa tumor cell lines and were also evaluated against a broad panel of DΝΑ and RNA viruses. Derivative 7c exhibited cytostatic activity against the three evaluated tumor cell lines (IC50 9-24 µΜ) and might be the basis for the synthesis of structure-related derivatives with improved cytostatic potential. Only analogue 6f weakly but significantly inhibited the replication of parainfluenza-3 virus, Sindbis virus and Coxsackie virus B4 in cell cultures at concentrations of 45-58 µM.

2.
Bioorg Chem ; 63: 152-65, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26551065

ABSTRACT

Eosinophil derived neurotoxin (EDN) is an eosinophil secretion protein and a member of the Ribonuclease A (RNase A) superfamily involved in the immune response system and inflammatory disorders. The pathological actions of EDN are strongly dependent on the enzymatic activity and therefore, it is of significant interest to discover potent and specific inhibitors of EDN. In this framework we have assessed the inhibitory potency of triazole double-headed ribonucleosides. We present here an efficient method for the heterologous production and purification of EDN together with the synthesis of nucleosides and their biochemical evaluation in RNase A and EDN. Two groups of double-headed nucleosides were synthesized by the attachment of a purine or a pyrimidine base, through a triazole group at the 3'-C position of a pyrimidine or a purine ribonucleoside, respectively. Based on previous data with mononucleosides these compounds were expected to improve the inhibitory potency for RNase A and specificity for EDN. Kinetics data revealed that despite the rational, all but one, double-headed ribonucleosides were less potent than the respective mononucleosides while they were also more specific for ribonuclease A than for EDN. Compound 11c (9-[3'-[4-[(cytosine-1-yl)methyl]-1,2,3-triazol-1-yl]-ß-d-ribofuranosyl]adenine) displayed a stronger preference for EDN than for ribonuclease A and a Ki value of 58µM. This is the first time that an inhibitor is reported to have a better potency for EDN than for RNase A. The crystal structure of EDN-11c complex reveals the structural basis of its potency and selectivity providing important guidelines for future structure-based inhibitor design efforts.


Subject(s)
Eosinophils/chemistry , Neurotoxins/antagonists & inhibitors , Ribonuclease, Pancreatic/antagonists & inhibitors , Ribonucleosides/pharmacology , Triazoles/pharmacology , Animals , Cattle , Dose-Response Relationship, Drug , Kinetics , Models, Molecular , Molecular Structure , Neurotoxins/metabolism , Ribonuclease, Pancreatic/metabolism , Ribonucleosides/chemistry , Structure-Activity Relationship , Triazoles/chemistry
3.
Bioorg Med Chem ; 22(17): 4810-25, 2014 Sep 01.
Article in English | MEDLINE | ID: mdl-25092521

ABSTRACT

Glycogen phosphorylase (GP) is a validated target for the development of new type 2 diabetes treatments. Exploiting the Zinc docking database, we report the in silico screening of 1888 N-acyl-ß-d-glucopyranosylamines putative GP inhibitors differing only in their R groups. CombiGlide and GOLD docking programs with different scoring functions were employed with the best performing methods combined in a 'consensus scoring' approach to ranking of ligand binding affinities for the active site. Six selected candidates from the screening were then synthesized and their inhibitory potency was assessed both in vitro and ex vivo. Their inhibition constants' values, in vitro, ranged from 5 to 377µM while two of them were effective at causing inactivation of GP in rat hepatocytes at low µM concentrations. The crystal structures of GP in complex with the inhibitors were defined and provided the structural basis for their inhibitory potency and data for further structure based design of more potent inhibitors.


Subject(s)
Drug Design , Enzyme Inhibitors/pharmacology , Glucosamine/analogs & derivatives , Glycogen Phosphorylase, Liver Form/antagonists & inhibitors , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Glucosamine/chemical synthesis , Glucosamine/chemistry , Glucosamine/pharmacology , Glycogen Phosphorylase, Liver Form/metabolism , Humans , Molecular Structure , Structure-Activity Relationship
4.
Bioorg Med Chem ; 20(24): 7184-93, 2012 Dec 15.
Article in English | MEDLINE | ID: mdl-23122937

ABSTRACT

Five ribofuranosyl pyrimidine nucleosides and their corresponding 1,2,3-triazole derivatives have been synthesized and characterized. Their inhibitory action to Ribonuclease A has been studied by biochemical analysis and X-ray crystallography. These compounds are potent competitive inhibitors of RNase A with low µM inhibition constant (K(i)) values with the ones having a triazolo linker being more potent than the ones without. The most potent of these is 1-[(ß-D-ribofuranosyl)-1,2,3-triazol-4-yl]uracil being with K(i) = 1.6 µM. The high resolution X-ray crystal structures of the RNase A in complex with three most potent inhibitors of these inhibitors have shown that they bind at the enzyme catalytic cleft with the pyrimidine nucleobase at the B(1) subsite while the triazole moiety binds at the main subsite P(1), where P-O5' bond cleavage occurs, and the ribose at the interface between subsites P(1) and P(0) exploiting interactions with residues from both subsites. The effect of a susbsituent group at the 5-pyrimidine position at the inhibitory potency has been also examined and results show that any addition at this position leads to a less efficient inhibitor. Comparative structural analysis of these RNase A complexes with other similar RNase A-ligand complexes reveals that the triazole moiety interactions with the protein form the structural basis of their increased potency. The insertion of a triazole linker between the pyrimidine base and the ribose forms the starting point for further improvement of these inhibitors in the quest for potent ribonucleolytic inhibitors with pharmaceutical potential.


Subject(s)
Pyrimidine Nucleosides/chemistry , Pyrimidine Nucleosides/pharmacology , Ribonuclease, Pancreatic/antagonists & inhibitors , Triazoles/chemistry , Triazoles/pharmacology , Animals , Cattle , Crystallography, X-Ray , Drug Design , Hydrogen Bonding , Kinetics , Models, Molecular , Molecular Structure , Protein Conformation , Pyrimidine Nucleosides/chemical synthesis , Ribonuclease, Pancreatic/chemistry , Ribonuclease, Pancreatic/metabolism , Triazoles/chemical synthesis
5.
ChemMedChem ; 13(3): 259-269, 2018 02 06.
Article in English | MEDLINE | ID: mdl-29314771

ABSTRACT

A member of the ribonuclease A superfamily, human angiogenin (hAng) is a potent angiogenic factor. Heteronuclear NMR spectroscopy combined with induced-fit docking revealed a dual binding mode for the most antiangiogenic compound of a series of ribofuranosyl pyrimidine nucleosides that strongly inhibit hAng's angiogenic activity in vivo. While modeling suggests the potential for simultaneous binding of the inhibitors at the active and cell-binding sites, NMR studies indicate greater affinity for the cell-binding site than for the active site. Additionally, molecular dynamics simulations at 100 ns confirmed the stability of binding at the cell-binding site with the predicted protein-ligand interactions, in excellent agreement with the NMR data. This is the first time that a nucleoside inhibitor is reported to completely inhibit the angiogenic activity of hAng in vivo by exerting dual inhibitory activity on hAng, blocking both the entrance of hAng into the cell and its ribonucleolytic activity.


Subject(s)
Pyrimidine Nucleosides/chemistry , Ribonuclease, Pancreatic/antagonists & inhibitors , Animals , Binding Sites , Cell Line , Chick Embryo , Chorioallantoic Membrane/blood supply , Chorioallantoic Membrane/drug effects , Computer Simulation , Humans , Molecular Dynamics Simulation , Neovascularization, Physiologic/drug effects , Nuclear Magnetic Resonance, Biomolecular , Structure-Activity Relationship
6.
Article in English | MEDLINE | ID: mdl-25774721

ABSTRACT

We report the synthesis of novel thiopurine pyranonucleosides. Direct coupling of silylated 6-mercaptopurine and 6-thioguanine with the appropriate pyranoses 1a-e via Vorbrüggen nucleosidation, gave the N-9 linked mercaptopurine 2a-e and thioguanine 4a-e nucleosides, while their N-7 substituted congeners 10a-e and 7a-e, were obtained through condensation of the same acetates with 6-chloro and 2-amino-6-chloropurines, followed by subsequent thionation. Nucleosides 3a-e, 5a-e, 8a-e, and 11a-e were evaluated for their cytostatic activity in three different tumor cell proliferative assays.


Subject(s)
Purine Nucleosides/chemical synthesis , Purine Nucleosides/pharmacology , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Inhibitory Concentration 50 , Mice
7.
Front Chem ; 3: 21, 2015.
Article in English | MEDLINE | ID: mdl-25853123

ABSTRACT

We describe the synthesis of C8-alkynyl adenine pyranonucleosides 4, 5, and 8-phenylethynyl-adenine (II), via Sonogashira cross-coupling reaction under microwave irradiation. Compounds 4e and II were less cytostatic than 5-fluorouracil (almost an order of magnitude) against murine leukemia (L1210) and human cervix carcinoma (HeLa) cells, while the same compounds proved to be more active than 5-fluorouracil against human lymphocyte (CEM) cells.

8.
Carbohydr Res ; 407: 170-8, 2015 Apr 30.
Article in English | MEDLINE | ID: mdl-25812993

ABSTRACT

A new series of 3'-C-trifluoromethyl- and 3'-C-methyl-ß-d-allopyranonucleosides of 5-fluorouracil and their deoxy derivatives has been designed and synthesized. Treatment of ketosugar 1 with trifluoromethyltrimethylsilane under catalytic fluoride activation and methyl magnesium bromide, gave 1,2:5,6-di-O-isopropylidene-3-C-trifluoromethyl (2a) and 3-C-methyl (2b)-α-D-allofuranose, respectively, in a virtually quantitative yield and with complete stereoselectivity. Hydrolysis followed by acetylation led to the 1,2,4,6-tetra-O-acetyl-3-C-trifluoromethyl (3a) and 3-C-methyl (3b)-ß-D-allopyranose. Compounds 3a,b were then condensed with silylated 5-fluorouracil and deacetylated to afford the target nucleosides 5a,b. Deoxygenation of the peracylated allopyranoses 3a,b followed by condensation with silylated 5-fluorouracil and subsequent deacetylation yielded the target 3'-deoxy-3'-C-trifluoromethyl and 3'-deoxy-3'-C-methyl-ß-d-glucopyranonucleosides 14a,b. The newly synthesized compounds were evaluated for their potential antiviral and cytostatic activities. The 3'-deoxy-3'-C-methyl- ribonucleoside 11b showed significant cytotoxic activity (∼7 µM) almost equally active against a variety of tumor cell lines.


Subject(s)
Antiviral Agents/pharmacology , Cytostatic Agents/pharmacology , Nucleosides/chemical synthesis , Oligosaccharides, Branched-Chain/chemical synthesis , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Carbohydrate Conformation , Cell Line, Tumor , Cell Proliferation/drug effects , Cytostatic Agents/chemical synthesis , Cytostatic Agents/chemistry , HeLa Cells , Humans , Mice , Nucleosides/chemistry , Nucleosides/pharmacology , Oligosaccharides, Branched-Chain/chemistry , Oligosaccharides, Branched-Chain/pharmacology
9.
Curr Top Med Chem ; 15(23): 2373-89, 2015.
Article in English | MEDLINE | ID: mdl-26088352

ABSTRACT

Glycogen phosphorylase (GP), a validated target for the development of anti-hyperglycaemic agents, has been targeted for the design of novel glycopyranosylamine inhibitors. Exploiting the two most potent inhibitors from our previous study of N-acyl-ß-D-glucopyranosylamines (Parmenopoulou et al., Bioorg. Med. Chem. 2014, 22, 4810), we have extended the linking group to -NHCONHCO- between the glucose moiety and the aliphatic/aromatic substituent in the GP catalytic site ß-cavity. The N-acyl-N´-(ß-D-glucopyranosyl) urea inhibitors were synthesized and their efficiency assessed by biochemical methods, revealing inhibition constant values of 4.95 µM and 2.53 µM. Crystal structures of GP in complex with these inhibitors were determined and analyzed, providing data for further structure based design efforts. A novel Linear Response - Molecular Mechanics Coulomb Surface Area (LR-MM-CBSA) method has been developed which relates predicted and experimental binding free energies for a training set of N-acyl-N´-(ß-D-glucopyranosyl) urea ligands with a correlation coefficient R(2) of 0.89 and leave-one-out cross-validation (LOO-cv) Q(2) statistic of 0.79. The method has significant applications to direct future lead optimization studies, where ligand entropy loss on binding is revealed as a key factor to be considered. ADMET property predictions revealed that apart from potential permeability issues, the synthesized N-acyl-N´-(ß-D-glucopyranosyl) urea inhibitors have drug-like potential without any toxicity warnings.


Subject(s)
Computational Biology , Diabetes Mellitus, Type 2/drug therapy , Glucose/analogs & derivatives , Glycogen Phosphorylase/antagonists & inhibitors , Hypoglycemic Agents/chemical synthesis , Urea/analogs & derivatives , Animals , Binding, Competitive , Crystallography, X-Ray , Diabetes Mellitus, Type 2/enzymology , Glucose/chemical synthesis , Glucose/chemistry , Glucose/pharmacokinetics , Glucose/pharmacology , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Ligands , Molecular Docking Simulation , Molecular Structure , Muscle, Skeletal/enzymology , Protein Binding , Rabbits , Serum Albumin/metabolism , Urea/chemical synthesis , Urea/chemistry , Urea/pharmacokinetics , Urea/pharmacology
10.
Carbohydr Res ; 383: 50-7, 2014 Jan 13.
Article in English | MEDLINE | ID: mdl-24291356

ABSTRACT

A novel series of 2'-spiro pyrimidine pyranonucleosides has been designed and synthesized. Their precursors, 2'-C-cyano nucleosides 5a,b and 6a,b, were obtained by subjecting 1a,b to the sequence of selective protection of the primary hydroxyl group, acetalation, oxidation, and finally treatment with sodium cyanide. Deoxygenation at the 2'-position of cyanohydrins 5a,b or 6a,b led to the 2'-deoxy derivatives 9a,b. Fully deprotection of 5a,b, 6a,b, and 9a,b gave the desired 2'-C-cyano 7a,b, 8a,b, and 2'-C-cyano-2'-deoxy pyranonucleosides 10a,b, respectively. Mesylation of the corresponding cyanohydrins 5a,b and 6a,b afforded compounds 11a,b and 12a,b which after base treatment and subsequent deprotection furnished the spiro nucleosides 15a,b and 16a. The new analogues were evaluated for their potential cytostatic activities in cell culture.


Subject(s)
Nucleosides/chemical synthesis , Pyrans/chemical synthesis , Spiro Compounds/chemical synthesis , Cell Proliferation/drug effects , HeLa Cells , Humans , Nucleosides/chemistry , Nucleosides/pharmacology , Pyrans/chemistry , Pyrans/pharmacology , Pyrimidines/chemistry , Sodium Cyanide/chemistry , Spiro Compounds/chemistry , Spiro Compounds/pharmacology
11.
Carbohydr Res ; 364: 8-14, 2012 Dec 15.
Article in English | MEDLINE | ID: mdl-23147040

ABSTRACT

A new series of 4'-C-cyano and 4'-C-cyano-4'-deoxy pyrimidine pyranonucleosides has been designed and synthesized. Commercially available 1,2,3,4,6-penta-O-acetyl-D-mannopyranose (1) was condensed with silylated 5-fluorouracil, uracil, and thymine, respectively to afford after deacetylation 1-(α-D-mannopyranosyl)nucleosides (2a-c). Subjecting 2a-c to the sequence of specific acetalation, selective protection of the primary hydroxyl group and oxidation, the 4'-ketonucleosides 6a-c and 7c were obtained. Reaction of compounds 6a,b, and 7c with sodium cyanide and subsequent deprotection gave the target 1-(4'-C-cyano-α-D-mannopyranosyl)nucleosides 12a-c. Deoxygenation at the 4'-position of cyanohydrins 8a,b, and 11c followed by deprotection led to the desired 1-(4'-C-cyano-4'-deoxy-α-D-talopyranosyl)nucleosides (15a-c). The newly synthesized compounds were evaluated for their potential antiviral and cytostatic activities in cell culture.


Subject(s)
Antineoplastic Agents/chemical synthesis , Fluorouracil/analogs & derivatives , Fluorouracil/chemical synthesis , Pyrimidine Nucleosides/chemical synthesis , Acetylation , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cytostatic Agents/chemical synthesis , Cytostatic Agents/chemistry , Cytostatic Agents/pharmacology , Drug Design , Fluorouracil/chemistry , Fluorouracil/pharmacology , HeLa Cells , Humans , Inhibitory Concentration 50 , Mannose/analogs & derivatives , Mannose/chemistry , Nitriles/chemistry , Oxidation-Reduction , Oxygen/chemistry , Pyrimidine Nucleosides/chemistry , Pyrimidine Nucleosides/pharmacology , Sodium Cyanide/chemistry , Stereoisomerism , Thymine/chemistry , Uracil/chemistry
12.
Article in English | MEDLINE | ID: mdl-22849646

ABSTRACT

This article describes the synthesis of (3 'S) and (3 'R)-3 '-amino-3 '-deoxy pyranonucleosides and their precursors (3 'S) and (3 'R)-3 '-azido-3 '-deoxy pyranonucleosides. Azidation of 1,2:5,6-di-O-isopropylidene-3-O-toluenesulfonyl-α-D-allofuranose followed by hydrolysis and subsequent acetylation afforded 3-azido-3-deoxy-1,2,4,6-tetra-O-acetyl-D-glucopyranose, which upon coupling with the proper silylated bases, deacetylation, and catalytic hydrogenation, obtained the target 3 '-amino-3 '-deoxy-ß-D-glucopyranonucleosides. The desired 1-(3 '-amino-3 '-deoxy-ß-D-allopyranosyl)5-fluorouracil was readily prepared from the suitable imidazylate sugar after azidation followed by a protection/deprotection sequence and reduction of the unprotected azido precursor. No antiviral activity was observed for the novel nucleosides. Moderate cytostatic activity was recorded for the 5-fluorouracil derivatives.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Nucleosides/chemistry , Nucleosides/pharmacology , Antineoplastic Agents/chemical synthesis , Antiviral Agents/chemical synthesis , Azides/chemical synthesis , Azides/chemistry , Azides/pharmacology , Cell Line, Tumor , Fluorouracil/chemical synthesis , Fluorouracil/chemistry , Fluorouracil/pharmacology , Humans , Neoplasms/drug therapy , Nucleosides/chemical synthesis , Pyrans/chemical synthesis , Pyrans/chemistry , Pyrans/pharmacology , Virus Diseases/drug therapy , Viruses/drug effects
13.
Eur J Med Chem ; 46(11): 5668-74, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21917363

ABSTRACT

This report describes the total and facile synthesis of 3'-C-cyano & 3'-C-cyano-3'-deoxy pyrimidine pyranonucleosides. Reaction of 3-keto glucoside 1 with sodium cyanide gave the desired precursor 3-C-cyano-1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (2). Hydrolysis followed by acetylation led to the 1,2,3,4,6-penta-O-acetyl-3-C-cyano-D-glucopyranose (4). Compound 4 was condensed with silylated 5-fluorouracil, uracil, thymine and N(4)-benzoylcytosine, respectively and deacetylated to afford the target 1-(3'-C-cyano-ß-D-glucopyranosyl)nucleosides 6a-d. Routine deoxygenation at position 3' of cyanohydrin 2, followed by hydrolysis and acetylation led to the 3-C-cyano-3-deoxy-1,2,4,6-tetra-O-acetyl-D-allopyranose (10). Coupling of sugar 10 with silylated pyrimidines and subsequent deacetylation yielded the target 1-(3'-C-cyano-3'-deoxy-ß-D-allopyranosyl)nucleosides 12a-d. The new analogues were evaluated for their antiviral and cytostatic activities. It was found that 6a was endowed with a pronounced anti-proliferative activity that was only 2- to 8-fold less potent than that shown for the parental base 5-fluorouracil. None of the compounds showed activity against a broad panel of DNA and RNA viruses.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Chemistry Techniques, Synthetic , Pyrimidine Nucleosides/chemical synthesis , Pyrimidine Nucleosides/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Humans , Pyrimidine Nucleosides/chemistry , Stereoisomerism , Substrate Specificity
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