|
Concentration required for coronary arteries vasodilation at the A2 adenosine receptor in langendorff guinea pig heart preparation
|
Cavia porcellus
|
51.29
nM
|
|
Journal : J. Med. Chem.
Title : 2-aralkoxyadenosines: potent and selective agonists at the coronary artery A2 adenosine receptor.
Year : 1991
Volume : 34
Issue : 4
First Page : 1340
Last Page : 1344
Authors : Ueeda M, Thompson RD, Arroyo LH, Olsson RA.
Abstract : A Langendorff guinea pig heart preparation served for the assay of agonist potency of a series of 26 2-aralkoxyadenosines at the A1 and A2 receptors of, respectively, the atrioventricular node (conduction block) and coronary arteries (vasodilation). All of the analogues are weak agonists at the A1 receptor, requiring concentrations greater than 9 microM to cause second degree heart block. At the A2 receptor 2-phenethoxyadenosine is the most potent of the 2-phenylalkyladenosines. The activity of ring-substituted (F, Cl, CH3, and OCH3) 2-phenethoxyadenosines increases ortho less than meta less than para. The EC50s of coronary vasoactivity of several para-substituted analogues are in the subnanomolar range. The most potent analogue, 2-[2-(4-methylphenyl)ethoxy]adenosine 19, has an EC50 for coronary vasodilation of 190 pM and an A1/A2 selectivity ratio of 44,000. Aryl groups such as thienyl, indoloyl, or naphthyl also support A2 agonist activity. Although 2-oxoadenosine is 3 times more vasoactive than 2-aminoadenosine, the activities of the phenyl derivatives are markedly different; 2-phenoxyadenosine is 23 times weaker than 2-(phenylamino)adenosine (CV-1808).
|
Coronary arteries vasodilation at the adenosine A2 receptor in langendorff guinea pig heart preparation
|
Cavia porcellus
|
51.29
nM
|
|
Journal : J. Med. Chem.
Title : 2-Alkoxyadenosines: potent and selective agonists at the coronary artery A2 adenosine receptor.
Year : 1991
Volume : 34
Issue : 4
First Page : 1334
Last Page : 1339
Authors : Ueeda M, Thompson RD, Arroyo LH, Olsson RA.
Abstract : A Langendorff guinea pig heart preparation served for the assay of agonist activity of a series of 24 2-alkoxyadenosines at the A1 and A2 adenosine receptors of, respectively, the atrioventricular node (conduction block) and coronary arteries (vasodilation). Activities are low at the A1 receptor and do not show a clear relationship to the size or hydrophobicity of the C-2 substituent. All the analogues are more potent at the A2 receptor, activity varying directly with the size and hydrophobicity of the alkyl group. The most potent analogue in this series, 2-(2-cyclohexylethoxy)adenosine has an EC50 of 1 nM for coronary vasodilation and is 8700-fold selective for the A2 receptor.
|
Affinity for Adenosine A1 receptor determined by [3H]N6-cyclohexyladenosine binding to rat brain membranes
|
Rattus norvegicus
|
12.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : High selectivity of novel isoguanosine analogues for the adenosine A1 receptor
Year : 1991
Volume : 1
Issue : 9
First Page : 481
Last Page : 486
Authors : Nair V, Fesbender AJ, Miller LP, Bruce JL
|
Inhibition of [3H]-CHA binding to rat brain membrane Adenosine A1 receptor
|
Rattus norvegicus
|
5.1
nM
|
|
Journal : J. Med. Chem.
Title : A novel synthesis of xanthines: support for a new binding mode for xanthines with respect to adenosine at adenosine receptors.
Year : 1990
Volume : 33
Issue : 12
First Page : 3127
Last Page : 3130
Authors : Peet NP, Lentz NL, Meng EC, Dudley MW, Ogden AM, Demeter DA, Weintraub HJ, Bey P.
|
Displacement of [3H]R-PIA from rat brain membrane Adenosine A1 receptor
|
Rattus norvegicus
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Methanocarba analogues of purine nucleosides as potent and selective adenosine receptor agonists.
Year : 2000
Volume : 43
Issue : 11
First Page : 2196
Last Page : 2203
Authors : Jacobson KA, Ji X, Li AH, Melman N, Siddiqui MA, Shin KJ, Marquez VE, Ravi RG.
Abstract : Adenosine receptor agonists have cardioprotective, cerebroprotective, and antiinflammatory properties. We report that a carbocyclic modification of the ribose moiety incorporating ring constraints is a general approach for the design of A(1) and A(3) receptor agonists having favorable pharmacodynamic properties. While simple carbocyclic substitution of adenosine agonists greatly diminishes potency, methanocarba-adenosine analogues have now defined the role of sugar puckering in stabilizing the active adenosine receptor-bound conformation and thereby have allowed identification of a favored isomer. In such analogues a fused cyclopropane moiety constrains the pseudosugar ring of the nucleoside to either a Northern (N) or Southern (S) conformation, as defined in the pseudorotational cycle. In binding assays at A(1), A(2A), and A(3) receptors, (N)-methanocarba-adenosine was of higher affinity than the (S)-analogue, particularly at the human A(3) receptor (N/S affinity ratio of 150). (N)-Methanocarba analogues of various N(6)-substituted adenosine derivatives, including cyclopentyl and 3-iodobenzyl, in which the parent compounds are potent agonists at either A(1) or A(3) receptors, respectively, were synthesized. The N(6)-cyclopentyl derivatives were A(1) receptor-selective and maintained high efficacy at recombinant human but not rat brain A(1) receptors, as indicated by stimulation of binding of [(35)S]GTP-gamma-S. The (N)-methanocarba-N(6)-(3-iodobenzyl)adenosine and its 2-chloro derivative had K(i) values of 4.1 and 2.2 nM at A(3) receptors, respectively, and were highly selective partial agonists. Partial agonism combined with high functional potency at A(3) receptors (EC(50) < 1 nM) may produce tissue selectivity. In conclusion, as for P2Y(1) receptors, at least three adenosine receptors favor the ribose (N)-conformation.
|
Evaluated for the binding affinity towards the Adenosine A1 receptor in corpora striata of rats using [3H]CHA as radioligand.
|
None
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : 4-Amino[1,2,4]triazolo[4,3-a]quinoxalines. A novel class of potent adenosine receptor antagonists and potential rapid-onset antidepressants.
Year : 1990
Volume : 33
Issue : 8
First Page : 2240
Last Page : 2254
Authors : Sarges R, Howard HR, Browne RG, Lebel LA, Seymour PA, Koe BK.
Abstract : A series of 4-amino[1,2,4]triazolo[4,3-a]quinoxalines has been prepared. Many compounds from this class reduce immobility in Porsolt's behavioral despair model in rats upon acute administration and may therefore have therapeutic potential as novel and rapid acting antidepressant agents. Optimal activity in this test is associated with hydrogen, CF3, or small alkyl groups in the 1-position, with NH2, NH-acetyl, or amines substituted with small alkyl groups in the 4-position, and with hydrogen or 8-halogen substituents in the aromatic ring. Furthermore, many of these 4-amino[1,2,4]triazolo[4,3-a]quinoxalines bind avidly, and in some cases very selectively, to adenosine A1 and A2 receptors. A1 affinity of these compounds was measured by their inhibition of tritiated CHA (N6-cyclohexyladenosine) binding in rat cerebral cortex membranes and A2 affinity by their inhibition of tritiated NECA (5'-(N-ethylcarbamoyl)adenosine) binding to rat striatal homogenate in the presence of cold N6-cyclopentyladenosine. Structure-activity relationship (SAR) studies show that best A1 affinity is associated with ethyl, CF3, or C2F5 in the 1-position, NH-iPr or NH-cycloalkyl in the 4-position, and with an 8-chloro substituent. Affinity at the A2 receptor is mostly dependent on the presence of an NH2 group in the 4-position and is enhanced by phenyl, CF3, or ethyl in the 1-position. The most selective A1 ligand by a factor of greater than 3000 is 121 (CP-68,247; 8-chloro-4-(cyclohexyl-amino)-1- (trifluoromethyl)[1,2,4]triazolo[4,3-a]quinoxaline) with an IC50 of 28 nM at the A1 receptor. The most potent A2 ligand is 128 (CP-66,713; 4-amino-8-chloro-1- phenyl[1,2,4]triazolo[4,3-a]quinoxaline) with an IC50 of 21 nM at the A2 receptor and a 13-fold selectivity for this receptor. Representatives from this series appear to act as antagonists at both A1 and A2 receptors since they antagonize the inhibiting action of CHA on norepinephrine-stimulated cAMP formation in fat cells and they decrease cAMP accumulation induced by adenosine in limbic forebrain slices. Thus certain members of this 4-amino[1,2,4]triazolo[4,3-a]quinoxaline series are among the most potent and A1 or A2 selective non-xanthine adenosine antagonists known.
|
Inhibition of binding of [3H]N6-cyclohexyladenosine to adenosine A1 receptor of rat whole brain membranes.
|
None
|
12.8
nM
|
|
Journal : J. Med. Chem.
Title : C2,N6-disubstituted adenosines: synthesis and structure-activity relationships.
Year : 1989
Volume : 32
Issue : 8
First Page : 1667
Last Page : 1673
Authors : Trivedi BK, Bruns RF.
Abstract : Extracellular adenosine receptors have been divided into two major subtypes, called A1 and A2. Substitution of the adenosine molecule with appropriate groups at C2 or N6 is known to impart selectivity for the A2 receptor over the A1 receptor. In the present study, we investigated whether substitution at both C2 and N6 would have additive effects on the A2/A1 affinity ratio, thereby providing compounds with greater A2 selectivity than presently available agents. Disappointingly, additivity appeared to hold only when an A1-selective group was present at N6. For instance, 2-(phenylamino) substitution of the A1-selective agonist N6-cyclopentyladenosine resulted in a 70-fold shift in selectivity in favor of the A2 receptor, but the same substitution applied to the A2-selective agonist N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl]adenosine resulted in a 100-fold loss of affinity with no change in A2 selectivity.
|
Displacement of specific [3H]-CGS- 21680 binding to adenosine A2A receptor in rat striatal membranes
|
Rattus norvegicus
|
30.0
nM
|
|
Journal : J. Med. Chem.
Title : Methanocarba analogues of purine nucleosides as potent and selective adenosine receptor agonists.
Year : 2000
Volume : 43
Issue : 11
First Page : 2196
Last Page : 2203
Authors : Jacobson KA, Ji X, Li AH, Melman N, Siddiqui MA, Shin KJ, Marquez VE, Ravi RG.
Abstract : Adenosine receptor agonists have cardioprotective, cerebroprotective, and antiinflammatory properties. We report that a carbocyclic modification of the ribose moiety incorporating ring constraints is a general approach for the design of A(1) and A(3) receptor agonists having favorable pharmacodynamic properties. While simple carbocyclic substitution of adenosine agonists greatly diminishes potency, methanocarba-adenosine analogues have now defined the role of sugar puckering in stabilizing the active adenosine receptor-bound conformation and thereby have allowed identification of a favored isomer. In such analogues a fused cyclopropane moiety constrains the pseudosugar ring of the nucleoside to either a Northern (N) or Southern (S) conformation, as defined in the pseudorotational cycle. In binding assays at A(1), A(2A), and A(3) receptors, (N)-methanocarba-adenosine was of higher affinity than the (S)-analogue, particularly at the human A(3) receptor (N/S affinity ratio of 150). (N)-Methanocarba analogues of various N(6)-substituted adenosine derivatives, including cyclopentyl and 3-iodobenzyl, in which the parent compounds are potent agonists at either A(1) or A(3) receptors, respectively, were synthesized. The N(6)-cyclopentyl derivatives were A(1) receptor-selective and maintained high efficacy at recombinant human but not rat brain A(1) receptors, as indicated by stimulation of binding of [(35)S]GTP-gamma-S. The (N)-methanocarba-N(6)-(3-iodobenzyl)adenosine and its 2-chloro derivative had K(i) values of 4.1 and 2.2 nM at A(3) receptors, respectively, and were highly selective partial agonists. Partial agonism combined with high functional potency at A(3) receptors (EC(50) < 1 nM) may produce tissue selectivity. In conclusion, as for P2Y(1) receptors, at least three adenosine receptors favor the ribose (N)-conformation.
|
Displacement of [125I]- AB-MECA from rat adenosine A3 receptor expressed in CHO cells
|
Rattus norvegicus
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : Methanocarba analogues of purine nucleosides as potent and selective adenosine receptor agonists.
Year : 2000
Volume : 43
Issue : 11
First Page : 2196
Last Page : 2203
Authors : Jacobson KA, Ji X, Li AH, Melman N, Siddiqui MA, Shin KJ, Marquez VE, Ravi RG.
Abstract : Adenosine receptor agonists have cardioprotective, cerebroprotective, and antiinflammatory properties. We report that a carbocyclic modification of the ribose moiety incorporating ring constraints is a general approach for the design of A(1) and A(3) receptor agonists having favorable pharmacodynamic properties. While simple carbocyclic substitution of adenosine agonists greatly diminishes potency, methanocarba-adenosine analogues have now defined the role of sugar puckering in stabilizing the active adenosine receptor-bound conformation and thereby have allowed identification of a favored isomer. In such analogues a fused cyclopropane moiety constrains the pseudosugar ring of the nucleoside to either a Northern (N) or Southern (S) conformation, as defined in the pseudorotational cycle. In binding assays at A(1), A(2A), and A(3) receptors, (N)-methanocarba-adenosine was of higher affinity than the (S)-analogue, particularly at the human A(3) receptor (N/S affinity ratio of 150). (N)-Methanocarba analogues of various N(6)-substituted adenosine derivatives, including cyclopentyl and 3-iodobenzyl, in which the parent compounds are potent agonists at either A(1) or A(3) receptors, respectively, were synthesized. The N(6)-cyclopentyl derivatives were A(1) receptor-selective and maintained high efficacy at recombinant human but not rat brain A(1) receptors, as indicated by stimulation of binding of [(35)S]GTP-gamma-S. The (N)-methanocarba-N(6)-(3-iodobenzyl)adenosine and its 2-chloro derivative had K(i) values of 4.1 and 2.2 nM at A(3) receptors, respectively, and were highly selective partial agonists. Partial agonism combined with high functional potency at A(3) receptors (EC(50) < 1 nM) may produce tissue selectivity. In conclusion, as for P2Y(1) receptors, at least three adenosine receptors favor the ribose (N)-conformation.
|
Affinity for Adenosine A2 receptor determined by [3H]NECA binding to rat striatal membranes
|
Rattus norvegicus
|
37.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : High selectivity of novel isoguanosine analogues for the adenosine A1 receptor
Year : 1991
Volume : 1
Issue : 9
First Page : 481
Last Page : 486
Authors : Nair V, Fesbender AJ, Miller LP, Bruce JL
|
Inhibitory activity of compound at 25 uM against adenosine deaminase
|
None
|
15.0
%
|
|
Journal : J. Med. Chem.
Title : Effect of a chemical modification on the hydrated adenosine intermediate produced by adenosine deaminase and a model reaction for a potential mechanism of action of 5-aminoimidazole ribonucleotide carboxylase.
Year : 1997
Volume : 40
Issue : 21
First Page : 3336
Last Page : 3345
Authors : Groziak MP, Huan ZW, Ding H, Meng Z, Stevens WC, Robinson PD.
Abstract : Using the hydrated adenosine intermediate (6R)-6-amino-1, 6-dihydro-6-hydroxy-9-(beta-D-ribofuranosyl)purine (2) produced by adenosine deaminase (ADA, EC 3.5.4.4) as a starting point, the active site probe and inhibitor platform 5-(formylamino)imidazole riboside (FAIRs, 4) was designed by removal of the-C6(OH)(NH2)-molecular fragment of 2 generated by the early events of the enzyme-catalyzed hydrolysis. FAIRs was synthesized directly from the sodium salt of 5-amino-1-(beta-D-ribofuranosyl)imidazole-4-carboxylic acid (CAIR) along a reaction sequence involving a tandem N-formylation/decarboxylation that may have a mechanistic connection to the Escherichia coli purE-catalyzed constitutional isomerization of N5-CAIR to CAIR. The physical and spectral properties of FAIRs were elucidated, its X-ray crystal and NMR solution structures were determined, and its interaction with ADA was investigated. Crystalline FAIRs exists solely as the Z-formamide rotamer and exhibits many of the same intramolecular hydrogen bonding events known to contribute to the association of Ado to ADA. In water and various organic solvents, however, FAIRs exists as NMR-distinct, slowly interconverting Z and E rotamers. This truncated enzymatic tetrahedral intermediate analog was determined to be a competitive inhibitor of ADA with an apparent Ki binding constant of 40 microM, a value quite close to that (33 microM) of the natural substrate's K(m). The actual species selected for binding by ADA, though, is likely the minor hydroxyimino prototropic form of Z-FAIRs possessing a far lower true Ki value. As the structural features of FAIRs appear well-suited to support its use as a template for constructing active site probes of both ADA and AIR carboxylases, a variety of carbohydrate-protected versions of FAIRs suitable for facile aglycon elaborations were synthesized. The N3-alkylation, N3-borane complexation, and C4-iodination of some of these were investigated in order to assess physicochemical properties that may assist in the elucidation of mechanisms for the AIR carboxylases. The survey of these properties taken together with a reasonable mechanism for the model CAIRs-->FAIRs synthetic transformation is interpreted to support a mechanism for the purE-catalyzed N5-CAIR-->CAIR biosynthetic one that involves a carboxylative sp3-rehybridization of the imidazole C4 atom rather than one possessing a dipole-stabilized C4 sp2 carbanionic intermediate.
|
Binding affinity for Adenosine A2 receptor in corpora striata of rats using [3H]NECA
|
Rattus norvegicus
|
5.0
nM
|
|
Journal : J. Med. Chem.
Title : 4-Amino[1,2,4]triazolo[4,3-a]quinoxalines. A novel class of potent adenosine receptor antagonists and potential rapid-onset antidepressants.
Year : 1990
Volume : 33
Issue : 8
First Page : 2240
Last Page : 2254
Authors : Sarges R, Howard HR, Browne RG, Lebel LA, Seymour PA, Koe BK.
Abstract : A series of 4-amino[1,2,4]triazolo[4,3-a]quinoxalines has been prepared. Many compounds from this class reduce immobility in Porsolt's behavioral despair model in rats upon acute administration and may therefore have therapeutic potential as novel and rapid acting antidepressant agents. Optimal activity in this test is associated with hydrogen, CF3, or small alkyl groups in the 1-position, with NH2, NH-acetyl, or amines substituted with small alkyl groups in the 4-position, and with hydrogen or 8-halogen substituents in the aromatic ring. Furthermore, many of these 4-amino[1,2,4]triazolo[4,3-a]quinoxalines bind avidly, and in some cases very selectively, to adenosine A1 and A2 receptors. A1 affinity of these compounds was measured by their inhibition of tritiated CHA (N6-cyclohexyladenosine) binding in rat cerebral cortex membranes and A2 affinity by their inhibition of tritiated NECA (5'-(N-ethylcarbamoyl)adenosine) binding to rat striatal homogenate in the presence of cold N6-cyclopentyladenosine. Structure-activity relationship (SAR) studies show that best A1 affinity is associated with ethyl, CF3, or C2F5 in the 1-position, NH-iPr or NH-cycloalkyl in the 4-position, and with an 8-chloro substituent. Affinity at the A2 receptor is mostly dependent on the presence of an NH2 group in the 4-position and is enhanced by phenyl, CF3, or ethyl in the 1-position. The most selective A1 ligand by a factor of greater than 3000 is 121 (CP-68,247; 8-chloro-4-(cyclohexyl-amino)-1- (trifluoromethyl)[1,2,4]triazolo[4,3-a]quinoxaline) with an IC50 of 28 nM at the A1 receptor. The most potent A2 ligand is 128 (CP-66,713; 4-amino-8-chloro-1- phenyl[1,2,4]triazolo[4,3-a]quinoxaline) with an IC50 of 21 nM at the A2 receptor and a 13-fold selectivity for this receptor. Representatives from this series appear to act as antagonists at both A1 and A2 receptors since they antagonize the inhibiting action of CHA on norepinephrine-stimulated cAMP formation in fat cells and they decrease cAMP accumulation induced by adenosine in limbic forebrain slices. Thus certain members of this 4-amino[1,2,4]triazolo[4,3-a]quinoxaline series are among the most potent and A1 or A2 selective non-xanthine adenosine antagonists known.
|
Inhibition of binding of [3H]NECA to adenosine A2 receptor of rat striatal membranes.
|
None
|
37.0
nM
|
|
Journal : J. Med. Chem.
Title : C2,N6-disubstituted adenosines: synthesis and structure-activity relationships.
Year : 1989
Volume : 32
Issue : 8
First Page : 1667
Last Page : 1673
Authors : Trivedi BK, Bruns RF.
Abstract : Extracellular adenosine receptors have been divided into two major subtypes, called A1 and A2. Substitution of the adenosine molecule with appropriate groups at C2 or N6 is known to impart selectivity for the A2 receptor over the A1 receptor. In the present study, we investigated whether substitution at both C2 and N6 would have additive effects on the A2/A1 affinity ratio, thereby providing compounds with greater A2 selectivity than presently available agents. Disappointingly, additivity appeared to hold only when an A1-selective group was present at N6. For instance, 2-(phenylamino) substitution of the A1-selective agonist N6-cyclopentyladenosine resulted in a 70-fold shift in selectivity in favor of the A2 receptor, but the same substitution applied to the A2-selective agonist N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl]adenosine resulted in a 100-fold loss of affinity with no change in A2 selectivity.
|
Concentration required to increase Adenosine A2A receptor mediated P12 Adenylate cyclase activity
|
Rattus norvegicus
|
150.0
nM
|
|
Journal : J. Med. Chem.
Title : Activity of N6-substituted 2-chloroadenosines at A1 and A2 adenosine receptors.
Year : 1991
Volume : 34
Issue : 12
First Page : 3388
Last Page : 3390
Authors : Thompson RD, Secunda S, Daly JW, Olsson RA.
Abstract : Radioligand binding studies of N6-substituted adenosines at the A1 and A2 adenosine receptors of rat brain cortex and rat brain striatum, respectively, show that a 2-chloro substituent does not consistently change the affinity or the selectivity of these analogues for the A1 receptor. A 2-chloro substituent lowers the characteristic stereoselectivity of the A1 receptor toward the R diastereomer of N6-(1-phenyl-2-propyl)adenosine. A 2-chloro substituent consistently increases potency of N6-substituted adenosines as agonists at an adenosine A2 receptor stimulatory to adenylate cyclase in PC12 cell membranes.
|
Inhibition of cellular DNA synthesis in BSCL cells at the dose of 20 ug/mL.
|
Cercopithecidae
|
86.79
%
|
|
Journal : J. Med. Chem.
Title : Antiviral compounds. 1. Structure-activity relationship of some antiviral enediones derived from aldehydo sugars.
Year : 1983
Volume : 26
Issue : 1
First Page : 30
Last Page : 34
Authors : Breuer E, Melumad D, Sarel S, Margalith E, Katz E.
Abstract : A series of aldehydo sugars was subjected to condensation reactions with active methylene compounds. Acetylacetone was condensed with 2,4-O-benzylidene-3,5-O-dibenzoyl-D-ribose (1), 2,4:3,5-O-dibenzylidene-D-ribose (6), 2,3,4,5-tetraacetyl-D-ribose (7), and 2,3,4,5,6-pentaacetyl-D-glucose (9) to yield 3-ylidene-2,4-pentanedione derivatives 2, 11, 12, and 13, respectively. Sugar derivatives 1 and 6 were also condensed with benzoylacetone to give 14 and 18, with acetoacetanilide to give 16 and 19, with malononitrile to give 17 and 20, and with alpha-(gamma-butyrolactonylidene)triphenylphosphorane to give 21 and 22, respectively. Condensation of 1 with dibenzoylmethane gave 15. The double bond in compounds 2 and 11 was saturated by hydrogenation to give 23 and 24. All alpha, beta-unsaturated carbonyl compounds obtained exhibited antiviral activity and cytotoxicity. Compound 11 was found to have the most significant and selective antiviral activity against herpes simplex virus.
|
Compound is tested for cytotoxicity in Chinese hamster ovary cells (CHO-K1-BH4) in the absence of S-9 microsome fraction at concentration 0.17 micro M
|
Cricetulus griseus
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Effects of tubercidin and its 5'-O-methyl ether on adenosine receptors and mediator release functions in mast cells.
Year : 1995
Volume : 38
Issue : 12
First Page : 2259
Last Page : 2262
Authors : Smith CG, Lee SJ, Marquardt DL.
Abstract : Tubercidin (7-deazaadenosine, Tu) is a highly cytotoxic nucleoside xenobiotic that, as the nucleoside or nucleotide derivatives, closely mimics the actions of adenosine (or its corresponding nucleotides) in a wide variety of biochemical/biological systems. In light of its acceptance in these test systems as an adenosine (Ado) surrogate, it was postulated that the compound might interact with adenosine receptors. To test this hypothesis, a nonphosphorylatable derivative (5'-O-methyl tubercidin, MeTu) was prepared and evaluated in comparison with tubercidin and Ado in a variety of biological systems. In a cell culture assay using Chinese hamster ovary cells, MeTu is approximately one-third as cytotoxic as is Ado and 10(5)-fold less cytotoxic than Tu. Both Tu and MeTu inhibited the antigen-stimulated release of beta-hexosaminidase from mouse bone marrow derived mast cells in vitro, but only Tu was active in the in vivo PCA test. The inhibitory effect of MeTu on mast cell mediator release does not appear to involve interaction with adenosine receptors or to be the result of conversion to Tu per se.
|
Compound is tested for cytotoxicity in Chinese hamster ovary cells (CHO-K1-BH4) in the absence of S-9 microsome fraction at concentration 1.1 micro M
|
Cricetulus griseus
|
8.0
%
|
|
Journal : J. Med. Chem.
Title : Effects of tubercidin and its 5'-O-methyl ether on adenosine receptors and mediator release functions in mast cells.
Year : 1995
Volume : 38
Issue : 12
First Page : 2259
Last Page : 2262
Authors : Smith CG, Lee SJ, Marquardt DL.
Abstract : Tubercidin (7-deazaadenosine, Tu) is a highly cytotoxic nucleoside xenobiotic that, as the nucleoside or nucleotide derivatives, closely mimics the actions of adenosine (or its corresponding nucleotides) in a wide variety of biochemical/biological systems. In light of its acceptance in these test systems as an adenosine (Ado) surrogate, it was postulated that the compound might interact with adenosine receptors. To test this hypothesis, a nonphosphorylatable derivative (5'-O-methyl tubercidin, MeTu) was prepared and evaluated in comparison with tubercidin and Ado in a variety of biological systems. In a cell culture assay using Chinese hamster ovary cells, MeTu is approximately one-third as cytotoxic as is Ado and 10(5)-fold less cytotoxic than Tu. Both Tu and MeTu inhibited the antigen-stimulated release of beta-hexosaminidase from mouse bone marrow derived mast cells in vitro, but only Tu was active in the in vivo PCA test. The inhibitory effect of MeTu on mast cell mediator release does not appear to involve interaction with adenosine receptors or to be the result of conversion to Tu per se.
|
Compound is tested for cytotoxicity in Chinese hamster ovary cells (CHO-K1-BH4) in the absence of S-9 microsome fraction at concentration 11 micro M
|
Cricetulus griseus
|
19.0
%
|
|
Journal : J. Med. Chem.
Title : Effects of tubercidin and its 5'-O-methyl ether on adenosine receptors and mediator release functions in mast cells.
Year : 1995
Volume : 38
Issue : 12
First Page : 2259
Last Page : 2262
Authors : Smith CG, Lee SJ, Marquardt DL.
Abstract : Tubercidin (7-deazaadenosine, Tu) is a highly cytotoxic nucleoside xenobiotic that, as the nucleoside or nucleotide derivatives, closely mimics the actions of adenosine (or its corresponding nucleotides) in a wide variety of biochemical/biological systems. In light of its acceptance in these test systems as an adenosine (Ado) surrogate, it was postulated that the compound might interact with adenosine receptors. To test this hypothesis, a nonphosphorylatable derivative (5'-O-methyl tubercidin, MeTu) was prepared and evaluated in comparison with tubercidin and Ado in a variety of biological systems. In a cell culture assay using Chinese hamster ovary cells, MeTu is approximately one-third as cytotoxic as is Ado and 10(5)-fold less cytotoxic than Tu. Both Tu and MeTu inhibited the antigen-stimulated release of beta-hexosaminidase from mouse bone marrow derived mast cells in vitro, but only Tu was active in the in vivo PCA test. The inhibitory effect of MeTu on mast cell mediator release does not appear to involve interaction with adenosine receptors or to be the result of conversion to Tu per se.
|
Compound is tested for cytotoxicity in Chinese hamster ovary cells (CHO-K1-BH4) in the absence of S-9 microsome fraction at concentration 1136 micro M
|
Cricetulus griseus
|
43.0
%
|
|
Journal : J. Med. Chem.
Title : Effects of tubercidin and its 5'-O-methyl ether on adenosine receptors and mediator release functions in mast cells.
Year : 1995
Volume : 38
Issue : 12
First Page : 2259
Last Page : 2262
Authors : Smith CG, Lee SJ, Marquardt DL.
Abstract : Tubercidin (7-deazaadenosine, Tu) is a highly cytotoxic nucleoside xenobiotic that, as the nucleoside or nucleotide derivatives, closely mimics the actions of adenosine (or its corresponding nucleotides) in a wide variety of biochemical/biological systems. In light of its acceptance in these test systems as an adenosine (Ado) surrogate, it was postulated that the compound might interact with adenosine receptors. To test this hypothesis, a nonphosphorylatable derivative (5'-O-methyl tubercidin, MeTu) was prepared and evaluated in comparison with tubercidin and Ado in a variety of biological systems. In a cell culture assay using Chinese hamster ovary cells, MeTu is approximately one-third as cytotoxic as is Ado and 10(5)-fold less cytotoxic than Tu. Both Tu and MeTu inhibited the antigen-stimulated release of beta-hexosaminidase from mouse bone marrow derived mast cells in vitro, but only Tu was active in the in vivo PCA test. The inhibitory effect of MeTu on mast cell mediator release does not appear to involve interaction with adenosine receptors or to be the result of conversion to Tu per se.
|
Compound is tested for cytotoxicity in Chinese hamster ovary cells (CHO-K1-BH4) in the absence of S-9 microsome fraction at concentration 114 micro M
|
Cricetulus griseus
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Effects of tubercidin and its 5'-O-methyl ether on adenosine receptors and mediator release functions in mast cells.
Year : 1995
Volume : 38
Issue : 12
First Page : 2259
Last Page : 2262
Authors : Smith CG, Lee SJ, Marquardt DL.
Abstract : Tubercidin (7-deazaadenosine, Tu) is a highly cytotoxic nucleoside xenobiotic that, as the nucleoside or nucleotide derivatives, closely mimics the actions of adenosine (or its corresponding nucleotides) in a wide variety of biochemical/biological systems. In light of its acceptance in these test systems as an adenosine (Ado) surrogate, it was postulated that the compound might interact with adenosine receptors. To test this hypothesis, a nonphosphorylatable derivative (5'-O-methyl tubercidin, MeTu) was prepared and evaluated in comparison with tubercidin and Ado in a variety of biological systems. In a cell culture assay using Chinese hamster ovary cells, MeTu is approximately one-third as cytotoxic as is Ado and 10(5)-fold less cytotoxic than Tu. Both Tu and MeTu inhibited the antigen-stimulated release of beta-hexosaminidase from mouse bone marrow derived mast cells in vitro, but only Tu was active in the in vivo PCA test. The inhibitory effect of MeTu on mast cell mediator release does not appear to involve interaction with adenosine receptors or to be the result of conversion to Tu per se.
|
Compound is tested for cytotoxicity in Chinese hamster ovary cells (CHO-K1-BH4) in the presence of S-9 microsome fraction at concentration 0.17 micro M
|
Cricetulus griseus
|
0.04
%
|
|
Journal : J. Med. Chem.
Title : Effects of tubercidin and its 5'-O-methyl ether on adenosine receptors and mediator release functions in mast cells.
Year : 1995
Volume : 38
Issue : 12
First Page : 2259
Last Page : 2262
Authors : Smith CG, Lee SJ, Marquardt DL.
Abstract : Tubercidin (7-deazaadenosine, Tu) is a highly cytotoxic nucleoside xenobiotic that, as the nucleoside or nucleotide derivatives, closely mimics the actions of adenosine (or its corresponding nucleotides) in a wide variety of biochemical/biological systems. In light of its acceptance in these test systems as an adenosine (Ado) surrogate, it was postulated that the compound might interact with adenosine receptors. To test this hypothesis, a nonphosphorylatable derivative (5'-O-methyl tubercidin, MeTu) was prepared and evaluated in comparison with tubercidin and Ado in a variety of biological systems. In a cell culture assay using Chinese hamster ovary cells, MeTu is approximately one-third as cytotoxic as is Ado and 10(5)-fold less cytotoxic than Tu. Both Tu and MeTu inhibited the antigen-stimulated release of beta-hexosaminidase from mouse bone marrow derived mast cells in vitro, but only Tu was active in the in vivo PCA test. The inhibitory effect of MeTu on mast cell mediator release does not appear to involve interaction with adenosine receptors or to be the result of conversion to Tu per se.
|
Compound is tested for cytotoxicity in Chinese hamster ovary cells (CHO-K1-BH4) in the presence of S-9 microsome fraction at concentration 1.1 micro M
|
Cricetulus griseus
|
22.0
%
|
|
Journal : J. Med. Chem.
Title : Effects of tubercidin and its 5'-O-methyl ether on adenosine receptors and mediator release functions in mast cells.
Year : 1995
Volume : 38
Issue : 12
First Page : 2259
Last Page : 2262
Authors : Smith CG, Lee SJ, Marquardt DL.
Abstract : Tubercidin (7-deazaadenosine, Tu) is a highly cytotoxic nucleoside xenobiotic that, as the nucleoside or nucleotide derivatives, closely mimics the actions of adenosine (or its corresponding nucleotides) in a wide variety of biochemical/biological systems. In light of its acceptance in these test systems as an adenosine (Ado) surrogate, it was postulated that the compound might interact with adenosine receptors. To test this hypothesis, a nonphosphorylatable derivative (5'-O-methyl tubercidin, MeTu) was prepared and evaluated in comparison with tubercidin and Ado in a variety of biological systems. In a cell culture assay using Chinese hamster ovary cells, MeTu is approximately one-third as cytotoxic as is Ado and 10(5)-fold less cytotoxic than Tu. Both Tu and MeTu inhibited the antigen-stimulated release of beta-hexosaminidase from mouse bone marrow derived mast cells in vitro, but only Tu was active in the in vivo PCA test. The inhibitory effect of MeTu on mast cell mediator release does not appear to involve interaction with adenosine receptors or to be the result of conversion to Tu per se.
|
Compound is tested for cytotoxicity in Chinese hamster ovary cells (CHO-K1-BH4) in the presence of S-9 microsome fraction at concentration 11 micro M
|
Cricetulus griseus
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Effects of tubercidin and its 5'-O-methyl ether on adenosine receptors and mediator release functions in mast cells.
Year : 1995
Volume : 38
Issue : 12
First Page : 2259
Last Page : 2262
Authors : Smith CG, Lee SJ, Marquardt DL.
Abstract : Tubercidin (7-deazaadenosine, Tu) is a highly cytotoxic nucleoside xenobiotic that, as the nucleoside or nucleotide derivatives, closely mimics the actions of adenosine (or its corresponding nucleotides) in a wide variety of biochemical/biological systems. In light of its acceptance in these test systems as an adenosine (Ado) surrogate, it was postulated that the compound might interact with adenosine receptors. To test this hypothesis, a nonphosphorylatable derivative (5'-O-methyl tubercidin, MeTu) was prepared and evaluated in comparison with tubercidin and Ado in a variety of biological systems. In a cell culture assay using Chinese hamster ovary cells, MeTu is approximately one-third as cytotoxic as is Ado and 10(5)-fold less cytotoxic than Tu. Both Tu and MeTu inhibited the antigen-stimulated release of beta-hexosaminidase from mouse bone marrow derived mast cells in vitro, but only Tu was active in the in vivo PCA test. The inhibitory effect of MeTu on mast cell mediator release does not appear to involve interaction with adenosine receptors or to be the result of conversion to Tu per se.
|
Compound is tested for cytotoxicity in Chinese hamster ovary cells (CHO-K1-BH4) in the presence of S-9 microsome fraction at concentration 1136 micro M
|
Cricetulus griseus
|
7.0
%
|
|
Journal : J. Med. Chem.
Title : Effects of tubercidin and its 5'-O-methyl ether on adenosine receptors and mediator release functions in mast cells.
Year : 1995
Volume : 38
Issue : 12
First Page : 2259
Last Page : 2262
Authors : Smith CG, Lee SJ, Marquardt DL.
Abstract : Tubercidin (7-deazaadenosine, Tu) is a highly cytotoxic nucleoside xenobiotic that, as the nucleoside or nucleotide derivatives, closely mimics the actions of adenosine (or its corresponding nucleotides) in a wide variety of biochemical/biological systems. In light of its acceptance in these test systems as an adenosine (Ado) surrogate, it was postulated that the compound might interact with adenosine receptors. To test this hypothesis, a nonphosphorylatable derivative (5'-O-methyl tubercidin, MeTu) was prepared and evaluated in comparison with tubercidin and Ado in a variety of biological systems. In a cell culture assay using Chinese hamster ovary cells, MeTu is approximately one-third as cytotoxic as is Ado and 10(5)-fold less cytotoxic than Tu. Both Tu and MeTu inhibited the antigen-stimulated release of beta-hexosaminidase from mouse bone marrow derived mast cells in vitro, but only Tu was active in the in vivo PCA test. The inhibitory effect of MeTu on mast cell mediator release does not appear to involve interaction with adenosine receptors or to be the result of conversion to Tu per se.
|
Compound is tested for cytotoxicity in Chinese hamster ovary cells (CHO-K1-BH4) in the presence of S-9 microsome fraction at concentration 114 micro M
|
Cricetulus griseus
|
36.0
%
|
|
Journal : J. Med. Chem.
Title : Effects of tubercidin and its 5'-O-methyl ether on adenosine receptors and mediator release functions in mast cells.
Year : 1995
Volume : 38
Issue : 12
First Page : 2259
Last Page : 2262
Authors : Smith CG, Lee SJ, Marquardt DL.
Abstract : Tubercidin (7-deazaadenosine, Tu) is a highly cytotoxic nucleoside xenobiotic that, as the nucleoside or nucleotide derivatives, closely mimics the actions of adenosine (or its corresponding nucleotides) in a wide variety of biochemical/biological systems. In light of its acceptance in these test systems as an adenosine (Ado) surrogate, it was postulated that the compound might interact with adenosine receptors. To test this hypothesis, a nonphosphorylatable derivative (5'-O-methyl tubercidin, MeTu) was prepared and evaluated in comparison with tubercidin and Ado in a variety of biological systems. In a cell culture assay using Chinese hamster ovary cells, MeTu is approximately one-third as cytotoxic as is Ado and 10(5)-fold less cytotoxic than Tu. Both Tu and MeTu inhibited the antigen-stimulated release of beta-hexosaminidase from mouse bone marrow derived mast cells in vitro, but only Tu was active in the in vivo PCA test. The inhibitory effect of MeTu on mast cell mediator release does not appear to involve interaction with adenosine receptors or to be the result of conversion to Tu per se.
|
Coronary vasoactivity in dogs
|
Canis lupus familiaris
|
0.12
nM
|
|
Journal : J. Med. Chem.
Title : N6-substituted N-alkyladenosine-5'-uronamides: bifunctional ligands having recognition groups for A1 and A2 adenosine receptors.
Year : 1986
Volume : 29
Issue : 9
First Page : 1683
Last Page : 1689
Authors : Olsson RA, Kusachi S, Thompson RD, Ukena D, Padgett W, Daly JW.
Abstract : The coronary vasoactivity of N-ethyl-1'-deoxy-1'-(6-amino-9H-purin-9-yl)-beta-D-ribofuranuronamide (NECA, 1) is over 2 orders of magnitude greater than that of adenosine, and the vasoactivity of certain N6-substituted adenosines is as much as 1 order of magnitude greater. Such results suggest that a combination of appropriate modifications at N6 and C-5' might additively augment the agonist potency of adenosine. At low temperatures 1-deoxy-1-(6-chloro-9H-purin-9-yl)-2',3'-O-isopropylidene- beta-D-ribofuranosyl chloride (5), obtained in three steps from inosine, reacts with amines to yield uronamides. The subsequent reaction of such uronamides with amines at elevated temperatures displaces the purine 6-chloro group to yield, after deblocking, N-alkyl(or aryl)-N6-alk(ar)yl-adenosine-5'-uronamides. At the coronary artery A2 receptor the potency of N6-modified analogues of 1 is similar to that of the N6-substituted adenosine, rather than equal to or greater than 1. As agonists in the A2 receptor-mediated stimulation of adenylate cyclase in plasma membranes of PC12 pheochromocytoma cells or human platelets, N6-substituted analogues of 1 are intermediate between the high potency of 1 and the lower potency of the N6-substituted adenosines. At the A1 receptor of rat brain the potency of an N6-substituted analogue of 1 is often greater than that of the corresponding N6-substituted adenosine. At all four receptors, replacing the ethyl group of N-ethyl-N6-3-pentyladenosine-5'-uronamide by larger alkyl groups reduces potency; amides of secondary amines are inactive or have only marginal activity. Analogues of 1 containing a chiral center in the N6 substituent retain the stereoselectivity characteristic of each of the four receptors. Thus, at either A1 or A2 adenosine receptors, adenosine analogues interact with both the N6 and the C-5' receptor regions. However, the effects of N6 and C-5' modifications on potency are less than additive, evidence that the interaction of a substituent with its receptor region influences the interaction of other substituents with their respective receptor regions.
|
Compound was evaluated for cytotoxicity against H.Ep.-2 cells, and concentration required to inhibit the growth of treated cells to 50% of untreated control.
|
Homo sapiens
|
700.0
nM
|
|
Journal : J. Med. Chem.
Title : (+/-)-3-(4-Amino-1H-pyrrolo[2,3-d]pyrimidin-1-yl)-5-(hydroxymethyl)- (1 alpha,2 alpha,3 beta,5 beta)-1,2-cyclopentanediol, the carbocyclic analogue of tubercidin.
Year : 1984
Volume : 27
Issue : 4
First Page : 534
Last Page : 536
Authors : Secrist JA, Clayton SJ, Montgomery JA.
Abstract : (+/-)-3-(4-Amino-1H-pyrrolo[2,3-d]pyrimidin-1-yl)-5-(hydroxymethyl)- 1 alpha,2 alpha,3 beta,5 beta)-1,2-cyclopentanediol (9), the carbocyclic analogue of tubercidin, prepared from (+/-)-3-amino-5-(hydroxymethyl)-(1 alpha,2 alpha,3 beta,5 beta)- 1,2-cyclopentanediol (6), is cytotoxic to cells containing adenosine kinase but not to cells that do not, indicating that its activity depends on phosphorylation. Although inactive against P388 leukemia in mice and against herpes and influenza viruses in vitro, it showed marginal activity against respiratory syncytial, vesicular stomatitis, and rhino viruses in vitro.
|
Growth inhibition against HSV-1 virus in BSCL cells at the dose of 20 ug/mL and 22h time of treatment.
|
Human herpesvirus 1
|
96.5
%
|
|
Journal : J. Med. Chem.
Title : Antiviral compounds. 1. Structure-activity relationship of some antiviral enediones derived from aldehydo sugars.
Year : 1983
Volume : 26
Issue : 1
First Page : 30
Last Page : 34
Authors : Breuer E, Melumad D, Sarel S, Margalith E, Katz E.
Abstract : A series of aldehydo sugars was subjected to condensation reactions with active methylene compounds. Acetylacetone was condensed with 2,4-O-benzylidene-3,5-O-dibenzoyl-D-ribose (1), 2,4:3,5-O-dibenzylidene-D-ribose (6), 2,3,4,5-tetraacetyl-D-ribose (7), and 2,3,4,5,6-pentaacetyl-D-glucose (9) to yield 3-ylidene-2,4-pentanedione derivatives 2, 11, 12, and 13, respectively. Sugar derivatives 1 and 6 were also condensed with benzoylacetone to give 14 and 18, with acetoacetanilide to give 16 and 19, with malononitrile to give 17 and 20, and with alpha-(gamma-butyrolactonylidene)triphenylphosphorane to give 21 and 22, respectively. Condensation of 1 with dibenzoylmethane gave 15. The double bond in compounds 2 and 11 was saturated by hydrogenation to give 23 and 24. All alpha, beta-unsaturated carbonyl compounds obtained exhibited antiviral activity and cytotoxicity. Compound 11 was found to have the most significant and selective antiviral activity against herpes simplex virus.
|
Inhibition of viral DNA synthesis in HSV-1 virus at the dose of 20 ug/mL.
|
Human herpesvirus 1
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : Antiviral compounds. 1. Structure-activity relationship of some antiviral enediones derived from aldehydo sugars.
Year : 1983
Volume : 26
Issue : 1
First Page : 30
Last Page : 34
Authors : Breuer E, Melumad D, Sarel S, Margalith E, Katz E.
Abstract : A series of aldehydo sugars was subjected to condensation reactions with active methylene compounds. Acetylacetone was condensed with 2,4-O-benzylidene-3,5-O-dibenzoyl-D-ribose (1), 2,4:3,5-O-dibenzylidene-D-ribose (6), 2,3,4,5-tetraacetyl-D-ribose (7), and 2,3,4,5,6-pentaacetyl-D-glucose (9) to yield 3-ylidene-2,4-pentanedione derivatives 2, 11, 12, and 13, respectively. Sugar derivatives 1 and 6 were also condensed with benzoylacetone to give 14 and 18, with acetoacetanilide to give 16 and 19, with malononitrile to give 17 and 20, and with alpha-(gamma-butyrolactonylidene)triphenylphosphorane to give 21 and 22, respectively. Condensation of 1 with dibenzoylmethane gave 15. The double bond in compounds 2 and 11 was saturated by hydrogenation to give 23 and 24. All alpha, beta-unsaturated carbonyl compounds obtained exhibited antiviral activity and cytotoxicity. Compound 11 was found to have the most significant and selective antiviral activity against herpes simplex virus.
|
Inhibition of ADP-induced platelet aggregation at 100 ug/mL
|
Oryctolagus cuniculus
|
64.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and enzymic activity of 6-carbethoxy- and 6-ethoxy-3,7-disubstituted-pyrazolo[1,5-a]pyrimidines and related derivatives as adenosine cyclic 3' ,5'-phosphate phosphodiesterase inhibitors.
Year : 1982
Volume : 25
Issue : 3
First Page : 235
Last Page : 242
Authors : Springer RH, Scholten MB, O'Brien DE, Novinson T, Miller JP, Robins RK.
Abstract : A number of 3,7-disubstituted 6-carbethoxypyrazolo [1,5-a] pyrimidines and 3,7-disubstituted 6-ethoxypyrazolo-[1,5-a]pyrimidines have been prepared and evaluated as adenosine cyclic 3',5'-phosphate (cAMP) phosphodiesterase (PDE) inhibitors vs. the low Km enzyme isolated from beef heart, rabbit lung, and kidney preparations. The results were found to be between 0.5 to 13 times as potent as theophylline as inhibitors of PDE, depending on the tissue source. A number of these PDE inhibitors exhibited significant physiological effects in different animal systems, suggesting it should be possible to obtain selective PDE inhibition in various tissues. Several of these heterocycles were found superior to adenosine in inhibiting ADP-induced platelet aggregation in vitro.
|
Inhibition of rabbit liver adenosine kinase
|
Oryctolagus cuniculus
|
930.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Biochemical and biological properties of 5-bromotubercidin: differential effects on cellular DNA-directed and viral RNA-directed RNA synthesis.
Year : 2008
Volume : 16
Issue : 3
First Page : 1481
Last Page : 1492
Authors : Brdar B, Reich E.
Abstract : We have studied the biochemical and biological properties of 5-bromotubercidin (4-amino-5-bromo-7-beta-d-ribofuranosyl-pyrrolo [2,3-d]pyrimidine) (BrTu), a synthetic analogue of the highly cytotoxic pyrrolo[2,3-d]pyrimidine ribonucleoside antibiotic tubercidin (Tu) that interferes with numerous cellular processes, and has been shown to possess biological specificity and selectivity. Thus, BrTu entered the mammalian cell nucleotide pool by phosphorylation, was incorporated into RNA in an unmodified form and, as a consequence, reversibly inhibited (15 microM) mammalian cell growth and the synthesis of high-molecular-weight cellular RNA species (i.e., mRNA and rRNA). However, BrTu (300 microM) did not inhibit picornavirus RNA synthesis or multiplication, and thus discriminated between virus RNA-dependent and all forms of DNA-dependent RNA synthesis whether of cellular or viral origin; because of this BrTu should prove valuable as a metabolic probe for studying the cell-virus relationship. Furthermore, BrTu is a substrate for adenosine kinase (K(m)=24 microM), and is also its potent inhibitor (K(i)=0.93 microM); thus, low concentrations of BrTu (1.5 microM), which did not inhibit cell growth, blocked phosphorylation and the cellular uptake of other, highly cytotoxic pyrrolo-pyrimidine nucleoside analogues (e.g., tubercidin). This block in cellular uptake and incorporation of toxic analogues was associated with the protective effect of BrTu against cell killing by the analogues, providing a mechanism by which BrTu and these analogues can, as we reported elsewhere [J. Virol.1999, 73, 6444], be used for the selective inactivation of replicating picornaviruses.
|
Inhibition of electrically-stimulated contraction in guinea pig ileum at 15 ug/ml
|
Cavia porcellus
|
85.0
%
|
|
Journal : J. Nat. Prod.
Title : Studies of Swedish Marine Organisms, Part X. Biologically Active Compounds from the Marine Sponge Geodia baretti
Year : 1988
Volume : 51
Issue : 6
First Page : 1277
Last Page : 1280
Authors : Lidgren G, Bohlin L, Christophersen C
|
Antiestrogenic activity in human MCF7 cells assessed as inhibition of E2-enhanced cell proliferation at 0.1 to 100 uM after 96 hrs by alamar blue assay
|
Homo sapiens
|
90.0
%
|
|
Journal : J. Nat. Prod.
Title : Antiestrogenic constituents of the Thai medicinal plants Capparis flavicans and Vitex glabrata.
Year : 2009
Volume : 72
Issue : 11
First Page : 1954
Last Page : 1959
Authors : Luecha P, Umehara K, Miyase T, Noguchi H.
Abstract : Antiestrogenic compounds were investigated from Thai indigenous plants for galactogogues since estrogen is reported to suppress lactation in breastfeeding women. The aerial parts of the Thai medicinal plant Capparis flavicans, which has traditionally been used to promote lactation, gave the new compound capparoside A (1), along with 28 known compounds. The leaves of Vitex glabrata belong to the same genus as the chaste tree (Vitex agnus-castus), which is used traditionally to support lactation, and afforded the new compounds khainaoside A (14), khainaoside B (15), and khainaoside C (16), together with six known compounds. The isolates were tested for their biological activity using the estrogen-responsive human breast cancer cell lines MCF-7 and T47D. Syringaresinol (3) and principin (6), from C. flavicans, and khainaoside A (14) showed the most potent inhibitory effects on estrogen-enhanced cell proliferation among all compounds isolated. These results suggest that the lactation-promoting properties of C. flavicans might be related to the inhibitory effect on excess estrogen of women who experience insufficient breastfeeding and highlight the possibility of using V. glabrata leaves for their antiestrogenic properties.
|
Agonist activity at human adenosine A3 receptor expressed in CHO cells assessed as increase of intracellular calcium level
|
Homo sapiens
|
290.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 4-Substituted-7-N-alkyl-N-acetyl 2-aminobenzothiazole amides: drug-like and non-xanthine based A2B adenosine receptor antagonists.
Year : 2010
Volume : 20
Issue : 14
First Page : 4140
Last Page : 4146
Authors : Cheung AW, Brinkman J, Firooznia F, Flohr A, Grimsby J, Gubler ML, Guertin K, Hamid R, Marcopulos N, Norcross RD, Qi L, Ramsey G, Tan J, Wen Y, Sarabu R.
Abstract : 7-N-Acetamide-4-methoxy-2-aminobenzothiazole 4-fluorobenzamide (compound 1) was chosen as a drug-like and non-xanthine based starting point for the discovery of A(2B) receptor antagonists because of its slight selectivity against A(1) and A(2A) receptors and modest A(2B) potency. SAR exploration of compound 1 described herein included modifications to the 7-N-acetamide group, substitution of the 4-methoxy group by halogens as well as replacement of the p-flouro-benzamide side chain. This work culminated in the identification of compound 37 with excellent A(2B) potency, modest selectivity versus A(2A) and A(1) receptors, and good rodent PK properties.
|
Agonist activity at human adenosine A1 receptor expressed in CHO cells assessed as increase of intracellular calcium level
|
Homo sapiens
|
310.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 4-Substituted-7-N-alkyl-N-acetyl 2-aminobenzothiazole amides: drug-like and non-xanthine based A2B adenosine receptor antagonists.
Year : 2010
Volume : 20
Issue : 14
First Page : 4140
Last Page : 4146
Authors : Cheung AW, Brinkman J, Firooznia F, Flohr A, Grimsby J, Gubler ML, Guertin K, Hamid R, Marcopulos N, Norcross RD, Qi L, Ramsey G, Tan J, Wen Y, Sarabu R.
Abstract : 7-N-Acetamide-4-methoxy-2-aminobenzothiazole 4-fluorobenzamide (compound 1) was chosen as a drug-like and non-xanthine based starting point for the discovery of A(2B) receptor antagonists because of its slight selectivity against A(1) and A(2A) receptors and modest A(2B) potency. SAR exploration of compound 1 described herein included modifications to the 7-N-acetamide group, substitution of the 4-methoxy group by halogens as well as replacement of the p-flouro-benzamide side chain. This work culminated in the identification of compound 37 with excellent A(2B) potency, modest selectivity versus A(2A) and A(1) receptors, and good rodent PK properties.
|
Agonist activity at human adenosine A2A receptor expressed in CHO cells assessed as increase of intracellular calcium level
|
Homo sapiens
|
700.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 4-Substituted-7-N-alkyl-N-acetyl 2-aminobenzothiazole amides: drug-like and non-xanthine based A2B adenosine receptor antagonists.
Year : 2010
Volume : 20
Issue : 14
First Page : 4140
Last Page : 4146
Authors : Cheung AW, Brinkman J, Firooznia F, Flohr A, Grimsby J, Gubler ML, Guertin K, Hamid R, Marcopulos N, Norcross RD, Qi L, Ramsey G, Tan J, Wen Y, Sarabu R.
Abstract : 7-N-Acetamide-4-methoxy-2-aminobenzothiazole 4-fluorobenzamide (compound 1) was chosen as a drug-like and non-xanthine based starting point for the discovery of A(2B) receptor antagonists because of its slight selectivity against A(1) and A(2A) receptors and modest A(2B) potency. SAR exploration of compound 1 described herein included modifications to the 7-N-acetamide group, substitution of the 4-methoxy group by halogens as well as replacement of the p-flouro-benzamide side chain. This work culminated in the identification of compound 37 with excellent A(2B) potency, modest selectivity versus A(2A) and A(1) receptors, and good rodent PK properties.
|
PUBCHEM_BIOASSAY: Luminescence Cell-Based Dose Confirmation HTS to Identify Inhibitors of Platelet Dense Granule Release. (Class of assay: confirmatory) [Related pubchem assays: 1663 (Primary HTS), 1678 (Summary of Project)]
|
None
|
759.0
nM
|
|
Title : PubChem BioAssay data set
|
Agonist activity at human adenosine A3 receptor expressed in CHO cells
|
Homo sapiens
|
290.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of benzothiazole-based adenosine A2B receptor antagonists with improved A2A selectivity.
Year : 2011
Volume : 21
Issue : 7
First Page : 1933
Last Page : 1936
Authors : Firooznia F, Cheung AW, Brinkman J, Grimsby J, Gubler ML, Hamid R, Marcopulos N, Ramsey G, Tan J, Wen Y, Sarabu R.
Abstract : The highly potent but modestly selective N-(2-amino-4-methoxy-benzothiazol-7-yl)-N-ethyl-acetamide derivative 2 was selected as the starting point for the design of novel selective A(2B) antagonists, due to its excellent potency, and good drug-like properties. A series of compounds containing nonaromatic amides or ureas of five- or six-membered rings, and also bearing an m-trifluoromethyl-phenyl group (shown to impart superior potency) was prepared and evaluated for their selectivity against the A(2A) and A(1) receptors. This work resulted in the identification of compound 30, with excellent potency and high selectivity against both A(2A) and A(1) receptors.
|
Agonist activity at human adenosine A1 receptor expressed in CHO cells
|
Homo sapiens
|
310.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of benzothiazole-based adenosine A2B receptor antagonists with improved A2A selectivity.
Year : 2011
Volume : 21
Issue : 7
First Page : 1933
Last Page : 1936
Authors : Firooznia F, Cheung AW, Brinkman J, Grimsby J, Gubler ML, Hamid R, Marcopulos N, Ramsey G, Tan J, Wen Y, Sarabu R.
Abstract : The highly potent but modestly selective N-(2-amino-4-methoxy-benzothiazol-7-yl)-N-ethyl-acetamide derivative 2 was selected as the starting point for the design of novel selective A(2B) antagonists, due to its excellent potency, and good drug-like properties. A series of compounds containing nonaromatic amides or ureas of five- or six-membered rings, and also bearing an m-trifluoromethyl-phenyl group (shown to impart superior potency) was prepared and evaluated for their selectivity against the A(2A) and A(1) receptors. This work resulted in the identification of compound 30, with excellent potency and high selectivity against both A(2A) and A(1) receptors.
|
Agonist activity at human adenosine A2A receptor expressed in CHO cells
|
Homo sapiens
|
700.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of benzothiazole-based adenosine A2B receptor antagonists with improved A2A selectivity.
Year : 2011
Volume : 21
Issue : 7
First Page : 1933
Last Page : 1936
Authors : Firooznia F, Cheung AW, Brinkman J, Grimsby J, Gubler ML, Hamid R, Marcopulos N, Ramsey G, Tan J, Wen Y, Sarabu R.
Abstract : The highly potent but modestly selective N-(2-amino-4-methoxy-benzothiazol-7-yl)-N-ethyl-acetamide derivative 2 was selected as the starting point for the design of novel selective A(2B) antagonists, due to its excellent potency, and good drug-like properties. A series of compounds containing nonaromatic amides or ureas of five- or six-membered rings, and also bearing an m-trifluoromethyl-phenyl group (shown to impart superior potency) was prepared and evaluated for their selectivity against the A(2A) and A(1) receptors. This work resulted in the identification of compound 30, with excellent potency and high selectivity against both A(2A) and A(1) receptors.
|
PUBCHEM_BIOASSAY: Dose responses of compounds that inhibit the Choline Transporter (CHT) - 5 point CRC. (Class of assay: confirmatory) [Related pubchem assays (depositor defined):AID488975, AID488997, AID493221, AID493222]
|
None
|
570.65
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Dose responses of compounds that inhibit the Choline Transporter (CHT) - 10 point CRC. (Class of assay: confirmatory)
|
None
|
199.53
nM
|
|
Title : PubChem BioAssay data set
|
Binding affinity to A2A adenosine receptor
|
None
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : Evaluation of molecular modeling of agonist binding in light of the crystallographic structure of an agonist-bound A₂A adenosine receptor.
Year : 2012
Volume : 55
Issue : 1
First Page : 538
Last Page : 552
Authors : Deflorian F, Kumar TS, Phan K, Gao ZG, Xu F, Wu H, Katritch V, Stevens RC, Jacobson KA.
Abstract : Molecular modeling of agonist binding to the human A(2A) adenosine receptor (AR) was assessed and extended in light of crystallographic structures. Heterocyclic adenine nitrogens of cocrystallized agonist overlaid corresponding positions of the heterocyclic base of a bound triazolotriazine antagonist, and ribose moiety was coordinated in a hydrophilic region, as previously predicted based on modeling using the inactive receptor. Automatic agonist docking of 20 known potent nucleoside agonists to agonist-bound A(2A)AR crystallographic structures predicted new stabilizing protein interactions to provide a structural basis for previous empirical structure activity relationships consistent with previous mutagenesis results. We predicted binding of novel C2 terminal amino acid conjugates of A(2A)AR agonist CGS21680 and used these models to interpret effects on binding affinity of newly synthesized agonists. d-Amino acid conjugates were generally more potent than l-stereoisomers and free terminal carboxylates more potent than corresponding methyl esters. Amino acid moieties were coordinated close to extracellular loops 2 and 3. Thus, molecular modeling is useful in probing ligand recognition and rational design of GPCR-targeting compounds with specific pharmacological profiles.
|
Agonist activity at human A1AR expressed in HEK293T/17 cells assessed as inhibition of isoproterenol-induced cAMP accumulation incubated for 10 mins by luciferase reporter assay
|
Homo sapiens
|
39.0
nM
|
|
Journal : J. Med. Chem.
Title : Orally active adenosine A(1) receptor agonists with antinociceptive effects in mice.
Year : 2012
Volume : 55
Issue : 14
First Page : 6467
Last Page : 6477
Authors : Korboukh I, Hull-Ryde EA, Rittiner JE, Randhawa AS, Coleman J, Fitzpatrick BJ, Setola V, Janzen WP, Frye SV, Zylka MJ, Jin J.
Abstract : Adenosine A(1) receptor (A(1)AR) agonists have antinociceptive effects in multiple preclinical models of acute and chronic pain. Although numerous A(1)AR agonists have been developed, clinical applications of these agents have been hampered by their cardiovascular side effects. Herein we report a series of novel A(1)AR agonists, some of which are structurally related to adenosine 5'-monophosphate (5'-AMP), a naturally occurring nucleotide that itself activates A(1)AR. These novel compounds potently activate A(1)AR in several orthogonal in vitro assays and are subtype selective for A(1)AR over A(2A)AR, A(2B)AR, and A(3)AR. Among them, UNC32A (3a) is orally active and has dose-dependent antinociceptive effects in wild-type mice. The antinociceptive effects of 3a were completely abolished in A(1)AR knockout mice, revealing a strict dependence on A(1)AR for activity. The apparent lack of cardiovascular side effects when administered orally and high affinity (K(i) of 36 nM for the human A(1)AR) make this compound potentially suitable as a therapeutic.
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
180.3
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of sodium fluorescein uptake in OATP1B3-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
96.48
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Antiinflammatory activity in rat polymorphonuclear leukocytes assessed as inhibition of PAF-induced release of glucuronidase at 10 uM
|
Rattus norvegicus
|
30.0
%
|
|
Journal : J. Nat. Prod.
Title : Homosecoiridoid alkaloids with amino acid units from the flower buds of Lonicera japonica.
Year : 2013
Volume : 76
Issue : 12
First Page : 2226
Last Page : 2233
Authors : Yu Y, Zhu C, Wang S, Song W, Yang Y, Shi J.
Abstract : Nine new homosecoiridoid alkaloids, named lonijaposides O-W (1-9), along with 19 known compounds, were isolated from an aqueous extract of the flower buds of Lonicera japonica. Their structures and absolute configurations were determined by spectroscopic data analysis and chemical methods. Lonijaposides O-W have structural features that involve amino acid units sharing the N atom with a pyridinium (1-5) or nicotinic acid (6-9) moiety. The absolute configurations of the amino acid units were determined by oxidation of each pyridinium ring moiety with potassium ferricyanide, hydrolysis of the oxidation product, and Marfey's analysis of the hydrolysate. This procedure was validated by oxidizing and hydrolyzing synthetic model compounds. The phenylalanine units in compounds 4, 5, and 9 have the d-configuration, and the other amino acid units in 1-3 and 6-8 possess the l-configuration. Compounds 1, 4, 6, and 9 and the known compounds 3,4-di-O-caffeoylquinic acid, 3,5-di-O-caffeoylquinic acid, and 5'-O-methyladenosine exhibited antiviral activity against the influenza virus A/Hanfang/359/95 (H3N2) with IC50 values of 3.4-11.6 μM, and 4 inhibited Coxsackie virus B3 replication with an IC50 value of 12.3 μM.
|
Inhibition of human erythrocyte purine nucleoside phosphorylase assessed as inhibition of guanosine phosphorylysis at 1.25 umol after 30 mins by orcinol reaction
|
Homo sapiens
|
30.0
%
|
|
Journal : J. Med. Chem.
Title : Stereoelectronic factors in the binding of substrate analogues and inhibitors to purine nucleoside phosphorylase isolated from human erythrocytes.
Year : 1978
Volume : 21
Issue : 9
First Page : 877
Last Page : 882
Authors : Jordan F, Wu A.
Abstract : Several aspects of the stereoelectronic requirements of substrates of human erythrocytic purine nucleoside phosphorylase (E.C. 2.4.2.1) were elucidated providing the following information: (a) the N1 position cannot have a nonhydrogen substituent; (b) the 5'-OH group must be present for catalytic activity to be exhibited but is not an essential functional group for inhibitory action to be observed; (c) on the C8 position groups larger than -NH2 or -Br cannot be accommodated; (d) the syn-glycosyl conformation (i.e., 8-bromoguanosine) is acceptable but may not be an absolute requirement for phosphorolysis; (e) among nucleic base inhibitors methylation at N3, N7, or N9 vastly decreases the inhibitory properties as does a nitrogen in lieu of C-H in the 8 position. The results clearly indicate that this enzyme differs in its stereoelectronic requirements from the Escherichia coli enzyme.
|
Agonist activity at human recombinant adenosine receptor A2a by cAMP assay
|
Homo sapiens
|
700.0
nM
|
|
Journal : J. Med. Chem.
Title : Adenosine A2A receptor as a drug discovery target.
Year : 2014
Volume : 57
Issue : 9
First Page : 3623
Last Page : 3650
Authors : de Lera Ruiz M, Lim YH, Zheng J.
Abstract : The adenosine A2A receptor is a G-protein-coupled receptor (GPCR) that has been extensively studied during the past few decades because it offers numerous possibilities for therapeutic applications. Herein we describe adenosine A2A receptor distribution, signaling pathways, pharmacology, and molecular structure, followed by a summary and SAR discussion of the most relevant series of adenosine A2A agonists and antagonists. This review also provides an update of the A2A ligands that are undergoing or have undergone clinical studies, including the two currently marketed agonists adenosine and regadenoson.
|
Agonist activity at human recombinant adenosine A1 receptor by cAMP assay
|
Homo sapiens
|
310.0
nM
|
|
Journal : J. Med. Chem.
Title : Adenosine A2A receptor as a drug discovery target.
Year : 2014
Volume : 57
Issue : 9
First Page : 3623
Last Page : 3650
Authors : de Lera Ruiz M, Lim YH, Zheng J.
Abstract : The adenosine A2A receptor is a G-protein-coupled receptor (GPCR) that has been extensively studied during the past few decades because it offers numerous possibilities for therapeutic applications. Herein we describe adenosine A2A receptor distribution, signaling pathways, pharmacology, and molecular structure, followed by a summary and SAR discussion of the most relevant series of adenosine A2A agonists and antagonists. This review also provides an update of the A2A ligands that are undergoing or have undergone clinical studies, including the two currently marketed agonists adenosine and regadenoson.
|
Agonist activity at human recombinant adenosine A3 receptor by cAMP assay
|
Homo sapiens
|
290.0
nM
|
|
Journal : J. Med. Chem.
Title : Adenosine A2A receptor as a drug discovery target.
Year : 2014
Volume : 57
Issue : 9
First Page : 3623
Last Page : 3650
Authors : de Lera Ruiz M, Lim YH, Zheng J.
Abstract : The adenosine A2A receptor is a G-protein-coupled receptor (GPCR) that has been extensively studied during the past few decades because it offers numerous possibilities for therapeutic applications. Herein we describe adenosine A2A receptor distribution, signaling pathways, pharmacology, and molecular structure, followed by a summary and SAR discussion of the most relevant series of adenosine A2A agonists and antagonists. This review also provides an update of the A2A ligands that are undergoing or have undergone clinical studies, including the two currently marketed agonists adenosine and regadenoson.
|
Cytotoxicity against mouse L1210 cells assessed as inhibition of cell viability after 72 hrs by MTT assay relative to control
|
Mus musculus
|
32.79
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antiproliferative activity of conjugates of adenosine with muramyl dipeptide and nor-muramyl dipeptide derivatives.
Year : 2014
Volume : 24
Issue : 15
First Page : 3587
Last Page : 3591
Authors : Samsel M, Dzierzbicka K, Trzonkowski P.
Abstract : We synthesized a series of MDP(D,D) and nor-MDP(D,D) derivatives conjugated with adenosine through a spacer as potential immunosuppressants. New conjugates 8a-k were evaluated on two leukemia cell lines (Jurkat and L1210) and PBMC from healthy donors. The conjugates 8a-k and MDP(D,D)/nor-MDP(D,D) derivatives 7e, f, i, j were active against L1210 cell line. Unconjugated nor-MDP(D,D) had better antiproliferative properties, but the conjugates 8b, f, g had the highest values of selectivity index. Both cell lines as well as PBMC were resistant to analogs 11a, b with the 6-aminohexanoic linker.
|
Antitumor activity against mouse L1210 cells assessed as inhibition of [3H]thymidine incorporation at 0.5 mg/ml after 72 hrs relative to control
|
Mus musculus
|
132.32
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antiproliferative activity of conjugates of adenosine with muramyl dipeptide and nor-muramyl dipeptide derivatives.
Year : 2014
Volume : 24
Issue : 15
First Page : 3587
Last Page : 3591
Authors : Samsel M, Dzierzbicka K, Trzonkowski P.
Abstract : We synthesized a series of MDP(D,D) and nor-MDP(D,D) derivatives conjugated with adenosine through a spacer as potential immunosuppressants. New conjugates 8a-k were evaluated on two leukemia cell lines (Jurkat and L1210) and PBMC from healthy donors. The conjugates 8a-k and MDP(D,D)/nor-MDP(D,D) derivatives 7e, f, i, j were active against L1210 cell line. Unconjugated nor-MDP(D,D) had better antiproliferative properties, but the conjugates 8b, f, g had the highest values of selectivity index. Both cell lines as well as PBMC were resistant to analogs 11a, b with the 6-aminohexanoic linker.
|
Cytotoxicity against human PBMC assessed as inhibition of cell viability at 0.5 mg/ml after 72 hrs by MTT assay
|
Homo sapiens
|
50.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antiproliferative activity of conjugates of adenosine with muramyl dipeptide and nor-muramyl dipeptide derivatives.
Year : 2014
Volume : 24
Issue : 15
First Page : 3587
Last Page : 3591
Authors : Samsel M, Dzierzbicka K, Trzonkowski P.
Abstract : We synthesized a series of MDP(D,D) and nor-MDP(D,D) derivatives conjugated with adenosine through a spacer as potential immunosuppressants. New conjugates 8a-k were evaluated on two leukemia cell lines (Jurkat and L1210) and PBMC from healthy donors. The conjugates 8a-k and MDP(D,D)/nor-MDP(D,D) derivatives 7e, f, i, j were active against L1210 cell line. Unconjugated nor-MDP(D,D) had better antiproliferative properties, but the conjugates 8b, f, g had the highest values of selectivity index. Both cell lines as well as PBMC were resistant to analogs 11a, b with the 6-aminohexanoic linker.
|
Agonist activity at human adenosine A1 receptor transfected in CHO cells assessed as changes in cAMP formation in the presence of nitrobenzylthioinosine
|
Homo sapiens
|
310.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of Molecular Therapeutics for Glaucoma: Challenges, Successes, and Promising Directions.
Year : 2016
Volume : 59
Issue : 3
First Page : 788
Last Page : 809
Authors : Donegan RK, Lieberman RL.
Abstract : Glaucoma, a heterogeneous ocular disorder affecting ∼60 million people worldwide, is characterized by painless neurodegeneration of retinal ganglion cells (RGCs), resulting in irreversible vision loss. Available therapies, which decrease the common causal risk factor of elevated intraocular pressure, delay, but cannot prevent, RGC death and blindness. Notably, it is changes in the anterior segment of the eye, particularly in the drainage of aqueous humor fluid, which are believed to bring about changes in pressure. Thus, it is primarily this region whose properties are manipulated in current and emerging therapies for glaucoma. Here, we focus on the challenges associated with developing treatments, review the available experimental methods to evaluate the therapeutic potential of new drugs, describe the development and evaluation of emerging Rho-kinase inhibitors and adenosine receptor ligands that offer the potential to improve aqueous humor outflow and protect RGCs simultaneously, and present new targets and approaches on the horizon.
|
Agonist activity at human adenosine A2A receptor transfected in CHO cells assessed as changes in cAMP formation in the presence of nitrobenzylthioinosine
|
Homo sapiens
|
730.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of Molecular Therapeutics for Glaucoma: Challenges, Successes, and Promising Directions.
Year : 2016
Volume : 59
Issue : 3
First Page : 788
Last Page : 809
Authors : Donegan RK, Lieberman RL.
Abstract : Glaucoma, a heterogeneous ocular disorder affecting ∼60 million people worldwide, is characterized by painless neurodegeneration of retinal ganglion cells (RGCs), resulting in irreversible vision loss. Available therapies, which decrease the common causal risk factor of elevated intraocular pressure, delay, but cannot prevent, RGC death and blindness. Notably, it is changes in the anterior segment of the eye, particularly in the drainage of aqueous humor fluid, which are believed to bring about changes in pressure. Thus, it is primarily this region whose properties are manipulated in current and emerging therapies for glaucoma. Here, we focus on the challenges associated with developing treatments, review the available experimental methods to evaluate the therapeutic potential of new drugs, describe the development and evaluation of emerging Rho-kinase inhibitors and adenosine receptor ligands that offer the potential to improve aqueous humor outflow and protect RGCs simultaneously, and present new targets and approaches on the horizon.
|
Agonist activity at human adenosine A3 receptor transfected in CHO cells assessed as changes in cAMP formation in the presence of nitrobenzylthioinosine
|
Homo sapiens
|
290.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of Molecular Therapeutics for Glaucoma: Challenges, Successes, and Promising Directions.
Year : 2016
Volume : 59
Issue : 3
First Page : 788
Last Page : 809
Authors : Donegan RK, Lieberman RL.
Abstract : Glaucoma, a heterogeneous ocular disorder affecting ∼60 million people worldwide, is characterized by painless neurodegeneration of retinal ganglion cells (RGCs), resulting in irreversible vision loss. Available therapies, which decrease the common causal risk factor of elevated intraocular pressure, delay, but cannot prevent, RGC death and blindness. Notably, it is changes in the anterior segment of the eye, particularly in the drainage of aqueous humor fluid, which are believed to bring about changes in pressure. Thus, it is primarily this region whose properties are manipulated in current and emerging therapies for glaucoma. Here, we focus on the challenges associated with developing treatments, review the available experimental methods to evaluate the therapeutic potential of new drugs, describe the development and evaluation of emerging Rho-kinase inhibitors and adenosine receptor ligands that offer the potential to improve aqueous humor outflow and protect RGCs simultaneously, and present new targets and approaches on the horizon.
|
Agonist activity at human Adenosine A1 receptor transfected in CHO-K1 cells assessed as inhibition of forskolin-stimulated cAMP production after 30 mins by multimode microplate reader analysis
|
Homo sapiens
|
2.344
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of Novel Adenosine Receptor Agonists That Exhibit Subtype Selectivity.
Year : 2016
Volume : 59
Issue : 3
First Page : 947
Last Page : 964
Authors : Knight A, Hemmings JL, Winfield I, Leuenberger M, Frattini E, Frenguelli BG, Dowell SJ, Lochner M, Ladds G.
Abstract : A series of N(6)-bicyclic and N(6)-(2-hydroxy)cyclopentyl derivatives of adenosine were synthesized as novel A1R agonists and their A1R/A2R selectivity assessed using a simple yeast screening platform. We observed that the most selective, high potency ligands were achieved through N(6)-adamantyl substitution in combination with 5'-N-ethylcarboxamido or 5'-hydroxymethyl groups. In addition, we determined that 5'-(2-fluoro)thiophenyl derivatives all failed to generate a signaling response despite showing an interaction with the A1R. Some selected compounds were also tested on A1R and A3R in mammalian cells revealing that four of them are entirely A1R-selective agonists. By using in silico homology modeling and ligand docking, we provide insight into their mechanisms of recognition and activation of the A1R. We believe that given the broad tissue distribution, but contrasting signaling profiles, of adenosine receptor subtypes, these compounds might have therapeutic potential.
|
Agonist activity at human Adenosine A3 receptor transfected in CHO-K1 cells assessed as inhibition of forskolin-stimulated cAMP production after 30 mins by multimode microplate reader analysis
|
Homo sapiens
|
1.148
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of Novel Adenosine Receptor Agonists That Exhibit Subtype Selectivity.
Year : 2016
Volume : 59
Issue : 3
First Page : 947
Last Page : 964
Authors : Knight A, Hemmings JL, Winfield I, Leuenberger M, Frattini E, Frenguelli BG, Dowell SJ, Lochner M, Ladds G.
Abstract : A series of N(6)-bicyclic and N(6)-(2-hydroxy)cyclopentyl derivatives of adenosine were synthesized as novel A1R agonists and their A1R/A2R selectivity assessed using a simple yeast screening platform. We observed that the most selective, high potency ligands were achieved through N(6)-adamantyl substitution in combination with 5'-N-ethylcarboxamido or 5'-hydroxymethyl groups. In addition, we determined that 5'-(2-fluoro)thiophenyl derivatives all failed to generate a signaling response despite showing an interaction with the A1R. Some selected compounds were also tested on A1R and A3R in mammalian cells revealing that four of them are entirely A1R-selective agonists. By using in silico homology modeling and ligand docking, we provide insight into their mechanisms of recognition and activation of the A1R. We believe that given the broad tissue distribution, but contrasting signaling profiles, of adenosine receptor subtypes, these compounds might have therapeutic potential.
|
Inhibition of Saccharomyces cerevisiae alpha-glucosidase using p-nitro-phenyl-alpha-D-glucopyranoside as substrate at 200 uM preincubated with enzyme followed by substrate addition measured after 10 mins for every 2.5 to 5 mins relative to control
|
Saccharomyces cerevisiae
|
10.3
%
|
|
Journal : Bioorg Med Chem Lett
Title : Chemical constituents from Taraxacum officinale and their α-glucosidase inhibitory activities.
Year : 2018
Volume : 28
Issue : 3
First Page : 476
Last Page : 481
Authors : Choi J, Yoon KD, Kim J.
Abstract : Three novel butyrolactones (1-3) and butanoates (4-6), namely taraxiroside A-F, were isolated from Taraxacum officinale along with twenty-two known compounds (7-28). Their chemical structures were elucidated by interpretation of spectroscopic data and comparison with those of literatures. All isolates were evaluated for their α-glucosidase inhibitory activities. Novel compounds 1-6 (IC50 145.3-181.3 μM) showed inhibitory activities similar to that of acarbose (IC50 179.9 μM). Compound 7 and 12 were the most potent inhibitor with IC50 values of 61.2 and 39.8 μM respectively. Compounds 2 and 12 showed as mixed-type inhibition, whereas compound 7 and acarbose showed competitive inhibition.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
-5.46
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Binding affinity to human recombinant adenosine receptor A2A expressed in CHO cells assessed as inhibitory constant by radioligand competition assay
|
Homo sapiens
|
700.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of 2-hydrazinyladenosine derivatives as A2A adenosine receptor ligands.
Year : 2019
Volume : 179
First Page : 310
Last Page : 324
Authors : Zhang M, Fan S, Zhou X, Xie F, Li S, Zhong W.
Abstract : To obtain potential A2A adenosine receptor agonists, a series of 2-hydrazinyladenosine derivatives were synthesized and assayed for adenosine receptors activity using radioligand binding activity assays. The binding activity of the subtypes was examined, and the structure-activity relationship of this class of compounds at the A2A receptor was investigated. A fragment-based computer-aided design method was used to modify the 2-position side chain structures with different structural fragments, and the newly generated molecules were docked to the A2A receptor to assess scoring and screening activity. To synthesize compounds with better scoring activity, the newly synthesized compounds were tested for in vitro receptor binding activity. 2-Hydrazinyladenosine derivatives of 32 new structural types were designed and synthesized, with the most potent adenosine derivative 23 exhibiting a Ki value of 1.8 nM for A2AAR and significant selectivity for the A2A receptor compared to the A1 receptor. In addition to, compound 23, 24, 30, 31, and 42 also exhibited potent A2A receptor selectivity, with Ki values for the A2A receptor of 6.4, 20, 67 and 6.3 nM, respectively. We also found that compound 35 has a high A1 receptor selectivity, with a Ki value for the A1 receptor of 4.5 nM. Further functional assays also demonstrated that these compounds have potent A2A receptor agonist activity. The study shows the applicability of an in silico fragment-based molecular design for rational lead optimization in A2AAR.
|
Inhibition of DOT1L (unknown origin) at 200 uM using chicken nucleosome as substrate in presence of [3H]SAM incubated for 1 hr by TopCount method
|
Homo sapiens
|
26.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : New small molecule inhibitors of histone methyl transferase DOT1L with a nitrile as a non-traditional replacement for heavy halogen atoms.
Year : 2016
Volume : 26
Issue : 18
First Page : 4518
Last Page : 4522
Authors : Spurr SS, Bayle ED, Yu W, Li F, Tempel W, Vedadi M, Schapira M, Fish PV.
Abstract : A number of new nucleoside derivatives are disclosed as inhibitors of DOT1L activity. SARs established that DOT1L inhibition could be achieved through incorporation of polar groups and small heterocycles at the 5-position (5, 6, 12) or by the application of alternative nitrogenous bases (18). Based on these results, CN-SAH (19) was identified as a potent and selective inhibitor of DOT1L activity where the polar 5-nitrile group was shown by crystallography to bind in the hydrophobic pocket of DOT1L. In addition, we show that a polar nitrile group can be used as a non-traditional replacement for heavy halogen atoms.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
31.99
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
13.7
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
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Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
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Chlorocebus sabaeus
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0.02
%
|
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Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
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Chlorocebus sabaeus
|
0.21
%
|
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Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
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Chlorocebus sabaeus
|
0.21
%
|
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Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
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Chlorocebus sabaeus
|
0.02
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
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Displacement of [3H]NECA from human adenosine A3 receptor expressed in HeLa cell membrane at 10 uM incubated for 180 mins by microplate beta scintillation counting based radioligand inhibition assay relative to control
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Homo sapiens
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10.0
%
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Displacement of [3H]ZM241385 from human adenosine A2A receptor expressed in HeLa cell membrane ay 10 uM incubated for 30 mins by microplate beta scintillation counting based radioligand inhibition assay relative to control
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Homo sapiens
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3.0
%
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Displacement [3H]DPCPX from human adenosine A1 receptor expressed in CHO cell membrane at 10 uM incubated for 60 mins by microplate beta scintillation counting based radioligand inhibition assay relative to control
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Homo sapiens
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13.0
%
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Displacement of [3H]DPCPX from human adenosine A2B receptor expressed in HEK cell membrane at 10 uM incubated for 30 mins by microplate beta scintillation counting based radioligand inhibition assay relative to control
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Homo sapiens
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4.0
%
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