Reduction of 3'-Azido-3'-deoxythymidine (AZT) and AZT Nucleotides by Thiols KINETICS AND PRODUCT ... more Reduction of 3'-Azido-3'-deoxythymidine (AZT) and AZT Nucleotides by Thiols KINETICS AND PRODUCT IDENTIFICATION*
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
6‐[[(Hydroxyimino)phenyl]methyl]‐1‐[(1‐methylethyl)sulfonyl]‐1H‐imidazo[4,5‐b]pyridin‐2‐amine (1)... more 6‐[[(Hydroxyimino)phenyl]methyl]‐1‐[(1‐methylethyl)sulfonyl]‐1H‐imidazo[4,5‐b]pyridin‐2‐amine (1), an aza analogue of enviroxime, was synthesized in eight steps from 6‐hydroxynicotinic acid (2). Acid 2 was nitrated, chlorinated with phosphorus pentachloride, and subjected to Friedel‐Crafts aroylation to give 6‐chloro‐5‐nitro‐3‐pyridyl phenyl ketone (5). Amination of 5 was followed by reduction of the nitro group and condensation with ethoxycarbonylisothiocyanate to give 6‐benzyl‐2‐ethoxycarbonylamino‐1H‐imidazo[4,5‐d]pyridine (8). The ethoxycarbonyl moiety of 8 was cleaved, N‐1 was isopropylsulfonylated, and the carbonyl moiety was condensed with hydroxylamine to give 1. Compound 1 was inactive against rhinovirus 1B and poliovirus type 1.
High field (360 MHz) 'H NMR studies have shown that the conformation of ring C in the oxymorphami... more High field (360 MHz) 'H NMR studies have shown that the conformation of ring C in the oxymorphamines is dramatically influenced by the stereochemistry of the C-amino group: ring C exists in a chair conformation in the 6Bepimer but adopts a twist boat conformation in the 6a-epimer.
A series of [[(guaninylalkyl)phosphinicolmethyllphosphonic acids, 2, was synthesized and tested a... more A series of [[(guaninylalkyl)phosphinicolmethyllphosphonic acids, 2, was synthesized and tested as inhibitors of human erythrocyte purine nucleoside phosphorylase (PNPase). The target (phosphinicomethy1)phosphonic acids 2 were synthesized in six or seven steps from alkenylphosphonates 4. The latter were converted to the intermediate alkylmesylates 9 in a series of steps that included (1) conversion of the diethyl phosphonates 4 t o the (phosphinoylmethy1)phosphonates 7 and (2) conversion of the terminal double bond of [(alkenylphosphinoyl)methyl]phosphonates 7 to the alkylmesylates 9. The pure 9-isomers 2 were obtained by alkylation of 2-amino-6-(2-methoxyethoxy)-9H-purine with alkylmesylates 9 followed by hydrolysis of the protecting groups with concentrated hydrochloric acid and ion exchange chromatography to give 2 as hydrated ammonium salts. The most potent inhibitor of human erythrocyte PNPase, [[[5-(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)pentyllphosphinicolmethyllphosphonic acid (2b), was a multisubstrate analogue inhibitor with a Ki' of 3.1 nM. Optimum PNPase inhibitory activity required the presence of zinc ions in the assay medium. These potent inhibitors of PNPase exhibited only weak activity against human leukemic T-cells in vitro. ' Division of Organic Chemistry.
ChemInform Abstract Die Desazapurine (I) werden synthetisiert. Bei kaum vorhandener Cytotoxizität... more ChemInform Abstract Die Desazapurine (I) werden synthetisiert. Bei kaum vorhandener Cytotoxizität gegenüber Säugetierzellen in Kultur zeigen diese Verbindungen teilweise bei entsprechenden in vivo-bzw. in vitro-Tests immunsuppressive und antiinflammatorische Wirkung.
N-Benzylpyruvamide cyclized under basic conditions to give a 70:30 trans:cis mixture of diastereo... more N-Benzylpyruvamide cyclized under basic conditions to give a 70:30 trans:cis mixture of diastereomers of N,1-dibenzyl-2,4-dihydroxy-4-methyl-5-oxo-2-pyrrolidinecarboxamide.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Drug metabolism and disposition: the biological fate of chemicals
A major metabolite of zidovudine (3'-azido-3'-deoxythymidine, AZT), which previously had ... more A major metabolite of zidovudine (3'-azido-3'-deoxythymidine, AZT), which previously had not been observed in a variety of experimental animals, was identified in samples of plasma and urine from cynomolgus monkeys and a patient treated with AZT. The urinary recoveries of metabolite from the monkeys and the patient were, respectively, 1.5- and 6.9-fold higher than the recoveries of unchanged drug. The metabolite was purified in gram quantities from the urines of the monkeys and the patient and was identified enzymatically, using beta-glucuronidase and a specific inhibitor of the enzyme, as a glucuronide conjugate of AZT. The metabolite was formed in vitro by incubating AZT with preparations of human liver in the presence of UDP-glucuronic acid. In addition, the metabolite was prepared synthetically and physical characterizations--including microanalysis and UV, IR, NMR and mass spectra--of compound from all three sources were identical and confirmed the metabolite to be the ...
Inverted and Suppressed Direct Response (IDR and SDR, respectively) HMQC-TOCSY experiments are ev... more Inverted and Suppressed Direct Response (IDR and SDR, respectively) HMQC-TOCSY experiments are evaluated relative to the conventional HMQC-TOCSY experiment in the assignment of the congested proton and carbon spectra of a 2-acetylpyridine thiocarbonohydrazone used to potentiate the antiviral drug acyclovir. Spectra with moderate overlap can be most expeditiously interpreted using the inverted direct response HMQC-TOCSY variant; spectra with severe overlap can be more readily interpreted if direct responses are suppressed.
ABSTRACT The structure of the epoxide of 1-ethyl-phenoxathiin 10,10-dioxide, a potential monoamin... more ABSTRACT The structure of the epoxide of 1-ethyl-phenoxathiin 10,10-dioxide, a potential monoamine oxidase-A inhibitor, was elucidated using a combination of 500 MHz homo- and heteronuclear NMR techniques. The proton reference spectrum and a COSY spectrum were obtained on a 30 μg sample (0.07 μMoles) of the metabolite in 35 μl of d6-DMSO using a Varian heteronuclear Nano-probe™. An inverse-detected (HMQC) heteronuclear shift correlation spectrum was obtained on the 30 μg sample of the metabolite in 120 μl of d6-DMSO using a Nalorac Z•SPEC™ 3 mm micro inverse probe.
An NMR technique for the determination of proton vicinal couplings relayed at the carbon chemical... more An NMR technique for the determination of proton vicinal couplings relayed at the carbon chemical shift is presented. With this technique, which is an extension of DEPT‐HMQC‐TOCSY, it is possible to generate phaseedited 2D NMR data in which the 1H13C relayed responses differ in phase as a function of the proton multiplicity of the carbon from whose proton(s) the response originates. A simple pulse scheme is presented to allow further simplification of the spectrum by eliminating the direct 1H13C correlations. Thus, responses arising from methines or methyls will be of opposite phase from responses originating from methylenes; direct correlations are eliminated to minimize congestion. An example is presented with the cardiac drug digoxin.
Pulsed field gradients (PFG) have the potential to revolutionize further potent, inverse‐detected... more Pulsed field gradients (PFG) have the potential to revolutionize further potent, inverse‐detected structural NMR techniques by eliminating artifacts and thermal noise in data taken with very small numbers of transients. A phase‐sensitive GE (gradient‐enhanced)‐HMQC‐TOCSY experiment is reported with features which allow the discrimination (or elimination) of direct correlations relative to the relayed TOCSY responses. Sensitivity losses which arise from molecular diffusion during the course of a pulse sequence are potentially serious when field gradients are employed for solutions containing small molecules. By carefully combining phase cycling with relatively weak pulsed field gradients, it is possible both to maintain good sensitivity and to suppress completely t1 noise in GE‐HMQC‐TOCSY data acquired with only two transients per t1, increment.
Reduction of 3'-Azido-3'-deoxythymidine (AZT) and AZT Nucleotides by Thiols KINETICS AND PRODUCT ... more Reduction of 3'-Azido-3'-deoxythymidine (AZT) and AZT Nucleotides by Thiols KINETICS AND PRODUCT IDENTIFICATION*
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
6‐[[(Hydroxyimino)phenyl]methyl]‐1‐[(1‐methylethyl)sulfonyl]‐1H‐imidazo[4,5‐b]pyridin‐2‐amine (1)... more 6‐[[(Hydroxyimino)phenyl]methyl]‐1‐[(1‐methylethyl)sulfonyl]‐1H‐imidazo[4,5‐b]pyridin‐2‐amine (1), an aza analogue of enviroxime, was synthesized in eight steps from 6‐hydroxynicotinic acid (2). Acid 2 was nitrated, chlorinated with phosphorus pentachloride, and subjected to Friedel‐Crafts aroylation to give 6‐chloro‐5‐nitro‐3‐pyridyl phenyl ketone (5). Amination of 5 was followed by reduction of the nitro group and condensation with ethoxycarbonylisothiocyanate to give 6‐benzyl‐2‐ethoxycarbonylamino‐1H‐imidazo[4,5‐d]pyridine (8). The ethoxycarbonyl moiety of 8 was cleaved, N‐1 was isopropylsulfonylated, and the carbonyl moiety was condensed with hydroxylamine to give 1. Compound 1 was inactive against rhinovirus 1B and poliovirus type 1.
High field (360 MHz) 'H NMR studies have shown that the conformation of ring C in the oxymorphami... more High field (360 MHz) 'H NMR studies have shown that the conformation of ring C in the oxymorphamines is dramatically influenced by the stereochemistry of the C-amino group: ring C exists in a chair conformation in the 6Bepimer but adopts a twist boat conformation in the 6a-epimer.
A series of [[(guaninylalkyl)phosphinicolmethyllphosphonic acids, 2, was synthesized and tested a... more A series of [[(guaninylalkyl)phosphinicolmethyllphosphonic acids, 2, was synthesized and tested as inhibitors of human erythrocyte purine nucleoside phosphorylase (PNPase). The target (phosphinicomethy1)phosphonic acids 2 were synthesized in six or seven steps from alkenylphosphonates 4. The latter were converted to the intermediate alkylmesylates 9 in a series of steps that included (1) conversion of the diethyl phosphonates 4 t o the (phosphinoylmethy1)phosphonates 7 and (2) conversion of the terminal double bond of [(alkenylphosphinoyl)methyl]phosphonates 7 to the alkylmesylates 9. The pure 9-isomers 2 were obtained by alkylation of 2-amino-6-(2-methoxyethoxy)-9H-purine with alkylmesylates 9 followed by hydrolysis of the protecting groups with concentrated hydrochloric acid and ion exchange chromatography to give 2 as hydrated ammonium salts. The most potent inhibitor of human erythrocyte PNPase, [[[5-(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)pentyllphosphinicolmethyllphosphonic acid (2b), was a multisubstrate analogue inhibitor with a Ki' of 3.1 nM. Optimum PNPase inhibitory activity required the presence of zinc ions in the assay medium. These potent inhibitors of PNPase exhibited only weak activity against human leukemic T-cells in vitro. ' Division of Organic Chemistry.
ChemInform Abstract Die Desazapurine (I) werden synthetisiert. Bei kaum vorhandener Cytotoxizität... more ChemInform Abstract Die Desazapurine (I) werden synthetisiert. Bei kaum vorhandener Cytotoxizität gegenüber Säugetierzellen in Kultur zeigen diese Verbindungen teilweise bei entsprechenden in vivo-bzw. in vitro-Tests immunsuppressive und antiinflammatorische Wirkung.
N-Benzylpyruvamide cyclized under basic conditions to give a 70:30 trans:cis mixture of diastereo... more N-Benzylpyruvamide cyclized under basic conditions to give a 70:30 trans:cis mixture of diastereomers of N,1-dibenzyl-2,4-dihydroxy-4-methyl-5-oxo-2-pyrrolidinecarboxamide.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Drug metabolism and disposition: the biological fate of chemicals
A major metabolite of zidovudine (3'-azido-3'-deoxythymidine, AZT), which previously had ... more A major metabolite of zidovudine (3'-azido-3'-deoxythymidine, AZT), which previously had not been observed in a variety of experimental animals, was identified in samples of plasma and urine from cynomolgus monkeys and a patient treated with AZT. The urinary recoveries of metabolite from the monkeys and the patient were, respectively, 1.5- and 6.9-fold higher than the recoveries of unchanged drug. The metabolite was purified in gram quantities from the urines of the monkeys and the patient and was identified enzymatically, using beta-glucuronidase and a specific inhibitor of the enzyme, as a glucuronide conjugate of AZT. The metabolite was formed in vitro by incubating AZT with preparations of human liver in the presence of UDP-glucuronic acid. In addition, the metabolite was prepared synthetically and physical characterizations--including microanalysis and UV, IR, NMR and mass spectra--of compound from all three sources were identical and confirmed the metabolite to be the ...
Inverted and Suppressed Direct Response (IDR and SDR, respectively) HMQC-TOCSY experiments are ev... more Inverted and Suppressed Direct Response (IDR and SDR, respectively) HMQC-TOCSY experiments are evaluated relative to the conventional HMQC-TOCSY experiment in the assignment of the congested proton and carbon spectra of a 2-acetylpyridine thiocarbonohydrazone used to potentiate the antiviral drug acyclovir. Spectra with moderate overlap can be most expeditiously interpreted using the inverted direct response HMQC-TOCSY variant; spectra with severe overlap can be more readily interpreted if direct responses are suppressed.
ABSTRACT The structure of the epoxide of 1-ethyl-phenoxathiin 10,10-dioxide, a potential monoamin... more ABSTRACT The structure of the epoxide of 1-ethyl-phenoxathiin 10,10-dioxide, a potential monoamine oxidase-A inhibitor, was elucidated using a combination of 500 MHz homo- and heteronuclear NMR techniques. The proton reference spectrum and a COSY spectrum were obtained on a 30 μg sample (0.07 μMoles) of the metabolite in 35 μl of d6-DMSO using a Varian heteronuclear Nano-probe™. An inverse-detected (HMQC) heteronuclear shift correlation spectrum was obtained on the 30 μg sample of the metabolite in 120 μl of d6-DMSO using a Nalorac Z•SPEC™ 3 mm micro inverse probe.
An NMR technique for the determination of proton vicinal couplings relayed at the carbon chemical... more An NMR technique for the determination of proton vicinal couplings relayed at the carbon chemical shift is presented. With this technique, which is an extension of DEPT‐HMQC‐TOCSY, it is possible to generate phaseedited 2D NMR data in which the 1H13C relayed responses differ in phase as a function of the proton multiplicity of the carbon from whose proton(s) the response originates. A simple pulse scheme is presented to allow further simplification of the spectrum by eliminating the direct 1H13C correlations. Thus, responses arising from methines or methyls will be of opposite phase from responses originating from methylenes; direct correlations are eliminated to minimize congestion. An example is presented with the cardiac drug digoxin.
Pulsed field gradients (PFG) have the potential to revolutionize further potent, inverse‐detected... more Pulsed field gradients (PFG) have the potential to revolutionize further potent, inverse‐detected structural NMR techniques by eliminating artifacts and thermal noise in data taken with very small numbers of transients. A phase‐sensitive GE (gradient‐enhanced)‐HMQC‐TOCSY experiment is reported with features which allow the discrimination (or elimination) of direct correlations relative to the relayed TOCSY responses. Sensitivity losses which arise from molecular diffusion during the course of a pulse sequence are potentially serious when field gradients are employed for solutions containing small molecules. By carefully combining phase cycling with relatively weak pulsed field gradients, it is possible both to maintain good sensitivity and to suppress completely t1 noise in GE‐HMQC‐TOCSY data acquired with only two transients per t1, increment.
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Papers by Ronald Crouch