PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Thionucleosides”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed2000

2,2'-Anhydro-4'-thionucleosides: precursors for 2'-azido- and 2'-chloro-4'-thionucleosides and for a novel thiolane to thietane rearrangement.

2,2'-Anhydro-4'-thio-beta- and alpha-nucleosides 9 and 10 have been prepared by an in situ 4-thio-1,2-glycal addition route. They undergo ring-opening by azide or chloride ion to give, after deprotection, the 2'-substituted-4'-thionucleosides 13 and 14, whereas reactions with cyanide or fluoride sources lead to the unsaturated nucleosides 17 or 18, depending upon conditions. An unexpected and clean rearrangement to the thietane 23 occurs on treatment of uracil derivative 20 with DAST.

Azides↗
PubMed2002

Requirement for IscS in biosynthesis of all thionucleosides in Escherichia coli.

Escherichia coli tRNA contains four naturally occurring nucleosides modified with sulfur. Cysteine is the intracellular sulfur source for each of these modified bases. We previously found that the iscS gene, a member of the nifS cysteine desulfurase gene family, is required for 4-thiouridine biosynthesis in E. coli. Since IscS does not bind tRNA, its role is the mobilization and distribution of sulfur to enzymes that catalyze the sulfur insertion steps. In addition to iscS, E. coli contains two other nifS homologs, csdA and csdB, each of which has cysteine desulfurase activity and could potentially donate sulfur for thionucleoside biosynthesis. Double csdA csdB and iscS csdA mutants were prepared or obtained, and all mutants were analyzed for thionucleoside content. It was found that unfractionated tRNA isolated from the iscS mutant strain contained <5% of the level of sulfur found in the parent strain. High-pressure liquid chromatography analysis of tRNA nuclease digests from the mutant strain grown in the presence of [(35)S]cysteine showed that only a small fraction of 2-thiocytidine was present, while the other thionucleosides were absent when cells were isolated during log phase. As expected, digests from the iscS mutant strain contained 6-N-dimethylallyl adenosine (i(6)A) in place of 6-N-dimethylallyl-2-methylthioadenosine and 5-methylaminomethyl uridine (mnm(5)U) instead of 5-methylaminomethyl-2-thiouridine. Prolonged growth of the iscS and iscS csdA mutant strains revealed a gradual increase in levels of 2-thiocytidine and 6-N-dimethylallyl-2-methylthioadenosine with extended incubation (>24 h), while the thiouridines remained absent. This may be due to a residual level of Fe-S cluster biosynthesis in iscS deletion strains. An overall scheme for thionucleoside biosynthesis in E. coli is discussed.

Carbon-Sulfur Lyases↗
PubMed2004

Recent advances in 4'-thionucleosides as potential antiviral and antitumor agents.

The classical 4'-oxonucleoside analogs exhibit interesting biological activities such as antibiotic, antiviral and antitumor, which are believed to be the result of inhibition of the viral or cellular DNA or RNA polymerase after being converted to their corresponding 5'-triphosphates. However, the activity of 4'-oxonucleosides were limited by their susceptibility to degradation by nucleoside phosphorylases or acid hydrolysis. This aspect called for the chemical modification of the carbohydrate portion. This compulsion led to two kinds of strategies; (1) replacement of the 4'-oxygen by the methylene group - carbocyclic nucleosides; (2) replacement of the 4' oxygen by sulphur-4'-thionucleosides. This group has also conferred the resistance to the nucleoside cleavage. Although, there were some pioneering work on 4'-thionucleosides in 1960s and 1970s, the interest in this group of compounds was rekindled by the antiviral activities of 2'-deoxy-4'-thionucleosides reported independently by Secrist et al. and Walker et al. Subsequent contributions by the other authors, enhanced its standing as an important class of antiviral agents. Following is a reasonably exhaustive account of this class of compounds reported after 1990.

Animals↗
PubMed1994

Identification and characterization of thionucleosides in the total tRNA of cucumber cotyledons.

Total tRNA isolated from cucumber cotyledons grown in the presence of radioactive sulfur was analyzed for the occurrence of thionucleosides. The analysis revealed the presence of at least five thionucleosides which were identified as 5-methylaminomethyl-2-thiouridine (mnm5s2U), 2-methylthio-N6-isopentenyladenosine (ms2i6A), 2-methylthio-N6-hydroxyisopentenyladenosine (ms2io6A), 5-methyl-2-thiouridine (m5s2U) and N-[(9-beta-ribofuranosyl-2- methylthiopurine-2-yl)-carbamoyl]-threonine (ms2t6A). A comparison of relative amounts of these thionucleosides in the total tRNAs of dark-, and light-grown cotyledons shows that the relative amounts of ms2i6A, ms2io6A and ms2t6A remain unchanged whereas mnm5s2U increases with a concomitant decrease in the relative amounts of m5s2U after light treatment of dark-grown cotyledons.

Autoradiography↗
PubMed1974

Studies on chemical modification of thionucleosides in the transfer ribonucleic acid of Escherichia coli.

(35)S-labelled tRNA from Escherichia coli was treated with chemical reagents such as CNBr, H(2)O(2), NH(2)OH, I(2), HNO(2), KMnO(4) and NaIO(4), under mild conditions where the four major bases were not affected. Gel filtration of the treated tRNA showed desulphurization to various extents, depending on the nature of the reagent. The treated samples after conversion into nucleosides were chromatographed on a phosphocellulose column. NH(2)OH, I(2) and NaIO(4) reacted with all the four thionucleosides of E. coli tRNA, 4-thiouridine (s(4)U), 5-methylaminomethyl-2-thiouridine (mnm(5)s(2)U), 2-thiocytidine (s(2)C) and 2-methylthio-N(6)-isopentenyladenosine (ms(2)i(6)A), to various extents. CNBr, HNO(2) and NaHSO(3) reacted with s(4)U, mnm(5)s(2)U and s(2)C, but not with ms(2)i(6)A. KMnO(4) and H(2)O(2) were also found to react extensively with thionucleosides in tRNA. Iodine oxidation of (35)S-labelled tRNA showed that only 6% of the sulphur was involved in disulphide formation. Desulphurization of E. coli tRNA with CNBr resulted in marked loss of acceptor activities for glutamic acid, glutamine and lysine. Acceptor activities for alanine, arginine, glycine, isoleucine, methionine, phenylalanine, serine, tyrosine and valine were also affected, but to a lesser extent. Five other amino acids tested were almost unaffected. These results indicate the fate of thionucleosides in tRNA when subjected to various chemical reactions and the involvement of sulphur in aminoacyl-tRNA synthetase recognition of some tRNA species of E. coli.

Chromatography, Gel↗
PubMed2004

Synthesis, structure-activity relationships, and mechanism of drug resistance of D- and L-beta-3'-fluoro-2',3'-unsaturated-4'-thionucleosides as anti-HIV agents.

Various D- and L-2',3'-unsaturated 3'-fluoro-4'-thionucleosides (D- and L-3'F-4'Sd4Ns) were synthesized for the studies of structure-activity relationships. The synthesized D-2',3'-unsaturated 3'-fluoro-4'-thionucleosides did not show any significant antiviral activity against HIV-1, while unnatural L-nucleosides such as cytosine 34 (EC(50) = 0.13 microM; EC(90) = 1.7 microM) and 5-fluorocytosine 35 (EC(50) = 0.031 microM; EC(90) = 0.35 microM) derivatives exhibited potent anti-HIV activity without significant toxicity. Molecular modeling study shows that the 3'-fluorine atom of the d-2',3'-unsaturated cytidine triphosphate (D-3'F-4'Sd4CTP) experiences unfavorable electrostatic interaction with its own triphosphate moiety, resulting in the decreased binding affinity to wild-type HIV-1 reverse transcriptase (RT), which may be one of the reasons for the insensitivity of HIV-1 RT to these compounds. On the other hand, L-3'F-4'Sd4CTP binds to the active site of wild-type HIV-1 RT without steric hindrance and there is a possible hydrogen bonding between the 3'-fluorine atom and Asp185, which correlates with its potent anti-HIV activity. However, L-3'F-4'Sd4C 34 and L-3'F-4'Sd4FC 35 showed high cross-resistance to 3TC-resistant mutant (M184V) RT. Like other unnatural L-nucleosides, the unfavorable steric hindrance of the sugar moiety of L-3'F-4'Sd4CTP with the side chain of Val184 explains its significant cross-resistance to the M184V mutant.

Anti-HIV Agents↗
PubMed1998

Synthesis of Novel Iso-4'-thionucleosides Using the Mitsunobu Reaction.

A novel class of isomeric 4'-thionucleosides with the base moiety at the 2'-position was synthesized from D-glucose. The coupling of 1,4-anhydro-4-thioarabitol (13) with various nucleobases using the Mitsunobu reaction was investigated. With both purines and N(3)-benzoyluracils, the reaction predominantly gave beta-isomers, suggesting that these were produced via an episulfonium intermediate. The beta-anomers produced by the reaction of N(3)-benzoyluracils included both N- and O-alkylated derivatives. Interestingly, only the reaction of N(3)-benzoyluracil gave a mixture of N-alkylated adduct (20d) and O-alkylated bipyrimidinyl adduct (22), the structure of which was unambiguously determined by NMR spectroscopic data including HMBC and NOE. Deprotection of the Mitsunobu reaction products gave the desired iso-4'-thionucleosides.

Journal Article↗
PubMed2004

Substitutions in an active site loop of Escherichia coli IscS result in specific defects in Fe-S cluster and thionucleoside biosynthesis in vivo.

IscS catalyzes the fragmentation of l-cysteine to l-alanine and sulfane sulfur in the form of a cysteine persulfide in the active site of the enzyme. In Escherichia coli IscS, the active site cysteine Cys(328) resides in a flexible loop that potentially influences both the formation and stability of the cysteine persulfide as well as the specificity of sulfur transfer to protein substrates. Alanine-scanning substitution of this 14 amino acid region surrounding Cys(328) identified additional residues important for IscS function in vivo. Two mutations, S326A and L333A, resulted in strains that were severely impaired in Fe-S cluster synthesis in vivo. The mutant strains were deficient in Fe-S cluster-dependent tRNA thionucleosides (s(2)C and ms(2)i(6)A) yet showed wild type levels of Fe-S-independent thionucleosides (s(4)U and mnm(5)s(2)U) that require persulfide formation and transfer. In vitro, the mutant proteins were similar to wild type in both cysteine desulfurase activity and sulfur transfer to IscU. These results indicate that residues in the active site loop can selectively affect Fe-S cluster biosynthesis in vivo without detectably affecting persulfide delivery and suggest that additional assays may be necessary to fully represent the functions of IscS in Fe-S cluster formation.

Alanine↗
PubMed2004

Novel stereoselective entry to 2'-beta-carbon-substituted 2'-deoxy-4'-thionucleosides from 4-thiofuranoid glycals.

2'-Beta-methyl- and 2'-beta-hydroxymethyl-2'-deoxy-4'-thionucleosides have been synthesized through PhSeCl-mediated electrophilic glycosidation using 4-thiofuranoid glycals having carbon substituents at the C2-position as a glycosyl donor. Preparation of these glycals were carried out by means of the C2 lithiation of 1-chloro-4-thiofuranoid glycal with LTMP followed by the Birch reduction of the chlorine atom. [reaction: see text]

Molecular Structure↗
PubMed2004

Synthesis of new 2',3'-dideoxy-6',6'-difluoro-3'-thionucleoside from gem-difluorohomoallyl alcohol.

[reaction: see text] 2',3'-Dideoxy-6',6'-difluoro-3'-thionucleoside 1b, an analogue of 3Tc that has high biological activities against HIV and HBV, has been synthesized from gem-difluorohomoallyl alcohol 3 in an efficient way. The key intermediate 4-amino-3,3-difluorotetrahydrothiophen-2-ylmethyl benzoate 15 was prepared from 2,2-difluoro-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]but-3-en-1-ol 3 in 11 steps. The construction of pyrimidine ring with the amino group of compound 15 gave the target compound 1.

Amino Alcohols↗
PubMed2006

Synthesis of L-beta-3'-deoxy-3',3'-difluoro-4'-thionucleosides.

[Structure: see text] An efficient route to L-beta-3'-deoxy-3',3'-difluoro-4'-thionucleosides, thio-containing analogues of highly bioactive gemcitabine, is described. Our synthesis highlighted the installation of the thioacetyl group in high efficiency and construction of 3-deoxy-3,3-difluorothiofuranose skeleton in a novel method.

Models, Molecular↗
PubMedDate not supplied

4-Thiofuranoid glycals: versatile synthons for stereoselective synthesis of 4'-thionucleosides.

Beta-anomers of 4'-thionucleosides have been synthesized stereoselectively, through PhSeCl- or N-iodosuccimide (NIS)-initiated electrophilic glycosidation to 3,5-O-(di-t-butylsilylene)-4-thiofuranoid glycal (1). This synthetic method has been applied to the synthesis of those analogues branched at the anomeric position using 1-C-carbon-substituted 3,5-O-(tetraisopropyldisiloxane-1,3-diyl)-4-thiofuranoid glycals (11-14) prepared based on lithiation of 10.

Furans↗
PubMed1999

Novel 6-azapyrimidine-2'-deoxy-4'-thionucleosides: synthesis, biological evaluation and conformational analysis.

We report the synthesis of novel 1-(2'-deoxy-4'-thio-beta-D-erythro-pentofuranosyl)-(6-azapyrimidine) nucleosides and the subsequent preparation of a series of N3-substituted analogues. All the novel compounds were evaluated against a range of viruses, however they lacked any measurable activity. The lack of anti-herpetic activity may be a result of the parent nucleoside having poor affinity for herpes simplex virus type 1 thymidine kinase. Conformational analysis of the parent nucleoside showed a twist (3T2) sugar conformation commonly displayed by 2'-deoxy-4'-thionucleosides and the anti-human immunodeficiency virus type 1 agents zidovudine and 3'-fluoro-ddT.

Animals↗
PubMed2002

Stereoselective synthesis and antiviral activity of D-2',3'-didehydro-2',3'-dideoxy-2'-fluoro-4'-thionucleosides.

As 2',3'-didehydro-2',3'-dideoxy-2'-fluoronucleosides have exhibited interesting antiviral effects against HIV-1 as well as HBV, it is of interest to synthesize the isosterically substituted 4'-thionucleosides in which 4'-oxygen is replaced by a sulfur atom. To study structure-activity relationships, various pyrimidine and purine nucleosides were synthesized from the key intermediate (2R,4S)-1-O-acetyl-5-O-(tert-butyldiphenylsilyl)-2,3-dideoxy-2-fluoro-2-phenylselenyl-4-thio-beta-D-ribofuranoside 8, which was prepared from the 2,3-O-isopropylidene-D-glyceraldehyde 1 in 13 steps. The antiviral activity of the synthesized compounds were evaluated against HIV-1 in human peripheral blood mononuclear (PBM) cells, among which cytidine 17, 5-fluorocytidine 18, adenosine 24, and 2-fluoroadenosine 32 showed moderate to potent anti-HIV activities (EC(50) 1.3, 11.6, 8.1, and 1.2 microM, respectively). It is noteworthy that 2-fluoroadenosine analogue 32 showed antiviral potency as well as high cytotoxicity (IC(50) 1.5, 1.1, and 7.6 microM for PBM, CEM, and Vero, respectively) whereas no other compound showed cytotoxicity up to 100 microM. The cytidine 17 and 5-fluorocytidine 18 analogues showed significantly decreased antiviral activity against the clinically important lamivudine-resistant variants (HIV-1(M184V)), whereas the corresponding D-2'-Fd4 nucleosides showed limited cross-resistance. Molecular modeling studies demonstrated that the larger van der Waals radius as well as the close proximity to Met184 of the 4'-sulfur atom of D-2'-F-4'-Sd4C (17) may be the reasons for the decreased antiviral potency of synthesized 4'-thio nucleosides against the lamivudine-resistant variants (HIV-1(M184V)).

Animals↗
PubMed2003

Synthesis, anti-HIV activity, and molecular mechanism of drug resistance of L-2',3'-didehydro-2',3'-dideoxy-2'-fluoro-4'-thionucleosides.

beta-l-2',3'-Didehydro-2',3'-dideoxy-2'-fluoro-4'-thionucleosides (beta-l-2'-F-4'-S-d4Ns) have been synthesized and evaluated against HIV-1 in primary human lymphocytes. The key intermediate 8, which was prepared from 2,3-O-isopropylidene-l-glyceraldehyde 1 in 13 steps, was condensed with various pyrimidine and purine bases followed by elimination and deprotection to give the target compounds, beta-l-2'-F-4'-S-d4Ns (17-20 and 27-30). The antiviral activity of the newly synthesized compounds was evaluated against HIV-1 in human peripheral blood mononuclear (PBM) cells, among which the cytosine 17, 5-fluorocytosine 18, and adenine 27 derivatives showed potent anti-HIV activities (EC(50) = 0.12, 0.15, and 1.74 microM, respectively) without significant cytotoxicity up to 100 microM in human PBM, CEM, and Vero cells. The cytosine derivative 17 (beta-l-2'-F-4'-S-d4C), however, showed cross-resistance to a 3TC-resistant variant (HIV-1(M184V)). Molecular modeling studies suggest that the pattern of antiviral activity, similar to that of beta-l-2'-F-d4N, stemmed from their conformational and structural similarities. The isosteric substitution of sulfur for 4'-oxygen was well tolerated in the catalytic site of HIV-1 reverse transcriptase in the wild-type virus. However, the steric hindrance between the sugar moiety of the unnatural l-nucleoside and the side chains of Val184 of M184V RT in 3TC-resistant mutant HIV strains destabilizes the RT-nucleoside triphosphate complex, which causes the cross-resistance to 3TC (M184V mutant).

Animals↗