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Journal of Molecular Modeling Aug 2012The structures, energetics, as well as several important chemical parameters, of antiretroviral drugs - nucleoside reverse transcriptase inhibitors (NRTIs) - and natural...
The structures, energetics, as well as several important chemical parameters, of antiretroviral drugs - nucleoside reverse transcriptase inhibitors (NRTIs) - and natural deoxyribonucleosides in both neutral, and positively and negatively charged states, are investigated. These studies are carried out within the frame work of first-principles density-functional theory (DFT), using the Becke-Lee-Yang-Parr (BLYP) generalized gradient corrections to the local spin density approximation exchange and correlation energy, norm-conserving pseudopotentials and a plane-wave expansion of Kohn-Sham orbitals. Conceptual DFT is used to determine global and local chemical reactivity parameters. Our results are in good agreement with the best available experiments to date. The variation in the bond lengths and bond angles on cation formation indicates that the electron is lost from the base part of these molecules. Further, the presence of the deoxyribose sugar moiety lowers their ionization potential and increases their electron affinity, in comparison to the isolated DNA base. The effectiveness of the drug action in terminating the viral DNA chain, is explained using the global reactivity parameters, by comparing the reactivities of the drug molecules with those of the competing deoxyribonucleosides. The widely followed clinical practice, of avoiding the simultaneous administration of certain drugs, is also explained from the hardness and softness parameters. For most of the drug molecules, our study validates the generally accepted wisdom, that monophosphorylation is the crucial reaction step in the phosphorylation reaction in DNA nucleotide synthesis.
Topics: Algorithms; Computer Simulation; Deoxyribonucleosides; Models, Molecular; Quantum Theory; Reverse Transcriptase Inhibitors
PubMed: 22434310
DOI: 10.1007/s00894-012-1391-6 -
Bioorganic & Medicinal Chemistry Sep 2012A series of novel sugar-modified derivatives of cytostatic 7-hetaryl-7-deazaadenosines (2'-C-methylribonucleosides, 2'-deoxy-2'-fluoroarabinonucleosides,...
Sugar-modified derivatives of cytostatic 7-(het)aryl-7-deazaadenosines: 2'-C-methylribonucleosides, 2'-deoxy-2'-fluoroarabinonucleosides, arabinonucleosides and 2'-deoxyribonucleosides.
A series of novel sugar-modified derivatives of cytostatic 7-hetaryl-7-deazaadenosines (2'-C-methylribonucleosides, 2'-deoxy-2'-fluoroarabinonucleosides, arabinonucleosides and 2'-deoxyribonucleosides) was prepared and screened for biological activity. The synthesis consisted of preparation of the corresponding sugar-modified 7-iodo-7-deazaadenine nucleosides and their aqueous-phase Suzuki-Miyaura cross-coupling reactions with (het)arylboronic acids or Stille couplings with hetarylstannanes in DMF. The synthesis of 7-iodo-7-deazaadenine nucleosides was based on a glycosidation of 6-chloro-7-iodo-7-deazapurine with a suitable sugar synthon or on an interconversion of 2'-OH stereocenter (for arabinonucleosides). Several examples of 2'-C-Me-ribonucleosides showed moderate anti-HCV activities in a replicon assay accompanied by cytotoxicity. Several 7-hetaryl-7-deazaadenine fluoroarabino- and arabinonucleosides exerted moderate micromolar cytostatic effects. The most active was 7-ethynyl-7-deazaadenine fluoroarabinonucleoside which showed submicromolar antiproliferative activity. However, all the sugar-modified derivatives were less active than the parent ribonucleosides.
Topics: Antineoplastic Agents; Antiviral Agents; Arabinonucleosides; Carbohydrates; Deoxyribonucleosides; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HL-60 Cells; HeLa Cells; Hepacivirus; Humans; Microbial Sensitivity Tests; Molecular Structure; Structure-Activity Relationship; Virus Replication
PubMed: 22877872
DOI: 10.1016/j.bmc.2012.07.003 -
Nucleosides, Nucleotides & Nucleic Acids 20077-Deaza-7-fluoro-purine 2'-deoxynucleosides as well as 2'-deoxy-2'-fluoroarabinofuranosyl nucleosides 1-8 were synthesized. The fluorine atom was introduced on the base...
7-Deaza-7-fluoro-purine 2'-deoxynucleosides as well as 2'-deoxy-2'-fluoroarabinofuranosyl nucleosides 1-8 were synthesized. The fluorine atom was introduced on the base level with Selectfluor. Nucleobase-anion glycosylation was then employed to form the nucleosides. Properties of the fluorine compounds were studied in solution and in solid state. Compound 4a was incorporated into oligonucleotides where the stabilizing effect was observed.
Topics: Carbohydrates; Deoxyribonucleosides; Fluorine Compounds; Purines; Thermodynamics; Transition Temperature
PubMed: 18066864
DOI: 10.1080/15257770701490357 -
The Journal of Organic Chemistry Sep 2000The stereocontrolled, de novo syntheses of beta-2'-deoxy-, alpha-2'-deoxy-, beta-3'-deoxy-, and beta-2', 3'-dideoxyribonucleosides are described. Strategically protected...
The stereocontrolled, de novo syntheses of beta-2'-deoxy-, alpha-2'-deoxy-, beta-3'-deoxy-, and beta-2', 3'-dideoxyribonucleosides are described. Strategically protected ribose, arabinose, and xylose glycosylation precursors were synthesized bearing C2-esters capable of directing Vorbrüggen glycosylation. The key step is the regioselective deoxygenation of the desired hydroxyl group as either the benzoyl- or 3-(trifluoromethyl)benzoyl derivative. This deoxygenation is accomplished via a photoinduced electron-transfer (PET) mechanism using carbazole derivatives as the photosensitizer. The syntheses of the desired deoxynucleoside generally proceed in three steps from a common, readily available precursor.
Topics: Arabinonucleosides; Deoxyribonucleosides; Ribonucleosides; Stereoisomerism
PubMed: 10987930
DOI: 10.1021/jo0003652 -
Journal of Medicinal Chemistry Nov 2004A series of chlorinated indole nucleosides has been synthesized and tested for activity against human cytomegalovirus (HCMV) and herpes simplex virus type-1 (HSV-1) and...
A series of chlorinated indole nucleosides has been synthesized and tested for activity against human cytomegalovirus (HCMV) and herpes simplex virus type-1 (HSV-1) and for cytotoxicity. The 2'- and 5'-deoxy derivatives of the reported 3-formyl-2,5,6-trichloro-1-(beta-D-ribofuranosyl)indole (FTCRI) and 3-cyano-2,5,6-trichloro-1-(beta-D-ribofuranosyl)indole (CTCRI) were synthesized by either a modification of the appropriate 3-unsubstituted sugar-modified nucleoside analogues or by a glycosylation of 3-substituted heterocycles with a protected alpha-chlorosugar. The modifications were guided in part by structural similarity to the corresponding series of chlorinated benzimidazole ribonucleosides and the fact that 5'-deoxy analogues of 2,5,6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole (TCRB) are very active against HCMV. The 5'-deoxy analogues of FTCRI and CTCRI were nearly as active as FTCRI and CTCRI, suggesting that the chlorinated benzimidazole nucleosides and the chlorinated indole nucleosides act in a similar manner. This hypothesis was supported by time-of-addition studies using FTCRI and by the resistance of TCRB-resistant strains of HCMV to four different 3-substituted indole ribonucleosides. The 2'-deoxy analogues of the trichlorinated indole nucleosides also had potent antiviral activity, in contrast to decreased activity and selectivity observed for 2'-deoxy TCRB compared to TCRB. In addition, 3-acetyl-2,5,6-trichloro-1-(2-deoxy-beta-d-ribofuranosyl)indole was also active and much less cytotoxic (HCMV IC50 = 0.30 microM, HFF CC50 >100 microM) than previous analogues. None of the analogues had significant activity against HSV-1.
Topics: Antiviral Agents; Cell Line; Cytomegalovirus; Deoxyribonucleosides; Herpesvirus 1, Human; Humans; Indoles; Molecular Conformation; Stereoisomerism; Structure-Activity Relationship
PubMed: 15509176
DOI: 10.1021/jm0400606 -
Nucleic Acids Research. Supplement... 2003We developed a novel method for the highly chemo- and regioselective phosphitylation of the 5'-hydroxy group of 2'-deoxyribonuleosides with bis(O-tert-butyl)...
We developed a novel method for the highly chemo- and regioselective phosphitylation of the 5'-hydroxy group of 2'-deoxyribonuleosides with bis(O-tert-butyl) N,N-diethylphosphoramidite. The tert-butyl groups introduced in the thymidine 5'-O-phosphite and 2'-deoxycytidine 5'-O-phosphite were simultaneously removed within 5 min by treatment with trimethylsilyl triflate in acetonitrile to give the corresponding H-phosphonate monoesters without any side reactions.
Topics: Deoxyribonucleosides; Phosphites
PubMed: 14510382
DOI: 10.1093/nass/3.1.65 -
Physical Chemistry Chemical Physics :... Apr 2019Computations using the combined quantum mechanical/molecular mechanical (QM/MM) method were performed to investigate excess electron attachment to and detachment from...
Computations using the combined quantum mechanical/molecular mechanical (QM/MM) method were performed to investigate excess electron attachment to and detachment from aqueous deoxyribonucleosides (dRNs). The QM/MM vertical electron affinities (VEAs) of four dRNs are higher than the values of the corresponding nucleobases by ∼0.20 eV. The QM/MM diabatic electron affinities (AEAs) are much larger than the calculations of the implicit solvent model. Bulk water induces evident VEA and AEA increases and boosts the vertical detachment energies by over 1.20 eV. It affects excess electron attachment to and detachment from aqueous dRNs and stabilizes the anions. Moreover, the water molecules around deoxyadenosine (dA) anions form intermolecular hydrogen bonds with dA and break the intramolecular hydrogen bond of dA which had been found in the gas structure. In vertical electron attachment, ∼50% of excess electrons would be delocalized over the water molecules around the dRNs. The anionic structural relaxations cause the transfer of ∼-0.30 e excess electrons from the water molecules to the dRN nucleobases. However, the main excess electrons (∼-0.76 e) would be localized on dRN nucleobases in the stable anionic structure.
Topics: Anions; DNA; Deoxyadenosines; Deoxyribonucleosides; Electrons; Hydrogen Bonding; Models, Molecular; Solvents; Water
PubMed: 30984941
DOI: 10.1039/c9cp00536f -
Mutagenesis Sep 2010Monitoring oxidative stress in vivo is made easier by the ability to use samples obtained non-invasively, such as urine. The analysis of DNA oxidation, by measurement of...
Monitoring oxidative stress in vivo is made easier by the ability to use samples obtained non-invasively, such as urine. The analysis of DNA oxidation, by measurement of oxidized 2'-deoxyribonucleosides in urine, particularly 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), has been reported extensively in the literature in many situations relating to various pathologies, populations and environmental exposures. Understanding the origins of urinary 8-oxodG, other than it simply being a marker of DNA oxidation or its synthetic precursors, is important to being able to effectively interpret differences in baseline urinary 8-oxodG levels between subject groups and changes in excretion. Diet and cell turnover play negligible roles in contributing to urinary 8-oxodG levels, leaving DNA repair as a primary source of this lesion. However, which repair processes contribute, and to what extent, to urinary 8-oxodG is still open to question. The most rational source would be the activity of selected members of the Nudix hydrolase family of enzymes, sanitizing the deoxyribonucleotide pool via the degradation of 8-oxo-7,8-dihydro-2'-deoxyguanosine-5'-triphosphate and 8-oxo-7,8-dihydro-2'-deoxyguanosine-5'-diphosphate, yielding mononucleotide products that can then be dephosphorylated to 8-oxodG and excreted. However, nucleotide excision repair (NER), transcription-coupled repair, nucleotide incision repair (NIR), mismatch repair and various exonuclease activities, such as proofreading function associated with DNA polymerases, can all feasibly generate initial products that could yield 8-oxodG after further metabolism. A recent study implying that a significant proportion of genomic 8-oxodG exists in the context of tandem lesions, refractory to repair by glycosylases, suggests the roles of NER and/or NIR remain to be further examined and defined as a source of 8-oxodG. 8-OxodG has been the primary focus of investigation, but other oxidized 2'-deoxyribonucleosides have been detected in urine, 2'-deoxythymidine glycol and 5-hydroxymethyl-2'-deoxyuridine; the origins of these compounds in urine, however, are presently even more speculative than for 8-oxodG.
Topics: 8-Hydroxy-2'-Deoxyguanosine; DNA; DNA Repair; Deoxyguanosine; Deoxyribonucleosides; Diet; Humans; Oxidation-Reduction
PubMed: 20522520
DOI: 10.1093/mutage/geq031 -
Journal of the American Society For... Jan 2010We determined the gas-phase acidities (DeltaH(acid)) of four deoxyribonucleosides, i.e., 2'-deoxyadenosine (dA), 2'-deoxyguanosine (dG), 2'-deoxycytidine (dC), and...
We determined the gas-phase acidities (DeltaH(acid)) of four deoxyribonucleosides, i.e., 2'-deoxyadenosine (dA), 2'-deoxyguanosine (dG), 2'-deoxycytidine (dC), and 2'-deoxythymidine (dT) by applying the extended kinetic method. The negatively charged proton-bound hetero-dimeric anions, [A - H - B](-) of the deoxyribonucleosides (A) and reference compounds (B) were generated under electrospray ionization conditions. Collision-induced dissociation spectra of [A - H - B](-) were recorded at four different collision energies using a triple quadrupole mass spectrometer. The abundance ratios of the individual monomeric product ions were used to determine the DeltaH(acid) of the deoxyribonucleosides. The obtained DeltaH(acid) value follows the order dA > dC > dT > dG. The DeltaG(acid) (298 K) values were determined by using DeltaG(acid) = DeltaH(acid) - TDeltaS(acid) where the DeltaH(acid) and DeltaS(acid) values were determined directly from the kinetic method plots. The DeltaH(acid) values were also predicted for the deoxyribonucleosides at the B3LYP/6-311+G**//B3LYP/6-311G** level of theory. The acidity trend obtained from the computational investigation shows good agreement with that obtained experimentally by the extended kinetic method. Theoretical calculations provided the most preferred deprotonation site as C5'-OH from sugar moiety in case of dA, and as -NH(2) (dC and dG) or -NH- (dT) from nitrogenous base moiety in the case of other deoxyribonucleosides.
Topics: Acids; Deoxyribonucleosides; Gases; Kinetics; Mass Spectrometry; Models, Molecular; Molecular Structure; Thermodynamics
PubMed: 19892566
DOI: 10.1016/j.jasms.2009.09.019 -
Biochemical Pharmacology Apr 1979
Topics: Animals; Cell Count; Cell Division; DNA, Neoplasm; Deoxyribonucleosides; Dideoxynucleosides; In Vitro Techniques; Leukemia L1210; Neoplasm Proteins; Pyrimidine Nucleosides; RNA, Neoplasm; Thymidine
PubMed: 444292
DOI: 10.1016/0006-2952(79)90292-2