The Experts below are selected from a list of 627 Experts worldwide ranked by ideXlab platform
Chung K. Chu - One of the best experts on this subject based on the ideXlab platform.
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asymmetric synthesis of 1 3 dioxolane pyrimidine nucleosides and their anti hiv activity
Journal of Medicinal Chemistry, 1992Co-Authors: H. O. Kim, Lak Shin Jeong, Raymond F. Schinazi, J. W. Beach, B. G. Choi, S K Ahn, Antonio J Alves, P Van Roey, Chung K. ChuAbstract:In order to study the structure-activity relationships of dioxolane nucleosides as potential anti-HIV agents, various enantiomerically pure dioxolane-pyrimidine nucleosides have been synthesized and evaluated against HIV-1 in human peripheral blood mononuclear cells. The enantiomerically pure key intermediate 8 has been synthesized in nine steps from 1,6-anhydro-D-mannose (1), which was condensed with 5-substituted pyrimidines to obtain various dioxolane-pyrimidine nucleosides. Upon evaluation of these compounds, Cytosine Derivative 19 was found to exhibit the most potent anti-HIV agent although it is the most toxic. The order of anti-HIV potency was as follows: Cytosine (beta-isomer) greater than thymine greater than Cytosine (alpha-isomer) greater than 5-chlorouracil greater than 5-bromouracil greater than 5-fluorouracil Derivatives. Uracil, 5-methylCytosine, and 5-iodouracil Derivatives were found to be inactive. Interestingly, alpha-isomer 20 showed good anti-HIV activity without cytotoxicity. As expected, other alpha-isomers did not exhibit any significant antiviral activity. (-)-Dioxolane-T was 5-fold less effective against AZT-resistant virus than AZT-sensitive virus.
David G Gorenstein - One of the best experts on this subject based on the ideXlab platform.
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base pairing properties of the oxidized Cytosine Derivative 5 hydroxy uracil
Biochemical and Biophysical Research Communications, 2008Co-Authors: Varatharasa Thiviyanathan, David E Volk, Anoma Somasunderam, Tapas K Hazra, Sankar Mitra, David G GorensteinAbstract:The most abundant base-substitution mutation resulting from oxidative damage to DNA is the GC to AT transition mutation. 5-hydroxyuracil (5-OHU), produced by the oxidative deamination of cystosine, has been established as the major chemical precursor for this most abundant transition mutation. Results from NMR spectroscopy and UV melting experiments show that 5-OHU would form the most stable pair with G, and the least stable pair with C. The hydroxyl group in the 5th position of the 5-OHU residue may play a role in increasing the stability of the 5-OHU:G pair over the normal Watson-Crick pair, the 5-OHU:A. The 5-OHU:C base pair would be least stable, and would destabilize the base-stacking in the duplex. Our results explain why certain DNA polymerases preferentially incorporate G opposite to 5-OHU over A and why C does not get incorporated against 5-OHU during DNA replication in vivo.
H. O. Kim - One of the best experts on this subject based on the ideXlab platform.
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asymmetric synthesis of 1 3 dioxolane pyrimidine nucleosides and their anti hiv activity
Journal of Medicinal Chemistry, 1992Co-Authors: H. O. Kim, Lak Shin Jeong, Raymond F. Schinazi, J. W. Beach, B. G. Choi, S K Ahn, Antonio J Alves, P Van Roey, Chung K. ChuAbstract:In order to study the structure-activity relationships of dioxolane nucleosides as potential anti-HIV agents, various enantiomerically pure dioxolane-pyrimidine nucleosides have been synthesized and evaluated against HIV-1 in human peripheral blood mononuclear cells. The enantiomerically pure key intermediate 8 has been synthesized in nine steps from 1,6-anhydro-D-mannose (1), which was condensed with 5-substituted pyrimidines to obtain various dioxolane-pyrimidine nucleosides. Upon evaluation of these compounds, Cytosine Derivative 19 was found to exhibit the most potent anti-HIV agent although it is the most toxic. The order of anti-HIV potency was as follows: Cytosine (beta-isomer) greater than thymine greater than Cytosine (alpha-isomer) greater than 5-chlorouracil greater than 5-bromouracil greater than 5-fluorouracil Derivatives. Uracil, 5-methylCytosine, and 5-iodouracil Derivatives were found to be inactive. Interestingly, alpha-isomer 20 showed good anti-HIV activity without cytotoxicity. As expected, other alpha-isomers did not exhibit any significant antiviral activity. (-)-Dioxolane-T was 5-fold less effective against AZT-resistant virus than AZT-sensitive virus.
Leutwyler Samuel - One of the best experts on this subject based on the ideXlab platform.
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Planarizing Cytosine: The S1 state structure, vibrations, and nonradiative dynamics of jet-cooled 5,6-trimethyleneCytosine
American Institute of Physics (AIP), 2020Co-Authors: Trachsel, Maria A., Lobsiger Simon, Schär Tobias, Blancafort San José Lluís, Leutwyler SamuelAbstract:We measure the S0 → S1 spectrum and time-resolved S1 state nonradiative dynamics of the “clamped” Cytosine Derivative 5,6-trimethyleneCytosine (TMCyt) in a supersonic jet, using two-color resonant two-photon ionization (R2PI), UV/UV holeburning, and ns time-resolved pump/delayed ionization. The experiments are complemented with spin-component scaled second-order approximate coupled cluster (SCS-CC2), time-dependent density functional theory, and multi-state second-order perturbation-theory (MS-CASPT2) ab initio calculations. While the R2PI spectrum of Cytosine breaks off ∼500 cm−1 above its 000 band, that of TMCyt extends up to +4400 cm−1 higher, with over a hundred resolved vibronic bands. Thus, clamping the Cytosine C5–C6 bond allows us to explore the S1 state vibrations and S0 → S1 geometry changes in detail. The TMCyt S1 state out-of-plane vibrations ν′1, ν′3, and ν′5 lie below 420 cm−1, and the in-plane ν′11, ν′12, and ν′23 vibrational fundamentals appear at 450, 470, and 944 cm−1. S0 → S1 vibronic simulations based on SCS-CC2 calculations agree well with experiment if the calculated ν′1, ν′3, and ν′5 frequencies are reduced by a factor of 2–3. MS-CASPT2 calculations predict that the ethylene-type S1 ⇝ S0 conical intersection (CI) increases from +366 cm−1 in Cytosine to >6000 cm−1 in TMCyt, explaining the long lifetime and extended S0 → S1 spectrum. The lowest-energy S1 ⇝ S0 CI of TMCyt is the “amino out-of-plane” (OPX) intersection, calculated at +4190 cm−1. The experimental S1 ⇝ S0 internal conversion rate constant at the S1(v′=0) level is kIC=0.98–2.2⋅108 s−1, which is ∼10 times smaller than in 1-methylCytosine and Cytosine. The S1(v′=0) level relaxes into the T1(3ππ*) state by intersystem crossing with kISC=0.41–1.6⋅108 s−1. The T1 state energy is measured to lie 24 580±560 cm−1 above the S0 state. The S1(v′=0) lifetime is τ=2.9 ns, resulting in an estimated fluorescence quantum yield of Φfl=24%. Intense two-color R2PI spectra of the TMCyt amino-enol tautomers appear above 36 000 cm−1. A sharp S1 ionization threshold is observed for amino-keto TMCyt, yielding an adiabatic ionization energy of 8.114±0.002 eVThe Bern group acknowledges support by the Schweizerische Nationalfonds (Project No. 200020-152816). L.B. acknowledges financial support from the Spanish Ministerio de Econom´ıa y Competitividad (CTQ2015-69363-P) and the Generalitat de Catalunya (2014SGR-2012
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Planarizing Cytosine: The S 1 state structure, vibrations, and nonradiative dynamics of jet-cooled 5,6-trimethyleneCytosine
'AIP Publishing', 2017Co-Authors: Trachsel, Maria A., Lobsiger Simon, Schär Tobias, Blancafort Lluís, Leutwyler SamuelAbstract:We measure theS0→S1spectrum and time-resolvedS1state nonradiative dynamics of the “clamped”Cytosine Derivative 5,6-trimethyleneCytosine (TMCyt) in a supersonic jet, using two-color resonanttwo-photon ionization (R2PI), UV/UV holeburning, and ns time-resolved pump/delayed ionization.The experiments are complemented with spin-component scaled second-order approximate cou-pled cluster (SCS-CC2), time-dependent density functional theory, and multi-state second-orderperturbation-theory (MS-CASPT2)ab initiocalculations. While the R2PI spectrum of Cytosine breaksoff∼500 cm1above its 000band, that of TMCyt extends up to +4400 cm1higher, with over a hun-dred resolved vibronic bands. Thus, clamping the Cytosine C5–C6bond allows us to explore theS1state vibrations andS0→S1geometry changes in detail. The TMCytS1state out-of-plane vibra-tionsν′1,ν′3, andν′5lie below 420 cm1, and the in-planeν′11,ν′12, andν′23vibrational fundamentalsappear at 450, 470, and 944 cm1.S0→S1vibronic simulations based on SCS-CC2 calculationsagree well with experiment if the calculatedν′1,ν′3, andν′5frequencies are reduced by a factorof 2–3. MS-CASPT2 calculations predict that the ethylene-typeS1S0conical intersection (CI)increases from +366 cm1in Cytosine to>6000 cm1in TMCyt, explaining the long lifetime andextendedS0→S1spectrum. The lowest-energyS1S0CI of TMCyt is the “amino out-of-plane”(OPX) intersection, calculated at +4190 cm1. The experimentalS1S0internal conversion rateconstant at theS1(v′=0) level iskIC=0.98–2.2·108s1, which is∼10 times smaller than in1-methylCytosine and Cytosine. TheS1(v′=0) level relaxes into theT1(3ππ∗) state by intersystemcrossing withkISC=0.41–1.6·108s1. TheT1state energy is measured to lie 24 580±560 cm1above theS0state. TheS1(v′=0) lifetime isτ=2.9 ns, resulting in an estimated fluorescencequantum yield ofΦfl=24%. Intense two-color R2PI spectra of the TMCyt amino-enol tautomersappear above 36 000 cm1. A sharpS1ionization threshold is observed for amino-keto TMCyt,yielding an adiabatic ionization energy of 8.114±0.002 eV
Varatharasa Thiviyanathan - One of the best experts on this subject based on the ideXlab platform.
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base pairing properties of the oxidized Cytosine Derivative 5 hydroxy uracil
Biochemical and Biophysical Research Communications, 2008Co-Authors: Varatharasa Thiviyanathan, David E Volk, Anoma Somasunderam, Tapas K Hazra, Sankar Mitra, David G GorensteinAbstract:The most abundant base-substitution mutation resulting from oxidative damage to DNA is the GC to AT transition mutation. 5-hydroxyuracil (5-OHU), produced by the oxidative deamination of cystosine, has been established as the major chemical precursor for this most abundant transition mutation. Results from NMR spectroscopy and UV melting experiments show that 5-OHU would form the most stable pair with G, and the least stable pair with C. The hydroxyl group in the 5th position of the 5-OHU residue may play a role in increasing the stability of the 5-OHU:G pair over the normal Watson-Crick pair, the 5-OHU:A. The 5-OHU:C base pair would be least stable, and would destabilize the base-stacking in the duplex. Our results explain why certain DNA polymerases preferentially incorporate G opposite to 5-OHU over A and why C does not get incorporated against 5-OHU during DNA replication in vivo.
