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Marco Garavelli - One of the best experts on this subject based on the ideXlab platform.
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uv induced long lived decays in solvated Pyrimidine Nucleosides resolved at the ms caspt2 mm level
Physical Chemistry Chemical Physics, 2018Co-Authors: Ana Julieta Pepino, Artur Nenov, Ivan Rivalta, Roberto Improta, Javier Segarramarti, Marco GaravelliAbstract:The most relevant ‘dark’ electronic excited states in DNA/RNA Pyrimidine Nucleosides are mapped in water employing hybrid MS-CASPT2/MM optimisations with explicit solvation and including the sugar. Conical intersections (CIs) between initially accessed bright 1ππ* and the lowest energy dark 1nπ* excited states, involving the lone pair localised on the oxygen and/or nitrogen atoms are characterised. They are found in the vicinities of the Franck–Condon (FC) region and are shown to facilitate non-adiabatic population transfer. The excited state population of the 1nOπ* state, localised in the carbonyl moiety on all Pyrimidine Nucleosides, is predicted to rapidly evolve to its minimum, displaying non-negligible potential energy barriers along its non-radiative decay, and accounting for the ps signal registered in pump–probe experiments as well as for an efficient population of the triplet state. Cytidine displays an additional 1nNπ* state localised in the N3 atom and that leads to its excited state minimum displaying large potential energy barriers in the pathway connecting to the CI with the ground state. Sugar-to-base hydrogen/proton transfer processes are assessed in solution for the first time, displaying a sizable barrier along its decay and thus being competitive with other slow decay channels in the ps and ns timescales. A unified deactivation scheme for the long-lived channels of Pyrimidine Nucleosides is delivered, where the 1nOπ* state is found to mediate the long-lived decay in the singlet manifold and act as the doorway for triplet population and thus accounting for the recorded phosphorescence and, more generally, for the transient/photoelectron spectral signals registered up to the ns timescale.
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UV-induced long-lived decays in solvated Pyrimidine Nucleosides resolved at the MS-CASPT2/MM level
Physical Chemistry Chemical Physics, 2018Co-Authors: Ana Julieta Pepino, Javier Segarra-martí, Artur Nenov, Ivan Rivalta, Roberto Improta, Marco GaravelliAbstract:The most relevant ‘dark’ electronic excited states in DNA/RNA Pyrimidine Nucleosides are mapped in water employing hybrid MS-CASPT2/MM optimisations with explicit solvation and including the sugar. Conical intersections (CIs) between initially accessed bright 1ππ* and the lowest energy dark 1nπ* excited states, involving the lone pair localised on the oxygen and/or nitrogen atoms are characterised. They are found in the vicinities of the Franck–Condon (FC) region and are shown to facilitate non-adiabatic population transfer. The excited state population of the 1nOπ* state, localised in the carbonyl moiety on all Pyrimidine Nucleosides, is predicted to rapidly evolve to its minimum, displaying non-negligible potential energy barriers along its non-radiative decay, and accounting for the ps signal registered in pump–probe experiments as well as for an efficient population of the triplet state. Cytidine displays an additional 1nNπ* state localised in the N3 atom and that leads to its excited state minimum displaying large potential energy barriers in the pathway connecting to the CI with the ground state. Sugar-to-base hydrogen/proton transfer processes are assessed in solution for the first time, displaying a sizable barrier along its decay and thus being competitive with other slow decay channels in the ps and ns timescales. A unified deactivation scheme for the long-lived channels of Pyrimidine Nucleosides is delivered, where the 1nOπ* state is found to mediate the long-lived decay in the singlet manifold and act as the doorway for triplet population and thus accounting for the recorded phosphorescence and, more generally, for the transient/photoelectron spectral signals registered up to the ns timescale.
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resolving ultrafast photoinduced deactivations in water solvated Pyrimidine Nucleosides
Journal of Physical Chemistry Letters, 2017Co-Authors: Ana Julieta Pepino, Artur Nenov, Roberto Improta, Marco Garavelli, Javier SegarramartiAbstract:For the first time, ultrafast deactivations of photoexcited water-solvated Pyrimidine Nucleosides are mapped employing hybrid QM(CASPT2)/MM(AMBER) optimizations that account for explicit solvation, sugar effects, and dynamically correlated potential energy surfaces. Low-energy S1/S0 ring-puckering and ring-opening conical intersections (CIs) are suggested to drive the ballistic coherent subpicosecond (<200 fs) decays observed in each Pyrimidine, the energetics controlling this processes correlating with the lifetimes observed. A second bright 1π2π* state, promoting excited-state population branching and leading toward a third CI with the ground state, is proposed to be involved in the slower ultrafast decay component observed in Thd/Cyd. The transient spectroscopic signals of the competitive deactivation channels are computed for the first time. A general unified scheme for ultrafast deactivations, spanning the sub- to few-picosecond time domain, is eventually delivered, with computed data that matches th...
Akira Matsuda - One of the best experts on this subject based on the ideXlab platform.
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Nucleosides and nucleotides 185 synthesis and biological activities of 4 alpha c branched chain sugar Pyrimidine Nucleosides
Journal of Medicinal Chemistry, 1999Co-Authors: Makoto Nomura, Satoshi Shuto, Takuma Sasaki, Motohiro Tanaka, Shuichi Mori, Shiro Shigeta, Akira MatsudaAbstract:A series of 4'alpha-C-branched-chain Pyrimidine Nucleosides was synthesized from 2'-deoxycytidine or uridine. In the 2'-deoxycytidine series, the substituent at the 4'alpha-position affected cytotoxicity against L1210 mouse leukemic cells in vitro in the order Me (23) > CN (22) > C(symbol)CH (21) > CH=CH(2) (19) > Et (24) > CH=CHCl (20). However, uridine and cytidine derivatives with ethynyl and cyano groups at the 4'alpha-position did not show any cytotoxicity. The antiviral activities of these Nucleosides against HSV-1, HSV-2, and HIV-1 in vitro were also examined. Compounds 22 and 23 showed antiviral activities against HSV-1 and HSV-2 without showing significant toxicity to the host cells (MRC-5 cells). Although almost all of the Nucleosides showed anti-HIV-1 activities, they were also cytotoxic to the host cells (MT-4).
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synthesis of l enantiomers of 4 thioarabinofuranosyl Pyrimidine Nucleosides
ChemInform, 1998Co-Authors: Hiroshi Satoh, Yuichi Yoshimura, Shinji Sakata, Shinji Miura, Haruhiko Machida, Akira MatsudaAbstract:l-Enantiomers of 4′-thioarabinofuranosyl Pyrimidine Nucleosides were synthesized from d-xylose. Methyl 2,3,5-tri-O-benzyl-d-xylofuranoside 6 was converted to the corresponding xylitol 7, which was treated with MsCl and then Na2S to give 1,4-anhydro-l-4-thioarabitol 8. As previously reported, Pummerer rearrangement of 8 followed by glycosylation with a silylated thymine and N4-acetylcytosine derivative and deprotection gave the corresponding α- and β-l-4′-thioarabinofuranosyl Pyrimidine Nucleosides.
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Nucleosides and nucleotides 124 chemical reactivity of the sugar moiety of 2 deoxy 2 methylidene Pyrimidine Nucleosides synthesis of 3 amino 2 3 dideoxy 2 methylidene Pyrimidine Nucleosides via 2 3 sigmatropic rearrangement of allylic selenides as po
Tetrahedron, 1994Co-Authors: Abdalla Elsayed A Hassan, Satoshi Shuto, Akira MatsudaAbstract:Abstract Nucleophilic substitution reactions of an allyl alcohol system in the 2′-deoxy-2′-methylidene Pyrimidine Nucleosides with various nucleophiles were investigated. The allyl alcohol system reacted with softer nucleophiles such as azide, thiophenoxide, and iodo anion through an SN2′ manner to afford 2′-substituted-methyl-2′,3′-didehydro-2′,3′-dideoxy Nucleosides, but with hard oxygen-nucleophiles such as benzoyloxy and phenoxide through an SN2 manner to afford 2′-deoxy-2′-methylidene-3′-substituted Nucleosides with inversion at the 3′-position. Based on this characteristic reactivity, 2′,3′-didehydro-2′,3′-dideoxy-2′-phenylselenomethyl Pyrimidine Nucleosides 16b and 16c were synthesized. These Nucleosides were converted into 3′-amino-2′,3′-dideoxy-2′-methylidene Pyrimidine Nucleosides 3b and 3c via oxidative [2,3]-sigmatropic rearrangement of the allylic selenides as a key step. The cytosine derivative 3a was also prepared from the corresponding uracil derivative.
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Nucleosides and nucleotides 104 radical and palladium catalyzed deoxygenation of the allylic alcohol systems in the sugar moiety of Pyrimidine Nucleosides 1
Nucleosides Nucleotides & Nucleic Acids, 1992Co-Authors: Akira Matsuda, Yuichi Yoshimura, Hitomi Okajima, Akira Masuda, Akio Kakefuda, Tohru UedaAbstract:Abstract New methods for the synthesis of 2′,3′-didehydro-2′,3′-dideoxy-2′ (and 3′)-methyl-5-methyluridines and 2′,3′-dideoxy-2′ (and 3′)-methylidene Pyrimidine Nucleosides have been developed from the corresponding 2′ (and 3′)-deoxy-2′ (and 3′)-methylidene Pyrimidine Nucleosides. Treatment of a 3′-deoxy-3′-methylidene-5-methyluridine derivative 8 with 1,1′-thiocarbonyldiimidazole gave the allylic rearranged 2′,3′-didehydro-2′,3′-dideoxy-3′-[(imidazol-1-yl)carbonylthiomethyl] derivative 24. On the other hand, reaction of 8 with methyloxalyl chloride afforded 2′-O-methyloxalyl ester 25. Radical deoxygenation of both 24 and 25 gave 26 exclusively. Palladium-catalyzed reduction of 2′,5′-di-O-acetyl-3′-deoxy-3′-methylidene-5-methyluridine (32) with triethylammonium formate as a hydride donor regioselectively afforded the 2′,3′-dideoxy-3′-methylidene derivative 35 and 2′,3′-didehydro-2′,3′-dideoxy-3′-methyl derivative 34 in a ratio of 95:5 in 78% yield. These reactions were used on the corresponding 2′-deoxy-2...
Anil Kumar - One of the best experts on this subject based on the ideXlab platform.
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Electron-Mediated Aminyl and Iminyl Radicals from C5 Azido-Modified Pyrimidine Nucleosides Augment Radiation Damage to Cancer Cells
Organic letters, 2018Co-Authors: Zhiwei Wen, Jufang Peng, Paloma R. Tuttle, Yaou Ren, Carol Garcia, Dipra Debnath, Sunny Rishi, Cameron G. Hanson, Samuel Ward, Anil KumarAbstract:Two classes of azido-modified Pyrimidine Nucleosides were synthesized as potential radiosensitizers; one class is 5-azidomethyl-2'-deoxyuridine (AmdU) and cytidine (AmdC), while the second class is 5-(1-azidovinyl)-2'-deoxyuridine (AvdU) and cytidine (AvdC). The addition of radiation-produced electrons to C5-azido Nucleosides leads to the formation of π-aminyl radicals followed by facile conversion to σ-iminyl radicals either via a bimolecular reaction involving intermediate α-azidoalkyl radicals in AmdU/AmdC or by tautomerization in AvdU/AvdC. AmdU demonstrates effective radiosensitization in EMT6 tumor cells.
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Electron-Mediated Aminyl and Iminyl Radicals from C5 Azido-Modified Pyrimidine Nucleosides Augment Radiation Damage to Cancer Cells
2018Co-Authors: Zhiwei Wen, Jufang Peng, Paloma R. Tuttle, Yaou Ren, Carol Garcia, Dipra Debnath, Sunny Rishi, Samuel Ward, Cameron Hanson, Anil KumarAbstract:Two classes of azido-modified Pyrimidine Nucleosides were synthesized as potential radiosensitizers; one class is 5-azidomethyl-2′-deoxyuridine (AmdU) and cytidine (AmdC), while the second class is 5-(1-azidovinyl)-2′-deoxyuridine (AvdU) and cytidine (AvdC). The addition of radiation-produced electrons to C5-azido Nucleosides leads to the formation of π-aminyl radicals followed by facile conversion to σ-iminyl radicals either via a bimolecular reaction involving intermediate α-azidoalkyl radicals in AmdU/AmdC or by tautomerization in AvdU/AvdC. AmdU demonstrates effective radiosensitization in EMT6 tumor cells
Chung K. Chu - One of the best experts on this subject based on the ideXlab platform.
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structure activity relationships of 1 2 deoxy 2 fluoro β l arabino furanosyl Pyrimidine Nucleosides as anti hepatitis b virus agents
Journal of Medicinal Chemistry, 1996Co-Authors: S B Pai, Y L Zhu, J S Lin, K Shanmuganathan, C Wang, H Kim, M G Newton, Yungchi Cheng, Chung K. ChuAbstract:Since 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil (L-FMAU) has been shown to be a potent anti-HBV agent in vitro, it was of interest to study the structure-activity relationships of related Nucleosides. Thus, a series of 1-(2-deoxy-2-fluoro-beta-L-arabinofuranosyl)Pyrimidine Nucleosides have been synthesized and evaluated for antiviral activity against HBV in 2.2.15 cells. For this study, L-ribose was initially used as the starting material. Due to the commercial cost of L-ribose, we have developed an efficient procedure for the preparation of L-ribose derivative 6. Starting from L-xylose, 6 was obtained in an excellent total yield (70%) through the pyridinium dichromate oxidation of the 3-OH group followed by stereoselective reduction with NaBH4. It was further converted to the 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-alpha-L-arabinofuranose (10), which was then condensed with various 5-substituted Pyrimidine bases to give the Nucleosides. Among the compounds synthesized, the lead compound, L-FMAU (13), exhibited the most potent anti-HBV activity (EC50 0.1 microM). None of the other uracil derivatives showed significant anti-HBV activity up to 10 microM. Among the cytosine analogues, the cytosine (27) and 5-iodocytosine (35) derivatives showed moderately potent anti-HBV activity (EC50 1.4 and 5 microM, respectively). The cytotoxicity of these nucleoside analogues has also been assessed in 2.2.15 cells as well as CEM cells. None of these compounds displayed any toxicity up to 200 microM in 2.2.15 cells. Thus, compound 13 (L-FMAU), 27, and 35 showed a selectivity of over 2000, 140, and 40, respectively.
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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.
Tadashi Miyasaka - One of the best experts on this subject based on the ideXlab platform.
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electrophilic addition to 4 thio furanoid glycal a highly stereoselective entry to 2 deoxy 4 thio Pyrimidine Nucleosides
Tetrahedron Letters, 1998Co-Authors: Kazuhiro Haraguchi, Ayako Nishikawa, Eiko Sasakura, Hiromichi Tanaka, Kazuo T Nakamura, Tadashi MiyasakaAbstract:Abstract 4-Thio furanoid glycals with different types of O -silyl protection have been prepared from benzyl 3,5-di- O -benzyl-2-deoxy-1,4-dithio-d- erythro -pentofuranoside. Face-selectivity for PhSeCl- or N -iodosuccimide-initiated addition of a Pyrimidine base to the thioglycal was found to be controlled by O -silyl protecting groups. Using the thioglycal protected with a 3,5- O -di- t -butylsilyl group, a highly stereoselective synthesis of β-2′-deoxy-4′-thio Pyrimidine Nucleosides has been accomplished.
