- Development of new sulfur-containing conjugated compounds as anti-HCV agents
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Various conjugated compounds containing a coumarin moiety and a heterocyclic nucleus were synthesized. Their activity against hepatitis C virus was tested on subgenomic replicon replication in Huh 5-2 cells. Some heterobicycle-coumarin conjugates with the - S - CH2linker were found to possess appealing antiviral activities. The sulfur atom in these conjugated compounds was found to be an essential element to their antiviral activity. Copyright Taylor & Francis Group, LLC.
- Hwu, Jih Ru,Lin, Shu-Yu,Tsay, Shwu-Chen,Singha, Raghunath,Pal, Benoy K.,Leyssen, Pieter,Neyts, Johan
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- Electrophilic sulfhydration of 8-nitro-cGMP involves sulfane sulfur
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The formation of 8-SH-cGMP from the reaction between hydrogen sulfide and 8-nitro-guanosine-3′,5′-cyclic monophosphate in the presence of thiols does not take place by nucleophilic attack of the hydrosulfide anion, as previously proposed, but first involv
- Terzic,Padovani,Balland,Artaud,Galardon
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- Oxidation of 8-thioguanosine gives redox-responsive hydrogels and reveals intermediates in a desulfurization pathway
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A disulfide made by oxidation of 8-thioguanosine is a supergelator. The hydrogels are redox-responsive, as they disassemble upon either reduction or oxidation of the S-S bond. We also identified this disulfide, and 2 other compounds, as intermediates in oxidative desulfurization of 8-thioG to guanosine. This journal is
- Chen, Fu,Davis, Jeffery T.,Gutierrez, Osvaldo,Lee, Wes,Xiao, Songjun,Zavalij, Peter Y.
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supporting information
p. 6981 - 6984
(2020/07/14)
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- Absorption Characteristics and Quantum Yields of Singlet Oxygen Generation of Thioguanosine Derivatives
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6-Thioguanine (1a) is considered to be photochemotherapeutic due to its specific characteristics of photosensitivity to UVA light and singlet molecular oxygen generation. To extend its phototherapeutic ability, two related thioguanines, 8-thioguanine (2a) and 6,8-dithioguanine (3a), have been designed and explored. Since the solubility of these thioguanines in dehydrated organic solvents is too poor to study, their triacetyl-protected ribonucleosides, that is, 2′,3′,5′-tri-O-acetyl-6-thioguanosine (1c), 2′,3′,5′-tri-O-acetyl-8-thioguanosine (2c) and 2′,3′,5′-tri-O-acetyl-6,8-dithioguanosine (3c) were prepared and investigated. The absorption maxima of 1c, 2c and 3c in acetonitrile were found at longer wavelengths than that of unthiolated guanosine (4c). Especially, 3c has the longest wavelength for absorption maximum and the highest value in terms of molar absorption coefficient among all thionucleobases and thionucleosides reported. These absorption properties were also well reproduced by quantum chemical calculations. Quantum yields of singlet oxygen generation of 2c and 3c were determined by near-infrared emission measurements to be as large as that of 1c. These results suggest that the newly synthesized thioguanosines, in particular 3c, can be further developed as a potential photosensitive agent for light-induced therapies.
- Miyata, Shoma,Yamada, Takeshi,Isozaki, Tasuku,Sugimura, Hideyuki,Xu, Yao–Zhong,Suzuki, Tadashi
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p. 677 - 684
(2018/04/05)
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- High-throughput five minute microwave accelerated glycosylation approach to the synthesis of nucleoside libraries
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The Vorbrueggen glycosylation reaction was adapted into a one-step 5 min/130 °C microwave assisted reaction. Triethanolamine in acetontrile containing 2% water was determined to be optimal for the neutralization of trimethylsilyl inflate allowing for direct MPLC purification of the reaction mixture. When coupled with a NH3/methanol deprotection reaction, a high-throughput method of nucleoside library synthesis was enabled. The method was demonstrated by examining the ribosylation of 48 nitrogen containing heteroaromatic bases that included 25 purines, four pyrazolopyrimidines, two 8-azapurines, one 2-azapurine, two imidazopyridines, two benzimidazoles, three imidazoles, three 1,2,4-triazoles, two pyrimidines, two 3-deazapyrimidines, one quinazolinedione, and one alloxazine. Of these, 32 yielded single regioisomer products, and six resulted in separable mixtures. Seven examples provided inseparable regioisomer mixtures of -two to three compounds (16 nucleosides), and three examples failed to yield isolable products. For the 45 single isomers isolated, the average two-step overall yield ± SD was 26 ± 16%, and the average purity ± SD was 95 ± 6%. A total of 58 different nucleosides were prepared of which 15 had not previously been accessed directly from glycosylation/deprotection of a readily available base.
- Bookser, Brett C.,Raffaele, Nicholas B.
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p. 173 - 179
(2007/10/03)
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- 8-Substituted purine derivatives: a new class of lipid-lowering agents
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A series of purine derivatives have been prepared and their in vivo abilities to lower plasma total cholesterol and triglyceride levels, and to elevate high density lipoprotein (HDL) cholesterol levels in hyperlipemic rats have been tested.Some compounds, among which 8-propylthio>adenosine 31, 8--2-oxopropylthio>adenosine 33 and 8--2-hydrazonecarboxamidepropylthio>adenosine 36 appear to be the most interesting, have been found to have both the desired profile of activity and no hepatotoxicity, when administered po at 50, 100 or 300 mg/kg.Compounds 31, 33 and 36, orally tested at the same doses in the 15-d test, lower triglyceride and VLDL/LDL (very low density lipoprotein / low density lipoprotein) cholesterol levels by 10-33percent and 13-46percent, respectively, and increase HDL-associated cholesterol levels by 10-32percent.These molecules have been chosen for further pharmacological and toxicological evaluations. adenosine / purine / cholesterol / triglyceride / hypolipemic agent
- Vanotti, E.,Bani, M.,Favara, D.,Gobetti, M.,Lombroso, M.,et al.
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p. 287 - 294
(2007/10/02)
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- Small-molecule immunostimulants. Synthesis and activity of 7,8- disubstituted guanosines and structurally related compounds
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A series of 7,8-disubstituted guanosine derivatives was designed and prepared as potential B-cell-selective activators of the humoral immune response. These compounds were evaluated for their ability to act as B-cell mitogens and to augment the antibody response of B cells to sheep red blood cell (SRBC) challenge (adjuvanticity). In addition, they were tested for their ability to stimulate the natural killer (NK) cell response in murine in vitro cell assays. Certain of the compounds demonstrated in vivo activity when administered either intravenously, subcutaneously, or orally. Analogues with a medium-length alkyl chain (2-4 carbons, 5-7) on the 7-position of 7- alkyl-8-oxoguanosines were found to be particularly potent. Compounds bearing hydroxyalkyl, aminoalkyl, or substituted aminoalkyl substituents on this 7- position were weakly active. However, benzyl groups, including those substituted with heteroatoms (e.g., p-nitrobenzyl, 14), were active. Oxo, thioxo, and seleno groups on C-8 of the guanosine ring all imparted strong activity, whereas other larger substituents did not (e.g., N=CN). Stereochemical inversion of the 2'-hydroxyl on the ribose ring in this series, giving arabinose analogue 70, lessened activity. However, removal of the 2'-hydroxyl, either with (64) or without (73) removal of the 3'-hydroxyl, resulted in excellent activity and improved solubility; 64 also displayed good oral in vivo activity as well. A series of ketals involving the 2',3'- hydroxyls were prepared; certain of the nonpolar ketals (e.g., 48) were remarkably active, pointing to an ancillary hydrophobic binding region that can augment activity. 5'-Phosphate derivative 57 was fairly active, and acyclovir analogue 90 displayed good NK-selective activity; other N-9 sugar mimetics were also active (97-104), although this activity did not carry over into the human B-cell assay. A total of 80 compounds were prepared and evaluated for their immunostimulating activity. Within this group, compounds could be divided into those that were active in all three assays, those that displayed some measure of selectivity for the adjuvanticity assay, and those that preferentially activated NK responses. Because of its overall biological profile and ease of synthesis, 7-allyl-8-oxoguanosine (6; loxoribine, RWJ- 21757) was chosen for further development. It is among the most potent compounds evaluated in the three biological assays.
- Reitz,Goodman,Pope,Argentieri,Bell,Burr,Chourmouzis,Come,Goodman,Klaubert,Maryanoff,McDonnell,Rampulla,Schott,Chen
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p. 3561 - 3578
(2007/10/02)
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- 8-Substituted guanosine and 2'-deoxyguanosine derivatives as potential inducers of the differentiation of Friend erythroleukemia cells
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A variety of 8-substituted guanosine and 2'-deoxyguanosine derivatives were synthesized and tested as inducers of the differentiation of Friend murine erythroleukemia cells in culture. The most active agents in the guanosine series were 8-substituted -N(CH3)2, -NHCH3, -NH2, -OH, and -SO2CH3, which caused 68, 42, 34, 33, and 30% of erythroleukemia cells to attain benzidine positivity, a functional measure of maturation, at concentrations of 5, 1, 0.4, 5, and 5 mM, respectively. The 8-OH derivative of the 2'-deoxyguanosine series produced comparable activity, causing 62% benzidine-positive cells at a level of 0.2 mM. These findings indicate that 8-substituted analogues of guanosine and 2'-deoxyguanosine have the potential to terminate leukemia cell proliferation through conversion to end-stage differentiated cells.
- Lin,Cheng,Ishiguro,Sartorelli
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p. 1194 - 1198
(2007/10/02)
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