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1.
Ramon Eritja Victor E. Marquez Ramon Güimil García 《Nucleosides, nucleotides & nucleic acids》2013,32(7-9):1111-1114
Abstract The preparation of a protected derivative of 5-aza-2′-deoxycytidine carrying the 2-(p-nitrophenyl)ethyl group is described. The new derivative is useful for the preparation of oligonucleotides containing 5-aza-2′-deoxycytidine using a special methodology that avoids the use of ammonia. 相似文献
2.
Jean M. J. Tronchet Mohammed Iznaden Françoise Barbalat-Rey Istvan Komaromi Naz Dolatshahi Gérald Bernardinelli 《Nucleosides, nucleotides & nucleic acids》2013,32(8):1737-1758
Abstract A series of 3′-branched 4′-azanucleoside analogues have been prepared. These compounds comprise three asymmetric atoms, two carbons and one nitrogen. They constitute nucleoside analogues imparted with a “flickering configuration”, the nitrogen inversion replacing a D-L epimerization of their natural congeners. The 1′,3′-cis and 1′,3′-trans isomers have been separated and their configuration established by 1H NMR and the X-ray diffraction structure of one crystalline example. The configurations of the frozen invertomers were assessed by low temperature 1H NMR experiments assisted by molecular mechanics simulations. None of these compounds exhibited any significant in vitro antiviral activity. 相似文献
3.
Manuel Luís Orta José Manuel Calderón-Monta?o Inmaculada Domínguez Nuria Pastor Estefanía Burgos-Morón Miguel López-Lázaro Felipe Cortés Santiago Mateos Thomas Helleday 《Nucleic acids research》2013,41(11):5827-5836
5-Aza-2′-deoxycytidine (5-azadC) is a DNA methyltransferase (DNMT) inhibitor increasingly used in treatments of hematological diseases and works by being incorporated into DNA and trapping DNMT. It is unclear what DNA lesions are caused by 5-azadC and if such are substrates for DNA repair. Here, we identify that 5-azadC induces DNA damage as measured by γ-H2AX and 53BP1 foci. Furthermore, 5-azadC induces radial chromosomes and chromatid breaks that depend on active replication, which altogether suggest that trapped DNMT collapses oncoming replication forks into double-strand breaks. We demonstrate that RAD51-mediated homologous recombination (HR) is activated to repair 5-azadC collapsed replication forks. Fanconi anemia (FA) is a rare autosomal recessive disorder, and deaths are often associated with leukemia. Here, we show that FANCG-deficient cells fail to trigger HR-mediated repair of 5-azadC-induced lesions, leading to accumulation of chromatid breaks and inter-chromosomal radial fusions as well as hypersensitivity to the cytotoxic effects of 5-azadC. These data demonstrate that the FA pathway is important to protect from 5-azadC-induced toxicity. Altogether, our data demonstrate that cytotoxicity of the epigenetic drug 5-azadC can, at least in part, be explained by collapsed replication forks requiring FA-mediated HR for repair. 相似文献
4.
5.
Xiangning Qiu Christoffer Hother Ulrik M. Ralfki?r Alexandra S?gaard Qianjin Lu Christopher T. Workman Gangning Liang Peter A. Jones Kirsten Gr?nb?k 《PloS one》2010,5(9)
Background
The hypomethylating agent 5-Azacytidine (5-Aza-CR) is the first drug to prolong overall survival in patients with myelodysplastic syndrome (MDS). Surprisingly, the deoxyribonucleoside analog 5-Aza-2′deoxycytidine (5-Aza-CdR) did not have a similar effect on survival in a large clinical trial. Both drugs are thought to exert their effects after incorporation into DNA by covalent binding of DNA methyltransferase (DNMT). While 5-Aza-CdR is incorporated into only DNA, 5-Aza-CR is also incorporated into RNA. Here, we have analyzed whether this difference in nucleic acid incorporation may influence the capacities of these drugs to regulate the expression of mRNA and microRNAs (miRNA), which may potentially affect the activities of the drugs in patients.Methodology/Principal Findings
A hematopoietic (HL-60; acute myeloid leukemia) and a solid (T24; transitional cell carcinoma) cancer cell line were treated with equitoxic doses of 5-Aza-CR and 5-Aza-CdR for 24 hrs, and the immediate (day 2) and lasting (day 8) effects on RNA expression examined. There was considerable overlap between the RNAs heritably upregulated by both drugs on day 8 but more RNAs were stably induced by the deoxy analog. Both drugs strongly induced expression of cancer testis antigens. On day 2 more RNAs were downregulated by 5-Aza-CR, particularly at higher doses. A remarkable downregulation of miRNAs and a significant upregulation of tRNA synthetases and other genes involved in amino acid metabolism was observed in T24 cells.Conclusions/Significance
Overall, this suggests that significant differences exist in the immediate action of the two drugs, however the dominant pattern of the lasting, and possible heritable changes, is overlapping. 相似文献6.
7.
Frank Seela Georg Becher Yaoming Chen 《Nucleosides, nucleotides & nucleic acids》2013,32(10-12):1581-1598
Abstract The fluorescence and the base pairing properties of 8-aza-7-deaza-2′-deoxyisoinosine (1) are described and compared with those of 2′-deoxyisoinosine (2). The corresponding phosphoramidites (11,12) are synthesized using the diphenyl-carbamoyl (DPC) residue for the 2-oxo group protection. The nucleosides 1 and 2 base pair with 2′-deoxy-5-methylisocytidine in DNA duplexes with antiparallel chain orientation and with 2′-deoxycytidine in a parallel DNA. These base pairs are less stable than the canonical dA-dT pair and that of 2′-deoxyinosine (4) with 2′-deoxycytidine. The fluorescence of the nucleosides 1 and 2 is quenched (~95%) in duplex DNA. The residual fluorescence is used to determine the Tm-values, which are found to be the same as determined UV-spectrophotometrically. 相似文献
8.
Danny P. C. McGee Chandra Vargeese Yansheng Zhai Gary P. Kirschenheuter Alecia Settle Colleen R. Siedem 《Nucleosides, nucleotides & nucleic acids》2013,32(6):1329-1339
Abstract The synthesis of 2′-amino-2′-deoxypyrimidine 5′-triphosphates is described. The 2′-amino-2′-deoxyuridine 5′-triphosphate is obtained from uridine in four steps with 25% overall yield. The 2′-amino-2′-deoxycytidine 5′-triphosphate is obtained from uridine in seven steps with 13% overall yield. 相似文献
9.
Yu-Bin Ding Chun-Lan Long Xue-Qing Liu Xue-Mei Chen Liang-Rui Guo Yin-Yin Xia Jun-Lin He Ying-Xiong Wang 《PloS one》2012,7(9)
Background
The DNA demethylating agent 5-aza-2′-deoxycytidine (5-aza-CdR) incorporates into DNA and decreases DNA methylation, sparking interest in its use as a potential therapeutic agent. We aimed to determine the effects of maternal 5-aza-CdR treatment on embryo implantation in the mouse and to evaluate whether these effects are associated with decreased levels of DNA methyltransferases (Dnmts) and three genes (estrogen receptor α [Esr1], progesterone receptor [Pgr], and homeobox A10 [Hoxa10]) that are vital for control of endometrial changes during implantation.Methods and Principal Findings
Mice treated with 5-aza-CdR had a dose-dependent decrease in number of implantation sites, with defected endometrial decidualization and stromal cell proliferation. Western blot analysis on pseudo-pregnant day 3 (PD3) showed that 0.1 mg/kg 5-aza-CdR significantly repressed Dnmt3a protein level, and 0.5 mg/kg 5-aza-CdR significantly repressed Dnmt1, Dnmt3a, and Dnmt3b protein levels in the endometrium. On PD5, mice showed significantly decreased Dnmt3a protein level with 0.1 mg/kg 5-aza-CdR, and significantly decreased Dnmt1 and Dnmt3a with 0.5 mg/kg 5-aza-CdR. Immunohistochemical staining showed that 5-aza-CdR repressed DNMT expression in a cell type–specific fashion within the uterus, including decreased expression of Dnmt1 in luminal and/or glandular epithelium and of Dnmt3a and Dnmt3b in stroma. Furthermore, the 5′ flanking regions of the Esr1, Pgr, and Hoxa10 were hypomethylated on PD5. Interestingly, the higher (0.5 mg/kg) dose of 5-aza-CdR decreased protein expression of Esr1, Pgr, and Hoxa10 in the endometrium on PD5 in both methylation-dependent and methylation-independent manners.Conclusions
The effects of 5-aza-CdR on embryo implantation in mice were associated with altered expression of endometrial Dnmts and genes controlling endometrial changes, suggesting that altered gene methylation, and not cytotoxicity alone, contributes to implantation defects induced by 5-aza-CdR. 相似文献10.
11.
干扰素是一类由干扰素诱生剂诱导生物机体有关细胞产生的糖蛋白,具有广泛的生物学活性,能抗病毒、抗癌肿、及免疫调节等功能。pppA_(2′)p_(5′)A_(2′)p_(5′)A(简称2′-5′P_3A_3)是由干扰素作用于细胞以后诱导产生的一种寡聚腺苷酸,它能表现干扰素的许多生物学功能,我们发现2′-5′P_3A_3能激活巨噬细胞,但激活特点与干扰素本身不同。干扰素激 相似文献
12.
Shan-Shan Gong Jian Sun Yue-Hai You Ji-Zong Chen Guo-Dong Liu 《Nucleosides, nucleotides & nucleic acids》2016,35(6):295-304
An efficient P(V)–N activation method for the synthesis of 5-carboxy-2′-deoxyuridine and 5-carboxy-2′-deoxycytidine triphosphates directly from the corresponding phosphoropiperidate precursors has been developed. 相似文献
13.
I. Basnak M. Sun T. A. Hamor F. Focher A. Verri S. Spadari 《Nucleosides, nucleotides & nucleic acids》2013,32(1-3):187-206
Abstract The synthesis and X-ray crystal structures of a series of 5-substituted-6-aza-2′-deoxyuridines is reported. These nucleoside analogues inhibit the phosphorylation of thymidine by HSV-1 TK but have no effect on the corresponding human enzyme. Detailed examination of one analogue proves it to be a competitive inhibitor of thymidine with a Ki of 0.34 μM and is a very poor substrate. The analogues are not substrates for the enzyme and also do not inhibit the degradation of thymidine by thymidine phosphorylase. Molecular modelling showed that the inhibitors fit well in the active site of HSV-1 TK, provided the conformation of the sugar moiety is the same for thymidine in the complex. 相似文献
14.
Cytomegalovirus (CMV) immediate early promoter is a powerful promoter frequently used for driving the expression of transgenes in mammalian cells. However, this promoter gradually becomes silenced in stably transfected cells. We employed Chinese Hamster Ovary (CHO) and human pancreatic cancer (Panc 1) cells stably tansfected with three glycogenes driven by a CMV promoter to study the activation of silenced glycogenes. We found that butyrate, tricostatin A (TSA), and 5-aza-2-deoxycytidine (5-Aza-dC) can activate these CMV-driven glycogenes. The increase in mRNA and protein of a glycogene occurred 8–10 h after butyrate treatment, suggesting an indirect effect of butyrate in the activation of the transgene. The enhanced expression of the trangenes by butyrate and TSA, known inhibitors of histone deacetylase, was independent of the transgene or cell type. However, the transgene can be activated by these two agents in only a fraction of the cells derived from a single clone, suggesting that inactivation of histone deacetylase can only partially explain silencing of the transgenes. Combination treatment of one or both agents with 5-Aza-dC, a known inhibitor of DNA methylase, resulted in a synergistic activation of the transgene, suggesting a cross-talk between histone acetylation and DNA demethylation. Understanding the mechanisms of the inactivation and reactivation of CMV promoter-controlled transgenes should help develop an effective strategy to fully activate the CMV promoter-controlled therapeutic genes silenced by the host cells. Published in 2005. 相似文献
15.
Subha R. Das 《Nucleosides, nucleotides & nucleic acids》2013,32(10):668-677
To extend the potential of 5′-noraristeromycin (and its enantiomer) as potential antiviral candidates, the enantiomers of the carbocyclic 5′-nor derivatives of 5′-methylthio-5′-deoxyadenosine and 5′-phenylthio-5′-deoxyadenosine have been synthesized and evaluated. None of the compounds showed meaningful antiviral activity. 相似文献
16.
P. P. Torrence D. Alster S. Huss G. Gosaelin J.-L. Imbach 《Nucleosides, nucleotides & nucleic acids》2013,32(1-2):521-522
Abstract Sequential substitution of xyloadenosine into the trimeric and tetrameric 2–5A cores1 allows evaluation of the importance of the 3′ hydroxyl groups to 2′5′-phosphodiesterase (PDE) activity. 相似文献
17.
Ravichandran Mahalingam Harish Ravivarapu Sanjeev Redkar Xiaoling Li Bhaskara R. Jasti 《AAPS PharmSciTech》2007,8(3):E28-E33
Delivery of 5-aza-2′-deoxycytidine (decitabine) across porcine buccal mucosa was evaluated as an alternative to the complex
intravenous infusion regimen currently used to administer the drug. A reproducible high-performance liquid chromatography
method was developed and optimized for the quantitative determination of this drug. Decitabine showed a concentration-dependent
passive diffusion process across porcine buccal mucosa. An increase in the ionic strength of the phosphate buffer from 100
to 400 mM decreased the flux from 3.57±0.65 to 1.89±0.61 μg/h/cm2. Trihydroxy bile salts significantly enhanced the flux of decitabine at a 100 mM concentration (P>.05). The steady-state flux of decitabine in the presence of 100 mM of sodium taurocholate and sodium glycocholate was 52.65±9.48
and 85.22±7.61 μg/cm2/h, respectively. Two dihydroxy bile salts, sodium deoxytaurocholate and sodium deoxyglycocholate, showed better enhancement
effect than did trihydroxy bile salts. A 38-fold enhancement in flux was achieved with 10 mM of sodium deoxyglycocholate.
Published: July 13, 2007 相似文献
18.
Kumi Nagaoka Yoshiaki Kitamura Yoshihito Ueno Yukio Kitade 《Bioorganic & medicinal chemistry letters》2010,20(3):1186-1188
Human ribonuclease L (RNase L), an interferon-induced endoribonuclease, becomes enzymatically active after binding to 2-5A. The 5′-phosphoryl group of 2-5A is reportedly necessary for the conformational change leading to RNase L activation. However, we found that 5′-O-dephosphorylated 2-5A tetramer analogs with 8-methyladenosine at the 2′-terminus were more effective as an activator of RNase L than the parent 2-5A tetramer. Introduction of 8-methyladenosine is thought to induce a dramatic shift of 2-5A in the binding site of RNase L. 相似文献
19.
《Nucleosides, nucleotides & nucleic acids》2013,32(5-8):1335-1338
Abstract Oligonucleotide analogues comprised of 2′-deoxy-2′-fluoro-β-D-arabinose units joined via P3′-N5′ phosphoramidate linkages (2′F-ANA5′N) were prepared for the first time. Among the compounds prepared were a series of 2′OMe-RNA-[GAP]-2′OMe-RNA ‘chimeras’, whereby the “GAP” consisted of DNA, DNA5′N, 2′F-ANA or 2′F-ANA5′N segments. The chimeras with the 2′F-ANA and DNA gaps exhibited the highest affinity towards a complementary RNA target, followed by the 5′-amino derivatives, i.e., 2′F-ANA > DNA > 2′F-ANA5′N > DNA5′N. Importantly, hybrids between these chimeras and target RNA were all substrates of both human RNase HII and E.coli RNase HI. In terms of efficiency of the chimera in recruiting the bacterial enzyme, the following order was observed: gap DNA > 2′F-ANA > 2′F-ANA5′N > DNA5′N. The corresponding relative rates observed with the human enzyme were: gap DNA > 2′F-ANA5′N > 2′F-ANA > DNA5′N. 相似文献
20.
《Nucleosides, nucleotides & nucleic acids》2013,32(5-8):1657-1659
Abstract 2′-2H- and 3′-2H-CDP were synthesized from 5′-MMT-3′-O-TBDMS and 2′,5′- O-diTBDMS cytidine derivatives, respectively, by oxidation followed by acidic removal of 5′-protection, reduction with [NaBD(OAc)3] and finally displacement of a tosyl group by pyrophosphate. 相似文献