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1.
《Bioorganic & medicinal chemistry》2014,22(10):2896-2906
Even number fatty acid residues—docosanoyl (behenoyl) and stearoyl were selected for introduction to the N4-position of (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine) (HPMPC, cidofovir), and its 5-azacytosine counterpart, (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine) (HPMP-5-azaC) with the aim to prepare a new type of lipophilic prodrugs. The study on the influence of these modifications to the stability and biological activity of both antivirals was performed. Different reactivity of both systems towards acylation reactions was also found: the 4-NH2 group of cidofovir was more reactive compared to that of HPMP-5-azaC. In 5-azacytosine derivatives, we found mostly a destabilizing effect of the N4-acylation but this could be compensated by a positive influence of the esterification of the phosphonate group. Chemical stability of the 5-azacytosine moiety in the HPMP series is increasing in the following order: HPMP-5-azaC < cyclic HPMP-5-azaC < HPMP-5-azaC esters. From the view of prodrug development, the best chemical stability was observed in case of the double prodrug 7: the N4-behenoyl derivative of the hexadecyloxyethyl ester of cyclic HPMP-5-azaC. The free phosphonic acid (N4-behenoyl-HPMPC) appeared to be a more potent and selective inhibitor of herpesvirus replication than the parent HPMPC derivative. 相似文献
2.
Marcela Krečmerová Milena Masojídková Antonín Holý 《Bioorganic & medicinal chemistry》2010,18(1):387-395
Two methods for preparation of 6-substituted derivatives of anti DNA-viral agent 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine (HPMP-5-azaC) were developed: (1) ammonia mediated ring-opening reaction of diisopropyl esters of HPMP-5-azaC (4) to carbamoylguanidine derivatives followed by ring-closure reaction with orthoesters and (2) condensation reaction of 6-substituted 5-azacytosines with diisopropyl (1S)-[2-hydroxy-1-tosyloxymethyl)ethoxy]methylphosphonate (15). Deprotection of diisopropyl esters to free phosphonic acids was performed with bromotrimethylsilane in acetonitrile followed by hydrolysis. In contrast to parent compound HPMP-5-azaC, a substantial decrease of antiviral activity in case of 6-substituted analogues occurred. Surprisingly, N-3 isomer of 6-methyl-HPMP-5-azaC in the form of isopropyl ester revealed activity against RNA viruses (Sindbis virus). 相似文献
3.
Natacha Coen Sophie Duraffour Lieve Naesens Marcela Kre?merová Joost Van den Oord Robert Snoeck Graciela Andrei 《Journal of virology》2013,87(22):12422-12432
Acyclic nucleoside phosphonates (ANPs), such as (S)-1-[(3-hydroxy-2-phosphonomethoxy)propyl)]cytosine (HPMPC), are an important group of broad-spectrum antiviral agents with activity against DNA viruses. In this report, we present the in vitro potencies of novel ANPs against gammaherpesviruses, including Kaposi''s sarcoma-associated herpesvirus, Epstein-Barr virus (EBV), and three animal gammaherpesviruses. 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine (HPMP-5-azaC), (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-3-deazaadenine (3-deaza-HPMPA), and their cyclic derivatives have emerged as highly potent antigammaherpesvirus agents. Interestingly, cyclic prodrugs of ANPs exhibited reduced activities against EBV strain P3HR-1, but not against EBV strain Akata. Cell culture metabolism studies with HPMPC and cyclic HPMPC revealed that these differences were attributable to an altered drug metabolism in P3HR-1 cells after EBV reactivation and, more specifically, to a reduced hydrolysis of cyclic HPMPC by cyclic CMP phosphodiesterase. We did not correlate this effect with phosphodiesterase downregulation, or to functional mutations. Instead, altered cyclic AMP levels in P3HR-1 cells indicated a competitive inhibition of the phosphodiesterase by this cyclic nucleotide. Finally, both HPMPC and HPMP-5-azaC emerged as highly effective inhibitors in vivo through significant inhibition of murine gammaherpesvirus replication and dissemination. With the current need for potent antigammaherpesvirus agents, our findings underline the requirement of appropriate surrogate viruses for antiviral susceptibility testing and highlight HPMP-5-azaC as a promising compound for future clinical development. 相似文献
4.
Manfred Klaas Manorama C. John Dring N. Crowell Richard M. Amasino 《Plant molecular biology》1989,12(4):413-423
We have optimized conditions for demethylation of the genome and induction of a silent, hypermethylated T-DNA gene (ipt) by 5-azacytosine (5-azaCyt) derivatives in a suspension culture of tobacco cells. In this system, 5-azacytidine (5-azaC) is more effective in causing genomic demethylation and ipt gene induction than 5-azaCyt or 5-azadeoxycytidine (5-azadC). A single treatment with 2.5 M 5-azaC resulted in a maximal level of ipt gene induction without inhibiting cell growth. However, we could not reduce the level of genomic methylation below approximately 2/3 of that found in untreated controls, even after extensive 5-azaC treatment. Furthermore, remethylation of the genome occurred after removal of 5-azaC. The use of 5-azaC as an inducer of silent plant genes is discussed, along with differences in the response of plant and animal genomes to demethylating agents.Abbreviations C
cytidine
- Cyt
cytosine
- 5-azaCyt
5-azacytosine
- 5-azaC
5-azacytidine
- 5-azadC
5-azadeoxycytidine
- m5Cyt
5-methylcytosine 相似文献
5.
5-氮胞苷对贵州小型猪淋巴细胞DNA损伤及修复的影响 总被引:1,自引:0,他引:1
目的 研究贵州小型猪淋巴细胞对化学物或药物引起的DNA损伤及修复影响的反应。方法 用单细胞凝胶电泳技术检测比较 5 氮胞苷对PHA刺激和未刺激淋巴细胞的DNA损伤及其修复过程。结果 5 氮胞苷引起未刺激淋巴细胞明显的DNA泳动 (彗星尾 ) ,经修复孵育 2h后 ,DNA泳动与孵育前比较无显著差异 ,而 5 氮胞苷引起的刺激细胞DNA泳动经 2h修复孵育后与孵育前比较显著减少。结论 5 氮胞苷引起贵州小型猪未刺激淋巴细胞DNA损伤经 2h孵育未能修复 ,而刺激细胞的DNA损伤明显修复。 相似文献
6.
DNA methylation levels in porcine fetal fibroblasts induced by an inhibitor of methylation, 5-azacytidine 总被引:1,自引:0,他引:1
Mohana Kumar B Jin HF Kim JG Song HJ Hong Y Balasubramanian S Choe SY Rho GJ 《Cell and tissue research》2006,325(3):445-454
Removal of the somatic DNA methylation pattern from donor cells and remodeling of embryonic status have been suggested as integral processes for successful nuclear transfer (NT) reprogramming. This study has investigated the effects of 5-azacytidine (5-azaC), a DNA methylation inhibitor, on global methylation changes in porcine fetal fibroblasts (PFF); this may improve NT attributable to the potential reprogramming of the methyl groups. PFF in 5th passage cultures were treated with 0, 0.5, 1.0, 2.0, and 3.0 μM 5-azaC for 96 h; 5-azaC inhibited the growth at all tested concentrations. At the higher concentrations of 5-azaC used, cells appeared to exhibit morphological changes and to become apoptotic as observed by TUNEL assay. Thus, cells were negatively affected by 5-azaC. Differences in cellular ploidy were also observed at higher concentrations. Analysis showed no considerable changes in the proportion of cells at the G1-phase of the cell cycle with 5-azaC concentrations. The fractional part of the methylated DNA of these cells was significantly reduced by 5-azaC treatment. Confocal microscopy confirmed the inhibition of methylation levels in PFF with increased concentrations of 5-azaC. Exposure to 5-azaC altered the expression of genes involved in imprinting (IGF2) or pro-apoptosis (BAX), whereas there was a reduction in the expression of the main enzyme responsible for replicating the DNA methylation pattern (DNMT1) and anti-apoptosis (BCL2L1). Therefore, 5-azaC induces a relative reduction in methylation in PFF, and cells treated with 0.5 μM 5-azaC may have enhanced potential for porcine NT.The financial support of BioGreen 21 (grant no. 100052004002000) and KOSEF (grant no. R05-2004-000-10702-0) in Korea is gratefully acknowledged. 相似文献
7.
8.
Effect of 5-azacytidine (5-azaC) on the induction of chromatid aberrations (CA) and sister-chromatid exchanges (SCE) 总被引:3,自引:0,他引:3
Experiments were carried out using human lymphocytes from a male donor in order to test the action of 5-azaC treatment on the induction of SCE and chromatid aberrations. The 5-azaC was found to increase the frequency of both baseline and MMC-induced SCEs. Using the same 5-azaC treatment conditions it was found that the frequency of X-ray-induced CA did not increase. 相似文献
9.
Genetic analysis of the 5-azacytidine sensitivity of Escherichia coli K-12. 总被引:3,自引:1,他引:2
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DNA containing 5-azacytidine (5-azaC) has been shown to form stable detergent-resistant complexes with cytosine methylases. We reasoned that if 5-azaC treatment causes protein-DNA cross-links in vivo, then mutations in DNA repair and recombination genes may increase the sensitivity of a cell to 5-azaC. We found that although recA (defective) and lexA (induction-negative) mutants of Escherichia coli were very sensitive to the drug, mutations in uvrA and ung genes had little effect on cell lethality. The sensitivity of recA strains to 5-azaC was dose dependent and was enhanced by the overproduction of a DNA cytosine methylase in the cell. Unexpectedly, a strain of E. coli carrying a recA mutation and a deletion of the DNA cytosine methylase gene (dcm) was found to be significantly sensitive to 5-azaC. Study of mutations in the pyrimidine salvage pathway of E. coli suggests that direct phosphorylation of 5-azaC, rather than phosphorylation of its degradation products, is largely responsible for the lethal effects of the drug. The addition of uracil to the growth medium has little effect on cell lethality of recA mutants, but it partially reversed the inhibition of cell growth caused by 5-azaC. This reversal of the bacteriostatic effects of the drug could not be achieved by adding cytosine or orotic acid to the growth medium and required the presence of functional UMP-pyrophosphorylase (gene upp) in the cell. 相似文献
10.
Free radicals generated by benzoyl peroxide-mediated catalytic decomposition of bromotrichloromethane (eg. trichloromethyl) were allowed to react under nitrogen or under air with uracil. Under nitrogen two reaction products were formed, one was identified as 5-chlorouracil and the other as a 5-bromouracil. Under air, besides the above two products other nine were also formed: 5,6-dihydrouracil; 5-hydroxyuracil; a chlorohydroxy adduct of uracil; a bromohydroxy derivative of uracil having the 5,6 bond in the saturated form; other bromohydroxy derivative of uracil having the double bond intact; 5,6-dihydroxyuracil; two dihalogenated hydroxylated uracil derivatives and one peak we were not able to descipher its structure. No single reaction product formed had carbon centered radicals (eg. trichloromethyl) added from CBrCl3 and consequently would be missed in 'in vivo' covalent binding studies where l4C haloalkane (CBrCl3 or carbon tetrachloride) were employed. If similar reaction products resulted during interaction of CBrCl3 reactive metabolites with uracil in RNAs, significant deleterious effects in their function would be expected. That possibility, however, remains to be established. 相似文献
11.
12.
Wei Jiang Ying-Qin Li Na Liu Ying Sun Qing-Mei He Ning Jiang Ya-Fei Xu Lei Chen Jun Ma 《PloS one》2014,9(4)
The radioresistance of tumor cells remains a major cause of treatment failure in nasopharyngeal carcinoma (NPC). Recently, several reports have highlighted the importance of epigenetic changes in radiation-induced responses. Here, we investigated whether the demethylating agent 5-azacytidine (5-azaC) enhances the radiosensitivity of NPC cells. The NPC cell lines CNE2 and SUNE1 were treated with 1 μmol/L 5-azaC for 24 h before irradiation (IR); clonogenic survival was then assessed. Tumor growth was investigated in a mouse xenograft model in vivo. The apoptosis, cell cycle progression and DNA damage repair were examined using flow cytometry, immunofluorescent staining and western blotting. Promoter methylation and the expression of four genes epigenetically silenced during the development of NPC were evaluated by pyrosequencing and real-time PCR. We found that pretreatment with 5-azaC significantly decreased clonogenic survival after IR compared to IR alone; the sensitivity-enhancement ratio of 5-azaC was 1.4 and 1.2 for CNE2 and SUNE1 cells, respectively. The combined administration of 5-azaC and IR significantly inhibited tumor growth in the mouse xenograft model, and enhanced radiation-induced apoptosis in vitro compared to 5-azaC alone or IR alone. 5-AzaC also decreased promoter methylation and upregulated the expression of genes which are epigenetically silenced both in vitro and in vivo in NPC. Thus, 5-azaC enhance the radiosensitivity of both the CNE2 and SUNE1 cell lines, possibly by altering DNA methylation levels and increasing the ability of irradiated cells to undergo apoptosis. The use of 5-azaC combined with IR maybe represent an attractive strategy for the treatment of NPC. 相似文献
13.
Güimil García R Brank AS Christman JK Marquez VE Eritja R 《Antisense & nucleic acid drug development》2001,11(6):369-378
The incorporation of 5-azacytosine residues into DNA causes potent inhibition of DNA (Cytosine-C5) methyltransferases. The synthesis of oligodeoxyribonucleotides incorporating single or multiple 5-aza-2'-deoxycytidine residues at precise sites was undertaken to generate an array of sequences containing the reactive 5-azacytosine base as specific target sites for enzymatic methylation. Preparation of these modified oligonucleotides requires the use of 2-(p-nitrophenyl)ethyloxycarbonyl (NPEOC) groups for the protection of exocyclic amino functions. These groups are removed under mild conditions, thus avoiding conventional protocols that are detrimental to the integrity of the 5-azacytosine ring. 相似文献
14.
Abd-Elrahman MI Ahmed MO Ahmed SM aboul-Fadl T El-Shorbagi A 《Biophysical chemistry》2002,97(2-3):113-120
Kinetics of solid state stability of seven derivatives of 3,5-disubstituted tetrahydro-2H-1,3,5-thiadiazine-2-thione (THTT) of glycine as a model for amino acids and peptide drugs were studied using differential scanning calorimetry (DSC). Each DSC curve for each derivative showed an endothermic peak followed by an exothermic one, which could be attributed to the melting and decomposition, respectively. The decomposition activation energy of each derivative was calculated using the Augis and Bennet, Kissinger equations and Mahadevan approximation. Also, the melting activation energies as well as the thermodynamic parameter (enthalpy) for the investigated derivatives were evaluated. The relative stability of the derivatives in the solid state according to the calculated values of the decomposition activation energy, frequency factors and half-life for each derivative could be determined. 相似文献
15.
This paper reports the synthesis of nucleotide antibiotics having N-acyl phosphoramidate linkages. The key reaction, the construction of the N-acyl phosphoramidate linkage was achieved by the reaction of nucleoside 5'-phosphoramidite derivatives with carboxamide derivatives in the presence of 5-(3,5-dinitrophenyl)-1H-tetrazole as a very effective activator. By use of this activator, Phosmidosine was synthesized by condensation of an appropriately protected 8-oxoadenosine 5'-O-phosphoramidite derivative with an N-protected prolinamide derivative. In the case of Agrocin 84, the two P-N bonds were constructed progressively. The N-acyl phosphoramidate linkage at the 5'-position of the ribose moiety was similarly synthesized. After phosphorylation of the amino group of the adenine moiety, a fully protected Agrocin 84 derivative, which would be converted to Agrocin 84, was successfully synthesized. 相似文献
16.
The stannic chloride catalyzed glycosylation of bis-tri-methylsilyl-6-methyl-5-azacytosine 2 with the halogenose 3 leading to the protected anomeric nucleosides 4a and 4b was investigated. Methanolysis of 4a and 4b afforded the corresponding free nucleosides 1a and 1b. Compounds 4a and 4b were also prepared by the isocyanate method via acetylamidinourea derivatives 6. Antileukemic activity in vitro and inhibition of growth of E. coli by the title compounds are reported. 相似文献
17.
Tiwari KN Cappellacci L Montgomery JA Secrist JA 《Nucleosides, nucleotides & nucleic acids》2003,22(12):2161-2170
1-O-Acetyl-2-deoxy-3,5-di-O-toluoyl-4-thio-D-erythro-pentofuranose and 2-deoxy-1,3,5-tri-O-acetyl-4-thio-L-threo-pentofuranose were coupled with 5-azacytosine to obtain alpha and beta anomers of nucleosides. All four nucleosides were reduced to the corresponding dihydro derivatives and deblocked to give target compounds. All eight target compounds were evaluated in a series of human cancer cell lines in culture. Only 2'-deoxy-4'-thio-5-azacytidine (3beta) was found to be cytotoxic in all the cell lines and was further evaluated in vivo. Details of the synthesis and biological activity are reported. 相似文献
18.
Effect of interaction between 5-azacytidine and DNA (cytosine-5) methyltransferase on C-to-G and C-to-T mutations in Escherichia coli. 总被引:2,自引:0,他引:2
The purpose of this study was to determine the effect of the Dcm cytosine methyltransferase on 5-azacytidine (5-azaC) mutagenesis in Escherichia coli. We used a Lac reversion assay to measure C-to-G and C-to-T mutations at a single, methylatable cytosine in the lacZ gene, in the presence and absence of Dcm. C-to-G mutations are stimulated by 5-azaC but are largely independent of Dcm. In contrast, C-to-T mutations are not stimulated by 5-azaC in either wild type or dcm cells. However, in cells which contain Dcm but are defective in very short patch repair, the normally high frequency of spontaneous C-to-T mutations is decreased by the analog in a dose-dependent manner. 相似文献
19.
Amanda J. Goddard Victor E. Marquez 《Nucleosides, nucleotides & nucleic acids》2013,32(5-6):1015-1018
Abstract The quantitative conversion of dihydro-5-azacytosine (5-DHAC) to 5-azacytosine (5-AC) has been accomplished in a dihydro-5-azacyti-dine/thymidine dimer (5-DHACpT). This newly developed procedure allows simi1ar possibilities with longer, 5-DHAC-modified oligodeoxynucleo-tides. 相似文献
20.
《Journal of Fermentation and Bioengineering》1995,79(6):617-619
The level of transient expression of the Escherichia coli β-galactosidase (β-Gal) gene transfected into three mammalian cell lines was enhanced by culturing the cells with 1–5 μM 5-azacytidine (5-azaC) after the transfection. This enhancement was similarly observed in four different transfection procedures tested. The enhancement of β-Gal expression was primarily due to the increase in the level of its mRNA. Since 5-azaC did not exhibit any obvious effect on the levels of endogenous gene products examined, it is suggested that 5-azaC may preferentially affect the transient expression of an exogenous gene. 相似文献