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A series of adenosine derivatives bearing a boron cluster were synthesized and evaluated for their cytotoxicity against primary peripheral mononuclear cells from the blood of 17 patients with leukemias (16 CLL and 1 very rare PLL), as well as from 5 healthy donors used as a control. Among the tested agents, two, i.e., compounds 1 and 2, displayed high in vitro cytotoxicity and proapoptotic potential on leukemic cells, with only scarce activity being seen against control cells. Biological tests related to apoptosis revealed the activation of the main execution apoptotic enzyme, procaspase-3, in CLL and PLL cells exposed to compounds 1 and 2. Moreover, the above compounds indicated high activity in the proteolysis of the apoptotic markers PARP-1 and lamin B1, fragmentation of DNA, and the induction of some changes in the expression of the Mcl-1, protein apoptosis regulator in comparison with control cells.  相似文献   
3.
Our chemo-enzymatic method was successfully applied to the synthesis of 2-chloro-2′-deoxyadenosine (CdA, cladribine) in two ways: 1) direct conversion of chemically synthesized 2-deoxy-α-D-ribose 1-phosphate (dRP) to CdA; 2) a two-step route via 9-(2-deoxy-β-D-ribos-1-yl)-2,6-dichloropurine (Cl2Pu-dR, 5).  相似文献   
4.
目的:使用表达N-脱氧核糖转移酶Ⅱ (Nucleoside deoxyribose transferase, NDT)的大肠杆菌重组工程菌E.coli BL21/pET-NDT,作为催化剂,合成克拉屈滨(Cladribine)。同时构建高通量的酶活筛选体系,利用其改造NDT,以期提高克拉屈滨的合成效率。方法:首先用野生型NDT催化克拉屈滨的合成。接着以黄嘌呤氧化酶和辣根过氧化物酶联合作用来检测NDT酶活。最后构建NDT随机突变体库,并筛选出突变体。结果:在10%DMSO的体系中,野生型NDT催化2-氯腺嘌呤合成克拉屈滨的转化率达到93%。同时使用构建的筛选体系在突变体库中筛选到了酶活发生改变的突变体。结论:本研究使用NDT作为催化剂,成功地一步合成了克拉屈滨。同时本研究构建的高通量筛选方法成功应用于改造NDT的酶学性质,为拓展NDT合成核苷类似物的能力提供了一种新的方法。  相似文献   
5.
2-Chloro-2′-deoxyadenosine (CdA) is a nucleoside analogue active in B-cell chronic lymphocytic leukemia (B-CLL). Although the mechanism of action of CdA has been extensively investigated in leukemic cells, the possibility that this nucleoside analogue interacts with the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway has never been explored. In this study, we show that CdA, at concentrations close to the IC50, activated the ERK pathway in the B-cell line EHEB. Because activation of this pathway is assumed to exert anti-apoptotic effect, we combined CdA with inhibitors of the ERK pathway. The latter were found to enhance CdA-induced apoptosis. These results suggest that the efficacy of CdA could be strengthened by combination with inhibitors of the ERK pathway.  相似文献   
6.
The effects of 2-chloro-2′-deoxyadenosine, β-D-arabinofuranosyl-2-fluoroadenine, and 5-aza-2′-deoxycytidine on promoter methylation of the selected tumor suppressor genes (i.e., ERα, BRCA1, E-cadherin, PTEN, and APC) were estimated using methylation-sensitive restriction analysis (MSRA) in K562 cells (human erythroleukemic cell line) and MCF-7 cells (human breast cancer cell line). In both cell lines all tested drugs completely reduced methylation of PTEN and APC promoters. The results indicate that the tested nucleoside analogues, which are known inhibitors of DNA synthesis, also are implicated in indirect (or direct in the case of 5-aza-dCyd) regulation of post-replicative DNA modifications (i.e., DNA methylation).  相似文献   
7.
The efficient synthesis of cladribine via the metal-free deoxygenation was developed. Using (Bu4N)2S2O8/HCO2Na instead of Bu3SnH/AIBN as deoxygenation system, cladribine could be obtained with good yield and even on tens of grams scales. The intermediates and product could be purified by simple work-up process and chromatography was avoided, which showed the good future for industrial applications.  相似文献   
8.
Various 2-substituted 2'-deoxyadenosines and 7-deazaadenosines have been synthesized. The phosphonate building block 9 of 2-chloro-7-deaza-2'-deoxyadenosine (7-deazacladribine; 2) was prepared by 4,4'-dimethoxytritylation of the parent nucleoside (-->7), followed by protection of the amino function with a formamidine residue (-->8). The latter was reacted with PCl3/N-methylmorpholine/1,2,4-triazole to give compound 9. Moreover, 2-methoxy-2'-deoxyadenosine (2'-deoxyspongosine; 1b) was converted into the fully protected derivative 12, which was then transformed into the 2-cyanoethyl phosphoramidite 14. Also the 2-(trifluoromethyl)-substituted 2'-deoxyadenosines 19-21 were prepared by glycosylation of the chromophore 16 with the halogenose 17, followed by one-pot deprotection and nucleophilic displacement of the 6-Cl substituent. The new DNA building blocks 9 and 14 were used--together with formerly prepared cladribine derivative 4--for solid-phase synthesis of a series of oligodeoxyribonucleotides. These were studied with respect to their thermal stability as well as of the base pairing mode (Watson-Crick vs. Hoogsteen) of modified bases.  相似文献   
9.
The aim of this study was to clarify the biochemical and molecular mechanisms behind the cross-resistance to nucleoside analogues (NAs) in four erythroleukemic cell lines with acquired resistance to the anthracycline daunorubicin and to the vinca alkaloid vincristine, expressing high levels of p-glycoprotein (P-gp, MDR1). All resistant strains exhibited cross-resistance to NA (cladribine and cytosine arabinoside)-induced apoptosis, assessed by caspase-3-like activation and were less sensitive to NA cytotoxicity in MTT assay. Real-time PCR and enzyme activity analysis showed reduced amounts of deoxycytidine kinase (35-80%) and elevated levels of 5'-nucleotidases (50-100%). The ratio 5'-nucleotidase to deoxycytidine kinase increased between 2.5- and 7.5-folds in resistant cells. This is in agreement with the observation that 5'-nucleotidase/deoxycytidine kinase ratio might be an important factor in predicting resistance to NAs. Implications of this finding for combining anthracyclines or vinca alkaloids with NAs toward leukemic cells are discussed.  相似文献   
10.
A new efficient route for the synthesis of 2-chloro-2′;-deoxyadenosine (Cladribine), CdA) has been developed. The key step of this method was selective deprotection of the acetyl group at the 2′ position; the 3′, 5′ acetyl groups were not affected. This can be accomplished efficiently with hydroxylamine hydrochloride and sodium acetate in pyridine. The 2′ hydroxyl group was removed by the Barton-McCombie reaction. Using this strategy, CdA was prepared in five steps and 31.0% yields.  相似文献   
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