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11.
Karpeisky A Sweedler D Haeberli P Read J Jarvis K Beigelman L 《Bioorganic & medicinal chemistry letters》2002,12(22):3345-3347
2'-Deoxy-2'-N-phthaloyl nucleosides were prepared from arabino nucleosides by triflate displacement with phthalimide in the presence of DBU. The corresponding phosphoramidites suitable for automated oligonucleotide synthesis were also synthesized. The scalability of described procedures was demonstrated on a 100-g scale preparation of 2'-deoxy-2'-amino-C phosphoramidite. 相似文献
12.
Synthesis and biological activities of a phosphorodithioate analog of 2',5'-oligoadenylate. 下载免费PDF全文
L Beigelman J Matulic-Adamic P Haeberli N Usman B Dong R H Silverman S Khamnei P F Torrence 《Nucleic acids research》1995,23(19):3989-3994
To enhance the resistance of 2-5A (pppA2'p5'A2'p5'A) to degradation by exo- and endonucleases, a phosphorodithioate analog was synthesized using a solid-phase phosphite triester approach with N6-benzoyl-5'-O-dimethoxytrityl-3'-O-t-butyldimethylsilyladenosine 2'-[S-(beta-thiobenzoylethyl)-pyrrolidinophosphorothioamidit e]. 5'-Monophosphorylation was accomplished with 2-[2-(4,4'-dimethoxytrityloxy)-ethylsulfonyl]ethyl-(2-cyanoe thyl)-(N,N- diisopropyl)-phosphoramidite. The resulting product, p5'A2'(s2p)- 5'A2'(s2p)5'A, was approximately 10-fold less effective as an activator of purified human recombinant 2-5A-dependent RNase than was 2-5A itself. This loss of activation ability was related directly to the loss of binding ability of the phosphorodiothioate analog. As predicted, p5'A2'(s2p)5'A2' (s2p)5'A was stable to snake venom phosphodiesterase and the nucleolytic activities of both human lymphoblastoid CEM cell extracts and human serum, under conditions that led to facile degradation of parent 2-5A. This nuclease stability permitted the observation of the CEM cell extracts and human serum phosphatase activity which led to 5'-dephosphorylation of p5'A2'(s2p)5'A2'(s2p)5'A. 相似文献
13.
Synthesis of 2'-modified nucleotides and their incorporation into hammerhead ribozymes. 总被引:1,自引:1,他引:0 下载免费PDF全文
L Beigelman A Karpeisky J Matulic-Adamic P Haeberli D Sweedler N Usman 《Nucleic acids research》1995,23(21):4434-4442
Several 2'-modified ribonucleoside phosphoramidites have been prepared for structure-activity studies of the hammerhead ribozyme. The aim of these studies was to design and synthesize catalytically active and nuclease-resistant ribozymes. Synthetic schemes for stereoselective synthesis of the R isomer of 2'-deoxy-2'-C-allyl uridine and cytidine phosphoramidites, based on the Keck allylation procedure, were developed. Protection of the 2'-amino group in 2'-deoxy-2'-aminouridine was optimized and a method for the convenient preparation of 5'-O-dimethoxytrityl-2'-deoxy-2'-phthalimidouridine 3'-O-(2-cyanoethyl-N,N-diisopropylphosphoramidite) was developed. During the attempted preparation of the 2'-O-t-butyldimethylsilyl-3'-O-phosphoramidite of arabinouridine a reversed regioselectivity in the silylation reaction, compared with the published procedure, was observed, as well as the unexpected formation of the 2,2'-anhydronucleoside. A possible mechanism for this cyclization is proposed. The synthesis of 2'-deoxy-2'-methylene and 2'-deoxy-2'-difluoromethylene uridine phosphoramidites is described. Based on a '5-ribose' model for essential 2'-hydroxyls in the hammerhead ribozyme these 2'-modified monomers were incorporated at positions U4 and/or U7 of the catalytic core. A number of these ribozymes had almost wild-type catalytic activity and improved stability in human serum, compared with an all-RNA molecule. 相似文献
14.
Inhibition of vascular smooth muscle cell proliferation by ribozymes that cleave c-myb mRNA. 下载免费PDF全文
T C Jarvis L J Alby A A Beaudry F E Wincott L Beigelman J A McSwiggen N Usman D T Stinchcomb 《RNA (New York, N.Y.)》1996,2(5):419-428
Proliferation of injured smooth muscle cells contributes to the reocclusion or restenosis of coronary arteries that often occurs following angioplasty procedures. We have identified and optimized nuclease-resistant ribozymes that efficiently cleave c-myb RNA. Three ribozymes targeting different sites in the c-myb mRNA were synthesized chemically and delivered to rat aortic smooth muscle cells with cationic lipids; all three inhibited serum-stimulated cell proliferation significantly. RNA molecules with two base substitutions in the catalytic core that render the ribozyme catalytically inactive had little effect on smooth muscle cell proliferation. Ribozymes with scrambled binding arm sequences also failed to affect cell cycle progression of vascular smooth muscle cells. Furthermore, inhibition of rat smooth muscle cell proliferation correlated with a reduction in intact c-myb mRNA. Efficacy of the chemically-modified ribozyme was compared directly to phosphorothioate antisense oligodeoxynucleotides targeting the same site in the c-myb RNA; the ribozyme had superior efficacy and showed greater specificity than the antisense molecules. Exogenously delivered ribozymes also inhibited porcine and human smooth muscle cell proliferation effectively. Ribozymes targeting c-myb or other regulators of smooth muscle cell proliferation may represent novel therapeutics for the treatment of restenosis after coronary angioplasty. 相似文献
15.
Functional groups on the cleavage site pyrimidine nucleotide are required for stabilization of the hammerhead transition state. 总被引:2,自引:2,他引:0 下载免费PDF全文
N Baidya G E Ammons J Matulic-Adamic A M Karpeisky L Beigelman O C Uhlenbeck 《RNA (New York, N.Y.)》1997,3(10):1135-1142
The role of individual functional groups on cytidine 17 in the hammerhead ribozyme was assessed by introducing modified pyrimidines into two kinetically well-characterized hammerheads. As long as the pyrimide ring size was maintained, the modifications had no effect on substrate binding, suggesting that the C17-C3 hydrogen bond observed in the X-ray structure is energetically neutral. However, modification of the exocyclic amino group and the carbonyl of C17 reduced the cleavage rate significantly, indicating that these groups are important in stabilizing the transition-state structure. C17 modifications did not affect the ratio of the forward and reverse reaction rates. Thus, unlike that believed previously, C17 is another one of many hammerhead residues critical in maintaining its active structure. 相似文献
16.
17.
1,2-Dideoxyribose 5-O-succinate, a component of solid support employed in the synthesis of ribozymes, was synthesized from thymidine. The key step was elimination of nucleobase from 2 to afford glycal 3. A number of catalysts for this reaction were tested, resulting in improved and scaleable synthesis. Hydrogenation of the resulting glycal afforded 1,2-dideoxyribose derivative 4 in a high yield. 相似文献
18.
1-Deazaadenosine: synthesis and activity of base-modified hammerhead ribozymes. 总被引:5,自引:3,他引:2 下载免费PDF全文
The incorporation of 1-deazaadenosine (c1A, 1b) into a hammerhead ribozyme and the resulting catalytic activity is described. For this purpose the phosphoramidite 2a and the 3'-phosphonate 2b as well as Fractosil-linked 1-deazaadenosine (3b) were prepared. The methoxyacetyl group was used for the 6-amino group protection and the triisopropylsilyl residue was introduced as the 2'-OH protecting group. Replacement of residues A14and A15.1 of the hammerhead ribozyme by 1-deazaadenosine resulted in a significantly reduced catalytic activity. Substitution of the A6, A9 and A13 residues has only a minor influence. The findings observed on ribozymes modified with 1-deazaadenosine were compared with those containing other adenosine analogues. 相似文献
19.
Functionalized nucleoside 5'-triphosphates for in vitro selection of new catalytic ribonucleic acids
Matulic-Adamic J Daniher AT Karpeisky A Haeberli P Sweedler D Beigelman L 《Bioorganic & medicinal chemistry letters》2000,10(11):1299-1302
A series of novel 2'-modified nucleoside 5'-triphosphates was synthesized. The amino, imidazole, and carboxylate functionalities were attached to the 5-position of pyrimidine base of these molecules through alkynyl and alkyl spacers, respectively. Two different phosphorylation methods were used to optimize the yields of these highly modified triphosphates. 相似文献
20.
Matulic-Adamic J Daniher AT Karpeisky A Haeberli P Sweedler D Beigelman L 《Nucleosides, nucleotides & nucleic acids》2001,20(4-7):1113-1115
2'-Modified pyrimidine nucleoside 5'-triphosphates comprising amino, imidazole and carboxylate functionality attached to the 5-position of the base were synthesized. Two different phosphorylation methods were used to optimize the yields of these highly modified triphosphates. 相似文献