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选用具有良好生物相容性的硫代修饰嵌段核酸为载体,将其非硫代修饰部分设计为靶向MUC-1蛋白的核酸适配体序列,同时在其硫代修饰部分通过硫代磷酸酯基团(Phosphorothioate,PS)接枝修饰四价顺铂前药,制备了两亲性核酸-顺铂前药缀合物MUC-1/PODNA-b-(PSDNA-g-Pt),并进一步自组装成类似球形核酸(Spherical nucleic acid,SNA)的含铂靶向纳米药物(MUC-1/Pt-SNAs).结果表明,该纳米药物递送体系载药率高、形貌稳定、分散性好,能够高效靶向MUC-1蛋白过表达的MCF-7乳腺癌细胞,并在体内外实验中表现出优异的抗肿瘤效果和极低的毒副作用. 相似文献
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Sylwia Studzińska Sandra Mounicou Joanna Szpunar Ryszard Łobiński Bogusław Buszewski 《Analytica chimica acta》2015
This text presents a novel method for the separation and detection of phosphorothioate oligonucleotides with the use of ion pair ultra high performance liquid chromatography coupled with inductively coupled plasma mass spectrometry The research showed that hexafluoroisopropanol/triethylamine based mobile phases may be successfully used when liquid chromatography is coupled with such elemental detection. However, the concentration of both HFIP and TEA influences the final result. The lower concentration of HFIP, the lower the background in ICP-MS and the greater the sensitivity. The method applied for the analysis of serum samples was based on high resolution inductively coupled plasma mass spectrometry. Utilization of this method allows determination of fifty times lower quantity of phosphorothioate oligonucleotides than in the case of quadrupole mass analyzer. Monitoring of 31P may be used to quantify these compounds at the level of 80 μg L−1, while simultaneous determination of sulfur is very useful for qualitative analysis. Moreover, the results presented in this paper demonstrate the practical applicability of coupling LC with ICP-MS in determining phosphorothioate oligonucleotides and their metabolites in serum within 7 min with a very good sensitivity. The method was linear in the concentration range between 0.2 and 3 mg L−1. The limit of detection was in the range of 0.07 and 0.13 mg L−1. Accuracy varied with concentration, but was in the range of 3%. 相似文献
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Ab initio HF and MP2 calculations on prototype model linkages of phosphorothioate DNA backbones illuminate the effects of phosphorothioation on electronic and structural properties of DNA backbone. The replacement of a bridging oxygen atom by sulfur in the phosphodiester linkage is energetically favored over that of replacement of a non-bridging oxygen atom. In phosphorothioate derivatives containing the P(OS)nb moiety, the non-bridging oxygen atom always bears a higher negative charge than the non-bridging sulfur. Additional calculations on protonated (neutral) adducts suggest that phosphorothioation of the phosphodiester linkage lowers its proton affinity. Moreover, protonation of the non-bridging oxygen atom at phosphorous is favored over the protonation of the non-bridging sulfur atom for linkages containing the P(OS)nb moiety. The ab initio calculated structural parameters are compared to the available crystallographic data of small phosphorothioate molecules and phosphorothioate oligodeoxynucleotides. These results have implications upon the biological activity of phosphorothioate DNA analogs. 相似文献
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Piotr Guga Boles?aw Karwowski Damian B?aziak Magdalena Janicka Andrzej Okruszek Beata R?bowska Wojciech J. Stec 《Tetrahedron》2006,62(11):2698-2704
The SP-isomer of 5′-OH-N4-benzoyl-2′-deoxycytidine-3′-O-(2-thio-4,4-pentamethylene-1,3,2-oxathiaphospholane) undergoes DBU-promoted intramolecular cyclization providing as a sole product SP-deoxycytidine cyclic 3′,5′-O,O-phosphorothioate. Unexpectedly, the RP-counterpart yields a mixture of products consisting of RP-deoxycytidine cyclic 3′,5′-O,O-phosphorothioate and macrocyclic oligo(deoxycytidine phosphorothioate)s. The results of molecular modeling indicate that the dychotomy observed for the RP substrate may result from remarkably higher energy of the corresponding transition states, caused by the presence of bulky ‘spiro’ pentamethylene substituent at the position C4 in the oxathiaphospholane ring. 相似文献
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本文对新合成的19个O-乙基-N-异丙基(取代硫脲基)硫代磷酰胺醋进行了质谱研究。讨论了P—N键的断裂,包括简单断裂和重排反应、失HS·反应及硫脲N上不同取代基的影响等问题。在亚稳态测定和高分辨精确质量测量的基础上得到了这类化合物的断裂规律和质谱特征。 相似文献
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Anna Leisvuori Zafar Ahmed Mikko Ora Leonid Beigelman Lawrence Blatt Harri Lönnberg 《Helvetica chimica acta》2012,95(9):1512-1520
2′‐C‐Methylnucleosides are known to exhibit antiviral activity against Hepatitis C virus. Since the inhibitory activity depends on their intracellular conversion to 5′‐triphosphates, dosing as appropriately protected 5′‐phosphates or 5′‐phosphorothioates appears attractive. For this purpose, four potential pro‐drugs of 2′‐C‐methylguanosine, i.e., 3′,5′‐cyclic phosphorothioate of 2′‐C‐methylguanosine and 2′‐C,O6‐dimethylguanosine, 1 and 2 , respectively, the S‐[(pivaloyloxy)methyl] ester of 2′‐C,O6‐dimethylguanosine 3′,5′‐cyclic phosphorothioate and the O‐methyl ester of 2′‐C,O6‐dimethylguanosine 3′,5′‐cyclic phosphate, 3 and 4 , respectively, have been prepared. 相似文献
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Synthetic oligonucleotides (ONs) are often prepared for development of therapeutic candidates. Among the modifications most often incorporated into therapeutic ONs are phosphorothioate (PT) linkages. The PT linkage introduces an additional chiral center at phosphorus to the chiral centers in D-ribose (and 2-deoxy-D-ribose) of the nucleic acid. Therefore, modified linkages can produce a diastereoisomer pair ([Rp] and [Sp]) at each PT linkage. These isomers are of identical length, sequence, charge and mass, and are not reliably separated by most chromatographic approaches (e.g., reversed phase chromatography) unless the ON is very short. Further these isomers are not distinguishable by single-stage mass spectrometry. During chromatography of a purified anti-NGF (nerve growth factor) aptamer containing 37 bases with 2 PT linkages by monolithic pellicular anion-exchange (pAE) column, we observed four components. The four components were postulated to be: (i) distinct folding conformations; (ii) fully and partially athioated aptamers; or (iii) PT diastereoisomers. Fractionation of the components, followed by de- and re-naturation failed to produce the original forms by refolding, eliminating option (i). Mass spectrometry of the fractionated, desalted samples revealed no significant mass differences, eliminating option (ii). Oxidative conversion of the PT to phosphodiester (PO) linkages in each of the purified components produced a single chromatographic peak, co-eluting with authentic PO aptamer, and having the PO aptamer mass. We conclude that the components resolved by pAE chromatography are diastereoisomers arising from the two PT linkages. Hence, pAE chromatography further enhances characterization of ON therapeutics harboring limited PT linkages and having up to 37 bases. 相似文献
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