Acyclic nucleoside phosphonates containing the amide bond: hydroxy derivatives.

IF 1.7 4区化学 Q3 CHEMISTRY, MULTIDISCIPLINARY Monatshefte Fur Chemie Pub Date : 2019-01-01 Epub Date: 2019-03-01 DOI:10.1007/s00706-019-2351-y

Iwona E Głowacka, Dorota G Piotrowska, Graciela Andrei, Dominique Schols, Robert Snoeck, Andrzej E Wróblewski

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引用次数: 1

Abstract

Abstract: To study the influence of a linker rigidity and changes in donor-acceptor properties, three series of nucleotide analogs containing a P-X-HN-C(O)- residue (X=CH(OH)CH₂, CH(OH)CH₂CH₂, CH₂CH(OH)CH₂) as a replacement for the P-CH₂-O-CHR- fragment in acyclic nucleoside phosphonates, e.g., adefovir, cidofovir, were synthesized. EDC proved to provide good yields of the analogs from the respective ω-amino-1- or -2-hydroxyalkylphosphonates and nucleobase-derived acetic acids. New phosphorus-nucleobase linkers are characterized by two fragments of the restricted rotation within amide bonds and in four-atom units (P-CH(OH)-CH₂-N, P-CH(OH)-CH₂-C and P-CH₂-CH(OH)-C) in which antiperiplanar disposition of P and N/C atoms was deduced from ¹H and ¹³C NMR spectral data. The synthesized analogs P-X-HNC(O)-CH₂B [X=CH(OH)CH₂, CH(OH)CH₂CH₂, CH₂CH(OH)CH₂] appeared inactive in antiviral assays on a wide variety of DNA and RNA viruses at concentrations up to 100 μM, while two phosphonates showed cytostatic activity towards myeloid leukemia (K-562) and multiple myeloma cells (MM.1S) with IC₅₀ of 28.8 and 40.7 μM, respectively.

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含酰胺键的无环核苷膦酸盐;羟基衍生物。

摘要:为了研究连接体刚性的影响和供体-受体性质的变化，合成了三个系列的核苷酸类似物，其中含有P-X-HN-C(O)-残基(X=CH(OH)CH2, CH(OH)CH2CH2, CH2CH(OH)CH2)来取代无环核苷膦酸盐(如阿德福韦，西多福韦)中的P-CH2-O-CHR-片段。经证明，EDC能从ω-氨基-1-或-2-羟基烷基膦酸盐和核碱基衍生的乙酸中获得很好的类似物。新的磷核碱基连接体在酰胺键和四原子单元(P- ch (OH)-CH2-N, P- ch (OH)-CH2-C和P- ch2 - ch (OH)-C)中有两个受限旋转片段，其中P和N/C原子的反周面分布是由1H和13C NMR数据推断出来的。合成的P-X-HNC(O)-CH2B [X=CH(OH)CH2, CH(OH)CH2CH2, CH2CH(OH)CH2]在100 μM的浓度下对多种DNA和RNA病毒表现出无活性，而两种磷酸盐对髓性白血病(K-562)和多发性骨髓瘤细胞(MM.1S)表现出细胞抑制活性，IC50分别为28.8和40.7 μM。图形化的简介:

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来源期刊

Monatshefte Fur Chemie 化学-化学综合

CiteScore

3.70

自引率

5.60%

发文量

116

审稿时长

3.3 months

期刊介绍： "Monatshefte für Chemie/Chemical Monthly" was originally conceived as an Austrian journal of chemistry. It has evolved into an international journal covering all branches of chemistry. Featuring the most recent advances in research in analytical chemistry, biochemistry, inorganic, medicinal, organic, physical, structural, and theoretical chemistry, Chemical Monthly publishes refereed original papers and a section entitled "Short Communications". Reviews, symposia in print, and issues devoted to special fields will also be considered.