Hydrolytic stability of nucleoside phosphotriesters derived from bis(hydroxymethyl)-1,3-dicarbonyl compounds and their congeners:: towards a novel pro-drug strategy for antisense oligonucleotides
Hydrolytic stability of nucleoside phosphotriesters derived from bis(hydroxymethyl)-1,3-dicarbonyl compounds and their congeners:: towards a novel pro-drug strategy for antisense oligonucleotides
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DOI：
10.1039/b101754n
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发表时间：
2001-01-01
期刊：
影响因子：
--
通讯作者：
Lönnberg, H
中科院分区：
文献类型：
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作者：
Ora, M;Mäki, E;Lönnberg, H
四种不同的核苷磷酸二酯保护基团衍生自双（羟甲基）-1,3-二羰基化合物及其同系物，已被制备并引入到5'-O-新戊酰胸苷3'-（2-甲氧基乙基）磷酸酯及其单硫代酸酯类似物中。具有2,2-双(乙氧基羰基)-3-(4,4'-二甲氧基三苯甲基氧基)丙基(1a)、2-氰基-2-甲氧基羰基-3-(4,4'-二甲氧基三苯甲基氧基)丙基(1b)、2,2-双(氰基)-3-(4,4'-二甲氧基三苯甲基氧基)丙基(1c)或已制备2-乙酰基-2-苯甲酰基-3-(4,4'-二甲氧基三苯甲氧基)丙基(1d)保护基。另外还合成了1b的O-和S-酯化的单硫代磷酸酯类似物。在酸性条件下除去二甲氧基三苯甲基后，每个脱三苯甲基化的保护基很容易通过涉及碱催化的逆羟醛缩合的反应从磷酸酯/硫代磷酸酯部分上裂解，并随后从形成的碳负离子中间体中消除磷酸二酯。氢氧根离子催化裂解的动力学已通过 HPLC 在 pH 范围 2-7 内进行了研究。在 pH 7 和 25°C 下，裂解半衰期从 0.3 秒（对于 1c）到 5500 秒（对于 1a）不等。结果证实，这些保护基团具有有前景的化学性质，可用于开发反义寡核苷酸前药策略。
Four different nucleoside phosphodiester protecting groups derived from bis(hydroxymethyl)-1,3-dicarbonyl compounds and their congeners have been prepared and introduced to 5'-O-pivaloylthymidine 3'-(2-methoxyethyl)phosphate and its monothioate analogs. Nucleoside phosphotriesters having either 2,2-bis(ethoxycarbonyl)-3-(4,4'-dimethoxytrityloxy)propyl (1a), 2-cyano-2-methoxycarbonyl-3-(4,4'-dimethoxytrityloxy)propyl (1b), 2,2-bis(cyano)-3-(4,4'-dimethoxytrityloxy)propyl (1c) or 2-acetyl-2-benzoyl-3-(4,4'-dimethoxytrityloxy)propyl (1d) protecting group have been prepared. Additionally were synthesized the O- and S-esterified phosphoromonothioate analogs of 1b. After removal of the dimethoxytrityl groupunder acidic conditions, each of the detritylated protecting groups is readily cleaved from the phosphate/thiophosphate moiety by a reaction suggested to involve a base-catalyzed retro-aldol condensation and following elimination of the phosphodiester from the formed carbanion intermediate. The kinetics of the hydroxide ion-catalyzed cleavage have been studied by HPLC over a pH range 2-7. The half-lives of the cleavage at pH 7 and 25 degreesC vary from 0.3 s (for 1c) to 5500 s (for 1a). The results confirm that these protecting groups have promising chemical properties for use in the development of antisense oligonucleotide pro-drug strategies.