Krečmerová Marcela, Pohl Radek, Masojídková Milena, Balzarini Jan, Snoeck Robert, Andrei Graciela
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, CZ-166 10, Prague 6, Czech Republic.
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, CZ-166 10, Prague 6, Czech Republic.
Bioorg Med Chem. 2014 May 15;22(10):2896-906. doi: 10.1016/j.bmc.2014.03.031. Epub 2014 Mar 26.
Even number fatty acid residues-docosanoyl (behenoyl) and stearoyl were selected for introduction to the N(4)-position of (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine) (HPMPC, cidofovir), and its 5-azacytosine counterpart, (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine) (HPMP-5-azaC) with the aim to prepare a new type of lipophilic prodrugs. The study on the influence of these modifications to the stability and biological activity of both antivirals was performed. Different reactivity of both systems towards acylation reactions was also found: the 4-NH2 group of cidofovir was more reactive compared to that of HPMP-5-azaC. In 5-azacytosine derivatives, we found mostly a destabilizing effect of the N(4)-acylation but this could be compensated by a positive influence of the esterification of the phosphonate group. Chemical stability of the 5-azacytosine moiety in the HPMP series is increasing in the following order: HPMP-5-azaC<cyclic HPMP-5-azaC<HPMP-5-azaC esters. From the view of prodrug development, the best chemical stability was observed in case of the double prodrug 7: the N(4)-behenoyl derivative of the hexadecyloxyethyl ester of cyclic HPMP-5-azaC. The free phosphonic acid (N(4)-behenoyl-HPMPC) appeared to be a more potent and selective inhibitor of herpesvirus replication than the parent HPMPC derivative.
选择偶数脂肪酸残基——二十二烷酰基（山嵛酰基）和硬脂酰基引入到（S）-1-[3-羟基-2-（膦酰甲氧基）丙基]胞嘧啶（HPMPC，西多福韦）及其5-氮杂胞嘧啶类似物（S）-1-[3-羟基-2-（膦酰甲氧基）丙基]胞嘧啶（HPMP-5-azaC）的N(4)位，旨在制备新型亲脂性前药。开展了这些修饰对两种抗病毒药物稳定性和生物活性影响的研究。还发现了两种体系对酰化反应的不同反应性：与HPMP-5-azaC相比，西多福韦的4-NH2基团反应性更强。在5-氮杂胞嘧啶衍生物中，我们发现N(4)-酰化大多具有去稳定化作用，但这可以通过膦酸酯基团酯化的积极影响来补偿。HPMP系列中5-氮杂胞嘧啶部分的化学稳定性按以下顺序增加：HPMP-5-azaC＜环状HPMP-5-azaC＜HPMP-5-azaC酯。从前药开发的角度来看，在双前药7的情况下观察到了最佳的化学稳定性：环状HPMP-5-azaC的十六烷氧基乙酯的N(4)-山嵛酰基衍生物。游离膦酸（N(4)-山嵛酰基-HPMPC）似乎比母体HPMPC衍生物更有效且更具选择性地抑制疱疹病毒复制。
