Synthesis, metabolic stability and antiviral evaluation of various alkoxyalkyl esters of cidofovir and 9-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine.
Synthesis, metabolic stability and antiviral evaluation of various alkoxyalkyl esters of cidofovir and 9-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine.
复制标题
西多福韦和9-(S)-[3-羟基-2-(膦酰甲氧基)丙基]腺嘌呤的各种烷氧基烷基酯的合成、代谢稳定性和抗病毒评价。
DOI：
10.1016/j.bmc.2011.03.034
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发表时间：
2011
影响因子：
3.5
通讯作者：
Hostetler,KarlY
中科院分区：
文献类型：
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作者：
Ruiz,Jacqueline;Beadle,JamesR;Buller,RMark;Schreiwer,Jill;Prichard,MarkN;Keith,KathyA;Lewis,KennethC;Hostetler,KarlY
西多福韦烷氧烷基酯（CDV）是一种口服活性药物，可抑制多种双链DNA （dsDNA）病毒的复制，包括天花病毒、牛痘病毒、痘痘病毒、单纯疱疹病毒、巨细胞病毒、腺病毒等。其中一种化合物hexadecyloxypropyl-CDV （HDP-CDV, CMX001）正处于临床开发阶段，用于预防和治疗痘病毒感染、疫苗接种并发症以及由巨细胞病毒、腺病毒、疱疹病毒和其他dsDNA病毒引起的感染。这类脂质类似物可能容易经历烷基部分的ω氧化，从而导致短链羧酸缺乏抗病毒活性。为了解决这一问题，我们合成了一系列烷基残基结构进行修饰的CDV和(S)-HPMPA的烷氧烷基或烷基甘油酯。在感染牛痘病毒、牛痘病毒或羊痘病毒的细胞中评估抗病毒活性。测定了大鼠、豚鼠、猴和人肝脏S9膜组分的代谢稳定性。所有化合物对感染牛痘、牛痘或羊痘的细胞均有显著的抗病毒活性。猴肝S9孵育时代谢稳定性最低，HDP- cdv和HDP-(S)- hpmpa迅速消失。当烷基链中存在ω-1甲基（15-甲基- hdp - cdv）或末端环丙基残基（14-环丙基-十四环氧基- cdv）时，猴子制剂的代谢稳定性显著提高。最稳定的化合物是1- o-十八烷基-2- o-苄基-sn-甘油-3- cdv (ODBG-CDV)，该化合物不被猴子肝脏S9广泛代谢。在大鼠、豚鼠或人类肝脏S9孵育中，大多数修饰过的抗病毒化合物相当稳定。
Alkoxyalkyl esters of cidofovir (CDV) are orally active agents which inhibit the replication of a variety of double stranded DNA (dsDNA) viruses including variola, vaccinia, ectromelia, herpes simplex virus, cytomegalovirus, adenovirus and others. One of these compounds, hexadecyloxypropyl-CDV (HDP-CDV, CMX001) is in clinical development for prevention and treatment of poxvirus infection, vaccination complications, and for infections caused by cytomegalovirus, adenovirus, herpesviruses and other dsDNA viruses. This class of lipid analogs is potentially prone to undergo omega oxidation of the alkyl moiety which can lead to a short chain carboxylic acid lacking antiviral activity. To address this issue, we synthesized a series of alkoxyalkyl or alkyl glycerol esters of CDV and (S)-HPMPA having modifications in the structure of the alkyl residue. Antiviral activity was assessed in cells infected with vaccinia, cowpox or ectromelia viruses. Metabolic stability was determined in S9 membrane fractions from rat, guinea pig, monkey and human liver. All compounds had substantial antiviral activity in cells infected with vaccinia, cowpox or ectromelia. Metabolic stability was lowest in monkey liver S9 incubations where rapid disappearance of HDP-CDV and HDP-(S)-HPMPA was noted. Metabolic stability in monkey preparations increased substantially when a ω-1 methyl group (15-methyl-HDP-CDV) or a terminal cyclopropyl residue (14-cyclopropyl-tetradecyloxypropyl-CDV) was present in the alkyl chain. The most stable compound was 1-O-octadecyl-2-O-benzyl-sn-glycero-3-CDV (ODBG-CDV) which was not metabolized extensively by monkey liver S9. In rat, guinea pig or human liver S9 incubations, most of the modified antiviral compounds were considerably more stable.
影响因子：
7.3
作者：
Beadle, JR;Wan, WB;Hostetler, KY
通讯作者：
Hostetler, KY
方便合成异甲基支链长链脂肪醛，已知对肉味有显着贡献
影响因子：
2.6
作者：
Y. Yuasa;H. Tsuruta
通讯作者：
H. Tsuruta
9-(S)-(3-羟基-2-膦酰基甲氧基丙基)腺嘌呤的潜在前药和代谢物的合成
影响因子：
--
作者：
I. Rosenberg;A. Holý
通讯作者：
A. Holý