PMEDAP的药理活性研究进展

9-(2-磷酸甲氧乙基)-2,6-二氨基嘌呤(PMEDAP)是无环核苷酸类化合物,结构上与9-(2-磷酸甲氧乙基)腺嘌呤(PMEA)相似,具有更广更强的抗病毒活性,尽管其有一定的细胞毒性,在抗病毒感染及抗肿瘤等领域仍具有开发前景。本文概括了近20年来PMEDAP及其部分取代的衍生物在抗逆转录病毒(如艾滋病毒等)、肝炎病毒(如人和鸭乙肝病毒等)、疱疹病毒(如简单疱疹病毒1型和2型、人类疱疹病毒6、7、8型等)和其他动植物病毒(如香蕉条纹病毒、腺病毒等)活性的研究进展。PMEDAP在具有广谱抗病毒作用的同时,具有一定的细胞毒性,在抗肿瘤方面有很高的研究意义。本文综述了PMEDAP在抗肿瘤方面的研究进展及其可能的作用机制,并根据现有的构效研究对PMEDAP在抗病毒和抗肿瘤两个方向的进一步研究提出了展望。     

Design,Synthesis and Anti-HIV Activity of Homologous PMEA Derivatives

This article describes an efficient route for synthesizing novel cyclopropyl homologous PMEA analogues. The condensation of the bromide 8 with nucleosidic bases (A, U, T, C, 5-FU, G) under standard nucleophilic substitution and deprotection conditions, afforded the target phosphonic acid analogues 14～18 and 21. These compounds were evaluated for their potential antiviral properties against various viruses. Guanine derivative 21 showed significant antiviral activity.     

PMEA涂层技术在小婴儿体外循环中的应用研究

目的研究通过一些炎症、补体等指标的测定及临床效果来评价PMEA(Poly2methoxyethylacrylate)涂层管道在小婴儿体外循环手术中的生物相容性,为临床应用提供依据。方法将接受体外循环下修补的20例大型室间隔缺损合并肺动脉高压患儿随机分为PMEA涂层管道组(A组)和非涂层组(B组),每组10例。两组患儿一般资料相仿。所有患儿均在麻醉成功开胸前(T1)、体外循环30min(T2)、体外循环结束鱼精蛋白中和后(T3)、术后4h(T4)和术后24h(T5)5个时间点采取动脉血,测定血常规、C反应蛋白、白介素(IL)1B、IL-6、IL-8、IL-10、TNF-α、补体C3a、C5a、D二聚体和凝血功能。术前、术后24小时常规测定肝肾功能、白球蛋白及电泳、cTnI值,并进行术后机械通气时间、术后24h尿量、心包引流量、血制品用量、ICU滞留时间及术后肺功能比较。结果术后即刻、4h血小板计数A组明显高于B组(P<0.05)。各时间点白细胞计数、白介素(IL)-10、TNF-α无明显差异。IL-6在术后4h和24h、C反应蛋白、IL-1β、IL-8在术后24hA组升高低于B组(P<0.05)。补体C3a、C5a两组相仿,凝血功能测定术后即刻Fib含量A组高于B组(P<0.05)。术后肝肾功能两组相仿;而cTnI A组升高低于B组(P= 0.023)。术后机械通气气道峰压A组低于B组,术后肺功能好于B组。术后尿量、机械通气时间、ICU滞留时间相仿。A组心包引流量及血制品用量少于B组(P<0.05)。结论PMEA涂层体外循环管道具有良好的生物相容性,具有减轻体外循环诱发的全身炎症反应和保护血小板的作用,临床上体现出良好的结果和对肺功能的保护。     

In vivo effects of antiviral acyclic nucleoside phosphonate 9-[2-(phosphonomethoxy)ethyl]adenine (adefovir) on cytochrome P450 system of rat liver microsomes

Summary Interference of antiviral agent adefovir, i.e. 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) with microsomal drug metabolizing system was investigated in rats. The content of total liver cytochrome P450 (CYP) was lowered while that of its denaturated form, P420, was elevated in animals intraperitoneally treated with PMEA (25 mg/kg). Similar effect was observed after treatment with a prodrug of adevofir, adefovir dipivoxil (bisPOM-PMEA). The CYP2E1-dependent formation of 4-nitrocatechol from p-nitrophenol was diminished, though the specific activity of p-nitrophenol hydroxylase remained unchanged. PMEA had no influence on expression of CYP2E1 protein and mRNA and mRNAs of other P450 isoenzymes (1A1, 1A2, 2C11, 3A1, 3A2, and 4A1). It may be concluded that repeated systemic administration of higher doses of PMEA results in a partial degradation of rat CYP protein to inactive P420.     

Short Synthesis and Antiviral Activity of Acyclic Phosphonic Acid Nucleoside Analogues

An efficient route for synthesizing novel allylic and cyclopropanoid phosphonic acid nucleoside analogues is described. The condensation of the bromine derivatives 6 and 18 with nucleoside bases (A, U, T, C, G) under standard nucleophilic substitution and deprotection conditions, afforded the target phosphonic acid nucleoside analogues. These compounds were evaluated for their antiviral properties against various viruses. Cyclopropanoid phosphonic adenine nucleoside analogue 23 showed significant anti-HIV activity.     

Recognition of nucleoside monophosphate substrates by Haemophilus influenzae class C acid phosphatase

The e (P4) phosphatase from Haemophilus influenzae functions in a vestigial NAD⁺ utilization pathway by dephosphorylating nicotinamide mononucleotide to nicotinamide riboside. P4 is also the prototype of class C acid phosphatases (CCAPs), which are nonspecific 5′,3′-nucleotidases localized to the bacterial outer membrane. To understand substrate recognition by P4 and other class C phosphatases, we have determined the crystal structures of a substrate-trapping mutant P4 enzyme complexed with nicotinamide mononucleotide, 5′-AMP, 3′-AMP, and 2′-AMP. The structures reveal an anchor-shaped substrate-binding cavity comprising a conserved hydrophobic box that clamps the nucleotide base, a buried phosphoryl binding site, and three solvent-filled pockets that contact the ribose and the hydrogen-bonding edge of the base. The span between the hydrophobic box and the phosphoryl site is optimal for recognizing nucleoside monophosphates, explaining the general preference for this class of substrate. The base makes no hydrogen bonds with the enzyme, consistent with an observed lack of base specificity. Two solvent-filled pockets flanking the ribose are key to the dual recognition of 5′-nucleotides and 3′-nucleotides. These pockets minimize the enzyme's direct interactions with the ribose and provide sufficient space to accommodate 5′ substrates in an anti conformation and 3′ substrates in a syn conformation. Finally, the structures suggest that class B acid phosphatases and CCAPs share a common strategy for nucleotide recognition.