Prodrugs of Nucleoside Triphosphates as a Sound and Challenging Approach: A Pioneering Work That Opens a New Era in the Direct Intracellular Delivery of Nucleoside Triphosphates

Synthetic nucleosides, designed to mimic naturally occurring nucleosides, are important antiviral and anticancer chemotherapeutic agents. However, nucleosides are not active as such and need to be metabolized, step by step, to their corresponding active nucleoside triphosphates (NTPs). This is mediated by phosphorylating enzymes, mainly host cellular kinases with strong specificity for their substrates; in many cases, this specificity prevents efficient conversion into the NTPs. To circumvent this metabolic handicap, successful nucleo(s/t)ide prodrugs have been developed as a valuable concept in the design of effective drugs. The unique concept of the TriPPPro approach, developed by Chris Meier and colleagues, is a powerful tool for the intracellular delivery of active NTPs, bypassing all the phosphorylation steps required by nucleosides to yield the active NTP metabolites. This concept is illustrated herein with general examples.     

The ProTides Boom

The masking of nucleoside phosphate and phosphonate groups by an aryl motif and an amino acid ester, nowadays known as the ‘ProTide’ technology, has proven to be effective in the discovery of nucleotide therapeutics. Indeed, this technology, which was invented by Chris McGuigan in the early 1990s, has inspired the discovery of two FDA‐approved antiviral nucleotide drugs, and many more are currently undergoing (pre)clinical development. The usefulness of this technology in the discovery of nucleotide therapeutics is showcased in this Highlight by discussing the ProTides development and the various ProTides that have reached clinical trials.     

有机含磷化合物溶解度的测定与关联

报道了三苯基膦（TPP）、三（4-甲氧基苯基）膦（TMOPP）和三（4-甲氧基苯基）氧化膦（TMOPPO）的合成及溶解度的测定。并对溶解度和温度进行了关联,回归了溶解度的经验方程。     

海水中溶解有机磷化合物的生态效应

随着有机磷农药在农业中的广泛使用,入海后对海洋微藻和海洋动物构成威胁,影响到海洋初级生产。介绍了海水中溶解有机磷的生态意义及其实验室常用分析方法,重点分析其致毒机理,指出应合理处理有机磷农药。     

磷系化合物对丙烯酸酯聚合物阻燃与耐热性能的影响

通过对一系列含有不同比例的五氧化二磷、磷酸三甲苯酯/丙烯酸酯材料的燃烧性能与耐热性能测试,系统地研究了磷化合物的结构与含量对丙烯酸酯类聚合物的燃烧与耐热性的影响及相应的阻燃机理。     

磷矿中磷的测定方法初探

采用“以二甲酚橙为指示剂 ,用硝酸铋标准溶液直接滴定试液中的 PO43 -”的方法来测定磷矿中的磷     

黄磷罐区工艺设计中的安全性研究

文章依据黄磷物料的相关物理化学特性,对黄磷罐区工艺流程进行研究。重点讨论了黄磷储罐的设计安装形式、黄磷罐区的工艺设计、物料和公用工程管线设置、自控仪表设置以及其它安全设施方案,并做出相应分析。为黄磷罐区工艺设计提供借鉴和参考。     

有机磷化合物的结构与迟发性神经毒性关系的研究

有机磷化合物（包括Ｉ型和Ⅱ型）对人和其它脊椎动物诱导迟发性神经毒性,日益引起人们的关切。此类化合物种类繁多,结构各异。那么,哪些可能产生迟发性神经毒性？本文就此问题论述了该类化合物的结构与迟发性神经毒性的关系。     

磷泥中黄磷的提取方法研究

磷泥是电炉法生产黄磷过程中产生的主要副产物之一,针对磷泥中黄磷回收的方法和研究现状,介绍了水煮法、蒸馏法、电场法、溶剂萃取法、盐酸-硝酸法、纯碱法、氨解法、碳铵-烧碱-双氧水法等,讨论了各种方法的特点,指出存在的问题和今后的研究重点。     

CycloSal‐phosphate Pronucleotides of Cytostatic 6‐(Het)aryl‐7‐deazapurine Ribonucleosides: Synthesis,Cytostatic Activity,and Inhibition of Adenosine Kinases

A series of cycloSal‐phosphate prodrugs of a recently described new class of nucleoside cytostatics (6‐hetaryl‐7‐deazapurine ribonucleosides) was prepared. The corresponding 2′,3′‐isopropylidene 6‐chloro‐7‐deazapurine nucleosides were converted into 5‐O′‐cycloSal‐phosphates. These underwent a series of Stille or Suzuki cross‐couplings with diverse (het)arylstannanes or ‐boronic acids to yield the protected 6‐(het)aryl‐7‐deazapurine pronucleotides that were subsequently deprotected to give 12 derivatives of free pronucleotides. The in vitro cytostatic effect of the pronucleotides was compared with parent nucleoside analogues. In most cases, the activity of the pronucleotide was similar to or somewhat lower than that of the corresponding parent nucleosides, with the exception of 7‐fluoro pronucleotides 13 a , 13 b , and 13 d , which had exhibited GIC₅₀ values that were improved by one order of magnitude (to the low nanomolar range). The presence of a cycloSal‐phosphate group also influenced selectivity toward various cell lines. Several pronucleotides were found which strongly inhibit human adenosine kinase but only weakly inhibit the MTB adenosine kinase.     

磷石膏中有效磷的测定方法比较

分别用EDTA、中性柠檬酸铵两种萃取剂萃取并测定磷石膏中有效磷含量,通过比较,选择能够完全萃取磷石膏中有效磷的萃取剂——中性柠檬酸铵,用于磷石膏中有效磷的分析测定。     

The Emerging Role of Tetrazines in Drug-Activation Chemistries

Traditionally, prodrug activation has been limited to enzymatic triggers or gross physiological aberrations, such as pH, that offer low selectivity and control over dosage. In recent years, the field of prodrug activation chemistry has been transformed by the use of bioorthogonal reactions that can be carried out under biological conditions at sub-millimolar concentrations, with the tetrazine-mediated inverse electron demand Diels–Alder reaction amongst the most recognised. Their high reaction rates, chemoselectivity and excellent biocompatibility make tetrazines ideal small molecules for activating prodrugs. Recently the tetrazine moiety has been used as a prodrug for a pyridazine thus broadening the scope of prodrug systems. This article discusses the concept of using tetrazines as small-molecule activators for prodrugs, and provides an overview of tetrazine-based prodrug systems, with a particular focus on the recently reported prodrug–prodrug activation strategy.     

复混肥料中水溶性磷和有效磷含量测定方法的改进

本文研究了复混肥料中测定水溶性磷和有效磷含量方法(GB15063-2001)的改进,在国标法基本原理的基础上,运用超声波常温下加适量水或硝酸溶液萃取5 min复混肥料中的水溶性磷或有效磷。与国标法比较,水溶性磷绝对误差在0.04~0.25%之间,极差在0.03~0.14%之间;有效磷绝对误差在0.02~0.17%之间,极差在0.03~0.12%之间;检测精密度和准确度都符合国标要求。此方法操作简便﹑快速高效﹑安全可靠,精密度和准确度都符合国家标准的要求,效果令人满意。     

反硝化聚磷菌在污水处理中的应用

综合国内外反硝化除磷技术的最新研究,着重分析反硝化聚磷菌的脱氮除磷机理和对反硝化除磷工艺有较大影响的各种因素,介绍反硝化聚磷菌在污水处理中的应用及目前反硝化除磷技术在工艺上的研究进展。     

Purinergic Signaling: Impact of GPCR Structures on Rational Drug Design

The purinergic signaling system includes membrane-bound receptors for extracellular purines and pyrimidines, and enzymes/transporters that regulate receptor activation by endogenous agonists. Receptors include: adenosine (A₁, A_2A, A_2B, and A₃) and P2Y (P2Y₁, P2Y₂, P2Y₄, P2Y₆, P2Y₁₁, P2Y₁₂, P2Y₁₃, and P2Y₁₄) receptors (all GPCRs), as well as P2X receptors (ion channels). Receptor activation, especially accompanying physiological stress or damage, creates a temporal sequence of signaling to counteract this stress and either mobilize (P2Rs) or suppress (ARs) immune responses. Thus, modulation of this large signaling family has broad potential for treating chronic diseases. Experimentally determined structures represent each of the three receptor families. We focus on selective purinergic agonists (A₁, A₃), antagonists (A₃, P2Y₁₄), and allosteric modulators (P2Y₁, A₃). Examples of applying structure-based design, including the rational modification of known ligands, are presented for antithrombotic P2Y₁R antagonists and anti-inflammatory P2Y₁₄R antagonists and A₃AR agonists. A₃AR agonists are a potential, nonaddictive treatment for chronic neuropathic pain.     

磷酸酯中结合磷与无机磷的分析测定

将试样在硝酸、硫酸、高氯酸中分解 ,用钒钼酸铵法以 72 1型分光光度计测定阴离子表面活性剂磷酸酯中的无机磷、结合磷的质量。     

新型磷系阻燃剂制备技术进展

介绍了近年来我国新型磷系阻燃剂制备技术进展,特别介绍了笼状磷酸酯、多螺环化合物、DOPO及其衍生物、磷—氮化合物类、磷—硅化合物类等阻燃剂制备技术现状,并对磷系阻燃剂发展前景作了展望     

与黄磷生产装置有关的制磷电炉规模问题探析

针对我国的磷矿资源分布、经济发展、交通与能源结构等实际情况,探讨了黄磷生产的电炉电耗、原材料消耗和产品质量及水电资源的合理利用,认为制磷企业根据当地资源情况配置多台制磷电炉是适宜的。