Phosphorothioate Analogues of Nucleotides—Tools for the Investigation of Biochemical Processes

Nucleoside phosphorothioates are analogues of nucleotides with a wide range of applications. Thus, on the one hand, in many but not all cases they are more stable against hydrolysis than the unmodified nucleotides—a property which they share with other nucleotide analogues. On the other hand, however, they are good substrates for many, but not all reactions where the nucleotide or the phosphorothioate group is transferred to an acceptor other than H₂O. As a consequence, once incorporated into a system such as DNA, phosphorothioates cannot be easily removed. What makes these compounds unique to a certain extent is the chirality at the phosphorus center if two nonequivalent residues are linked to the phosphorothioate group. This opens the way for the use of these compounds to investigate stereochemical aspects of enzymatic reactions. In addition to these properties, there are those expected from exchange of an oxygen for a sulfur atom in a phosphate group, e.g. the increased affinity towards mercury derivatives and the large chemical shift of the ³¹P-NMR sinals. If one considers how many biologically interesting compounds contain phosphate groups, the considerable interest in these nucleotide analogues is not surprising.     

Stereocontrolled Synthesis of Oligo(nucleoside phosphorothioate)s

Encouraging results obtained for modulation of gene expression by antisense oligonucleotides and their analogues have kindled hopes for a new generation of therapeutics against viral infections, cancer, and many other diseases. Among such analogues, oligo(nucleoside phosphorothioate)s (Oligo-S) have generally shown the highest efficacy in inhibiting the biosynthesis of “unwanted” proteins. The first clinical trials of antisense agents are now in progress using Oligo-S against genital warts and acute myeloid leukemia, and tests of Oligo-S against AIDS should follow soon. Nevertheless, their mechanism of action, internalization, cellular trafficking, subcellular localization, and interaction with cellular proteins is still poorly understood. It is assumed a priori that application involves rapid and efficient molecular recognition of target RNA by Oligo-S; however, the effects of the chirality of Oligo-S have so far been unappreciated, because Oligo-S has not yet been synthesized with stereocontrol. Indeed, the diastereomeric composition of Oligo-S has never been determined, primarily because of the lack of appropriate analytical methods. Since each of the diastereomers is a stereochemically unique chemical entity, questions arise as to which diastereomer is responsible for an observed biological response, including positive (curative) or possibly negative (toxic) side effects. In this review we intend provide a perhaps somewhat speculative assessment of the problems associated with the stereo-controlled synthesis of Oligo-S and to discuss the state-of-the-art in this field including strategies that may lead to Oligo-S of predetermined chirality. This article is not intended to discourage researchers from further studies of dia-steromeric mixtures of Oligo-S as potential pharmaceuticals. Throughout the history of medicinal chemistry numerous useful medicines were discovered, developed, and employed without the detailed knowledge of their structure. Indeed, the composition of the vaccines discovered by Pasteur is a subject of vigorous study still today.     

Synthesis of S-monofluoromethyl phosphorothioates from PⅤ-H compounds and PhSO2SCH2F

S-Monofluoromethyl phosphorothioates represent an important class of organofluorine compounds and are re ported here for the first time.A series of S-monofluoromethyl phosphorothioates are conveniently synthesized from different P^Ⅴ-H compounds and PhSO₂SCH₂F under mild conditions.The method is compatible with common functional groups and provides potential opportunities to synthesize new bioactive molecules for medicinal chemistry.     

Mercury trifluoroacetate-catalyzed conversion of Se-alkyl phosphoroselenolates into the corresponding phosphates

The role of mercuric trifluoroacetate as reactive agent and activator in reactions of various Se-alkyl phosphoroselenoates with O- and N-nucleophiles is examined. The formation of mercury-complexed intermediates of putative mixed anhydride-like structure is indicated.     

Synthesis and application of phosphonothioates,phosphonodithioates, phosphorothioates,phosphinothioates and related compounds

Methods for the preparation of phosphonothioates, phosphonodithioates, phosphorothioates, phosphinothioates and related compounds are reviewed. The application of these compounds as synthetic intermediates is also discussed.     

C[sbnd]C Asymmetric Bond Formation Mediated by Optically Active Sulfoxides

Abstract

Highly stereoselective C[sbnd]C bond forming reactions can be performed with a variety of optically active sulfinyl derivatives to afford, after desulfurization, optically active sulfur-free products.     

O-乙基-N-烷基(取代硫脲基)硫代磷酰胺酯的合成及其生物活性

采用O-乙基-N-烷基(异硫氰基)硫代磷酰胺酯与不同胺的加成反应,合成了一系列新型的O-乙基-N-烷基(取代硫脲基)硫代磷酰胺酯,其结构经元素分析、IR及¹HNMR证实.生物活性初步测定表明,这类化合物均具有一定的广谱杀菌及除草活性.     

O-乙基-N-异丙基(取代硫脲基)硫代磷酰胺酯类衍生物杀菌作用的构效关系研究

研究了一系列O-乙基-N-异丙基(取代硫脲基)硫代磷酰胺酯类化合物的杀菌活性,发现分子的活性中心在硫脲基上,其氮原子上所连的取代基对活性有重要影响。采用取代基物理参数及化合物对多种植物病菌的抑制活性,进行了结构与活性定量关系的研究。建立了较好的结构与活性的相关式,预测出更高活性的化合物并得到实验证实。     

A simple and rapid synthesis of nucleotide analogues containing a phosphorothioate moiety at the terminal position of the phosphate chain

A straightforward method for the synthesis of nucleotide analogues bearing a phosphorothioate moiety at the terminal position of the polyphosphate chain is described. Several nucleoside 5′-(2-thiodiphosphates) and 5′-(3-thiotriphosphates) were synthesized by treatment of the appropriate nucleotide imidazolide derivative with a ca. 4-fold excess of thiophosphate triethylammonium salt in DMF in the presence of zinc chloride. The HPLC reaction yields varied from 80% to 100%, in the majority of cases exceeding 90%. Separation was accomplished by Sephadex ion-exchange chromatography or reverse-phase HPLC with preparative yields of about 70%.