The Synthesis and Properties of Some Fluorinated Dialkyl Phosphoramidates

The synthesis and physical properties of the first fluorinated dialkyl phosphoramidates of structure (RCH 2 O) 2 P(O)NHCH 2 R F , where R = CH 3 , CF 3 or CCl 3 and R F = CF 3 or C 2 F 5 , are described. They were obtained by treatment of the respective dialkyl phosphorochloridates with trifluoroethylamine or pentafluoropropylamine in ether in the presence of triethylamine.     

Structure-toxicity relationships of thiono and seleno phosphoramidate compounds: new type of acetylcholinesterase inhibitors

Novel thiono and seleno phosphoramidate compounds with the general formula (X)(Y)P(C₆H₅)₂; (X = NMe₂ & Y = S, 1a; X = NEt₂ & Y = S, 2a; X = NMe(CH₂Ph) & Y = S, 3a; X = NH(CH₂Ph) & Y = S, 4a; X = NEt(CH₂Ph) & Y = S, 5a; X = N(C(Me)₃) (CH₂Ph) & Y = S, 6a; X = N(CH₂Ph)₂ & Y = S, 7a; X = NMe₂ & Y = Se, 1b; X = NEt₂ & Y = Se, 2b; X = NMe(CH₂Ph) & Y = Se, 3b; X = NH (CH₂Ph) & Y = Se, 4b; X = NEt(CH₂Ph) & Y = Se, 5b; X = N(C(Me)₃)(CH₂Ph) & Y = Se, 6b and X = N(CH₂Ph)₂ & Y = Se, 7b) were prepared and characterized by ¹H, ³¹P and ¹³C NMR and IR spectroscopy and elemental analysis. ³¹P chemical shift of thiono and seleno derivatives didn’t show significant different because of their little difference in electronegativity sulfur and selenium. Hydrophobic parameter of compounds was determined by measurement of octanol-water partition coefficient by shake-flask technique. Determination of human erythrocyte acetylcholinesterase (hAChE) activity was carried out according to the Ellman’s modified kinetic method. IC₅₀ values of the selected thiono and seleno compounds varied from 3.4 to 0.11 and 9.9 to 5.1 mM, respectively. The seleno compounds show lower affinities for hAChE relative to the thino compounds. These results demonstrate that hydrophobic and electronic factors of the organophosphorus compounds play a key role on the inhibitory potency.     

Efficient preparation of amine-modified oligodeoxynucleotide using modified H-phosphonate chemistry for DNA microarray fabrication

Amine-modified oligodeoxynucleotides (AMO) are commonly used probe oligodeoxynucleotides for DNA microarray preparation. Two methods are currently used for AMO preparation—use of amine phosphoramidites protected by acid-labile monomethoxytrityl (MMT) groups or alkali-labile trifluoroacetyl (TFA) groups. Because conventional AMO preparation procedures have defects, for example stringent acidic conditions are required for deprotection of MMT and hydrophobic purification cannot be used for TFA-protected amino groups, conventional preparation of AMO is unlikely to result in the expected outcome. In this paper a method of AMO synthesis using modified H-phosphonate chemistry is suggested. An aliphatic diamine is coupled with a phosphonate group forming a phosphoramidate linkage to the last internucleotide phosphate of oligodeoxynucleotides. In this method dimethoxytrityl (DMT) purification steps are used and stringent acid deprotection is not required to obtain the AMO. Although the method could lead to formation of AMO diastereomers, melting-temperature and CD analysis showed for two AMO that DNA duplex formation was the same as when normal oligodeoxynucleotides were used. Also, when these AMO were used as probes for DNA microarrays the immobilization efficiency was similar to that for AMO probes prepared by conventional means using an amino-modifier unit. The hybridization performance of these AMO was better than for those prepared conventionally. The procedures suggested would be useful for preparation of efficient AMO for fabrication of DNA microarrays and DNA-based nanoparticle systems. Nagendra Kumar Kamisetty and Seung Pil Pack have equally contributed to this work.     

O-(1-甲硫基乙叉胺基)磷酰胺酯(或磷酸酯)的合成及其生物活性研究

首次合成了30种新型O-(1-甲硫基乙叉胺基)磷酰胺酯及磷酸酯类化合物,生物活性测定表明,部分化合物具有一定的杀菌和除草活性,化合物(R¹O)₂P(O)-ON＝C(SCH₃)CH₃(V)具有一定的杀虫活性.     

大环手性磷酰胺对氨基酸衍生物的分子识别研究

以(S)-α-甲基苯乙胺和天然氨基酸(L-丙氨酸、L-苯甘氨酸及L-苯丙氨酸)为手性源,以2,5-二(邻羟基苯基)-1,3,4- 二唑和2,4-二(邻羟基苯基)-1,3,5- 二唑为刚性单元,合成了一系列具有光学活性的新型含 二唑磷酰胺和磷酯手性大环化合物.用NMR,IR和FABMS方法研究了所合成的手性大环对氨基酸甲酯盐酸盐和二肽的分子间相互作用和分子识别.结果表明,这些主体对D-或L-氨基酸甲酯盐酸盐和二肽具有选择性的结合作用.     

N＇，N＇－二－（2－氯乙基）－O－芳基－N~3－芳基硫脲基磷酰胺酯的合成、结构及性质研究

合成了１４种含有氮芥结构及芳基取代硫脲基的磷酰胺酯，其结构经１ＨＮＭＲ、ＩＲ、ＭＳ和元素分析证实。研究了它们的波谱性质及结构和化学位移的关系，讨论了磷原子上取代基对反应的影响．初步生测结果表明，部分化合物具有良好的抗ＴＭＶ病毒活性和良好的抗肿瘤活性．     

N,N-二(2-氯乙基)果糖基磷酰胺酯的合成及其抗肿瘤活性研究

糖基磷酸酯类化合物,特别是葡萄糖基磷酸酯类化合物的合成及其生物活性的研究已有报道。1988年Hayachi等发现葡萄糖基磷酸酯衍生物具有抗肿瘤、抗病毒等生物活性,可用作医用药物。但果糖基磷酰胺酯及其衍生物的合成与抗肿瘤活性尚未见文献报道。为研究糖基磷酰胺酯的合成方法并筛选出有抗肿瘤活性的化合物,以期发现新型、高效、低毒、有应     

Synthesis and Biological Activity of Novel Diphenyl N- Substituted Carbamimidoylphosphoramidate Derivatives

Abstract

An efficient synthesis of a series of novel diphenyl N-substituted carbamimidoyl phosphoramidate derivatives was accomplished in two steps. Diphenyl phosphorochloridate (1) was reacted with cyanamide (2) in the presence of 1,4–dimethylpiperazine as a base in THF at 50–55 °C to form an intermediate, diphenyl cyanophosphoramidate (3). Subsequently 3 was reacted with various aromatic/heterocyclic amines (4) in the presence of 1,4–dimethyl piperazine as a base at 55–60 °C to form the corresponding title compounds 5(a-k). The title compounds were tested for antiviral activity against Tobacco mosaic virus (TMV) in vitro, antibacterial and antifungal activities at two different concentrations of 50 and 100 μg/mL. The title compounds exhibited good antiviral and antimicrobial activities when compared to the standards.     

Direct conversion of epoxides into aziridines with N-arylphosphoramidates

Treatment of terminal epoxides with N-arylphosphoramidate anions leads directly to N-aryl aziridines. Existing methods for this transformation employ either multi-step syntheses or an iminophosphorane in conjunction with a Lewis acid. The described method therefore presents an advantage in terms of brevity and atom economy.     

Insertion of Chemical Handles into the Backbone of DNA during Solid-Phase Synthesis by Oxidative Coupling of Amines to Phosphites

Conjugation of molecules or proteins to oligonucleotides can improve their functional and therapeutic capacity. However, such modifications are often limited to the 5′ and 3′ end of oligonucleotides. Herein, we report the development of an inexpensive and simple method that allows for the insertion of chemical handles into the backbone of oligonucleotides. This method is compatible with standardized automated solid-phase oligonucleotide synthesis, and relies on formation of phosphoramidates. A unique phosphoramidite is incorporated into a growing oligonucleotide, and oxidized to the desired phosphoramidate using iodine and an amine of choice. Azides, alkynes, amines, and alkanes have been linked to oligonucleotides via internally positioned phosphoramidates with oxidative coupling yields above 80 %. We show the design of phosphoramidates from secondary amines that specifically hydrolyze to the phosphate only at decreased pH. Finally, we show the synthesis of an antibody-DNA conjugate, where the oligonucleotide can be selectively released in a pH 5.5 buffer.