N,N-diisopropyl-O-P-nitrophenyl-P-methylphosphonoamidite: novel difunctional PIII reagent in oligonucleoside methylphosphonate synthesis containing 4-nitrophenoxy group

Heliñski, Jan; Dąbkowski, Wojciech; Michalski, Jan

doi:10.1016/s0040-4039(00)93513-5

Cited by 26 publications

(15 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The one-pot, four-step process (Scheme 2) takes 18 h and affords a 52% yield of desired product, and 1 is characterized by a 31 P NMR shift of 29.3 ppm that is identical when compared to the authentic material. 19 The synthetic sequence relies upon in situ protonation of the phosphonamidite nitrogen to convert the diisopropylamine to a better leaving group and permit reaction with the weakly nucleophilic fluoroethanol.…”

Section: Resultsmentioning

confidence: 99%

“…Thin-layer chromatography (TLC) was visualized by UV and/or staining by 2,6-dibromoquinone-4-chloroimide (DBQ) or iodine. The 1 H-, 19 F-, and 31 P NMR spectra were recorded on a Varian Avance 400-MHz spectrometer. High resolution mass spectrometry was performed with a Micromass LCT - Waters 2795 HPLC with a 2487 UV detector using caffeine as a molecular weight standard.…”

Section: Methodsmentioning

confidence: 99%

“…The reaction was allowed to continue for 1 h at 25 °C whereupon a solution of p -nitrophenol (0.14 g, 0.98 mmol) and triethylamine (0.13 mL, 0.98 mmol) in dry THF (10 mL) were added at 25 °C with vigorous stirring over 3 h. Immediate formation of triethylamine hydrochloride occurred, and the formation of intermediate 4 ( 31 P NMR 128.0 ppm) was observed along with the protonated intermediate 5 ( 31 P NMR 185.71 ppm). To this reaction mixture was added 2-fluoroethanol (0.063 mL, 1.1 mmol) in dry THF (5 mL) at 25 °C.…”

Section: Methodsmentioning

confidence: 99%

“…13 C NMR (100.63 MHz, CDCl 3 ) δ /ppm 155.14, 144.75, 125.89, 121.11, 82.72, 81.35, 12.21 (d, J CP = 144.15 Hz). 31 P NMR (162.0 MHz, CDCl 3 ) δ /ppm 29.33. 19 F NMR (376.55 MHz, CDCl 3 ) δ /ppm −224.47.…”

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Novel Organophosphate Ligand O-(2-Fluoroethyl)-O-(p-Nitrophenyl)Methylphosphonate: Synthesis, Hydrolytic Stability and Analysis of the Inhibition and Reactivation of Cholinesterases

Chao

Ahmed

Gerdes

et al. 2016

Chem. Res. Toxicol.

View full text Add to dashboard Cite

The organophosphate O-(2-fluoroethyl)-O-(p-nitrophenyl) methyphosphonate 1 is the first-in-class, fluorine-18 radiolabeled organophosphate inhibitor ([18F]1) of acetylcholinesterase (AChE). In rats, [18F]1 localizes in AChE rich regions of the brain and other tissues where it likely exists as the (CH3)(18FCH2CH2O)P(O)-AChE adduct (ChE-1). Characterization of this adduct would define the inhibition mechanism and subsequent postinhibitory pathways and reactivation rates. To validate this adduct, the stability (hydrolysis) of 1 and ChE-1 reactivation rates were determined. Base hydrolysis of 1 yields p-nitrophenol and (CH3) (FCH2CH2O)P(O)OH with pseudo first order rate constants (kobsd) at pH 7.4 (PBS) of 3.25 × 10−4 min−1 (t1/2 = 35.5 h) at 25 °C and 8.70 × 10−4 min−1 (t1/2 = 13.3 h) at 37 °C. Compound 1 was a potent inhibitor of human acetylcholinesterase (HuAChE; ki = 7.5 × 105 M−1 min−1), electric eel acetylcholinesterase (EEAChE) (ki = 3.0 × 106 M−1 min−1), and human serum butyrylcholinesterase (HuBChE; 1.95 × 105 M−1 min−1). Spontaneous and oxime-mediated reactivation rates for the (CH3) (FCH2CH2O)P(O)-serine ChE adducts using 2-PAM (10 μM) were (a) HuAChE 8.8 × 10−5 min−1 (t1/2 = 131.2 h) and 2.41 × 10−2 min−1 (t1/2 = 0.48 h), (b) EEAChE 9.32 × 10−3 min−1 (t1/2 = 1.24 h) and 3.33 × 10−2 min−1 (t1/2 = 0.35 h), and (c) HuBChE 1.16 × 10−4 min−1 (t1/2 = 99.6 h) and 4.19 × 10−2 min−1 (t1/2 = 0.27 h). All ChE-1 adducts undergo rapid and near complete restoration of enzyme activity following addition of 2-PAM (30 min), and no aging was observed for either reactivation process. The fast reactivation rates and absence of aging of ChE-1 adducts are explained on the basis of the electron-withdrawing fluorine group that favors the nucleophilic reactivation processes but disfavors cation-based dealkylation aging mechanisms. Therefore, the likely fate of radiolabeled compound 1 in vivo is the formation of (CH3)(FCH2CH2O)P(O)-serine adducts and monoacid (CH3)(FCH2CH2O)P(O)OH from hydrolysis and reactivation.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Novel Organophosphate Ligand O-(2-Fluoroethyl)-O-(p-Nitrophenyl)Methylphosphonate: Synthesis, Hydrolytic Stability and Analysis of the Inhibition and Reactivation of Cholinesterases

Chao

Ahmed

Gerdes

et al. 2016

Chem. Res. Toxicol.

View full text Add to dashboard Cite

show abstract

“…Compounds 3 and 4 were reacted with (i-Pr) 2 NH (for acid-catalyzed substitution) or 4-nitrophenolate (for base-catalyzed substitution). This reaction proceeded smoothly by a procedure adapted from [34] [35]. For analytical purposes, compounds 6b and 7b were transformed into their oxidized forms 6c and 7c, resp., with 3-chloroperoxybenzoic acid (MCPBA) [36] [37].…”

mentioning

confidence: 99%

‘Ethylene‐Bis[phosphonate] Nucleic Acids’: Novel Monomeric Synthons for the Solid‐Phase Synthesis of (PCH₂CH₂P)‐Bridged Oligonucleotides

Farschtschi¹

2004

Chemistry & Biodiversity

View full text Add to dashboard Cite

An efficient synthesis of modified deoxyribonucleosidic building units, containing the 'ethylene-bisphosphonate nucleic acids' (EBPNAs) 1 or 2, has been developed. By means of solution-phase incorporation of 11, the oxidized form of 2, dinucleotide analogs of type 13 were prepared. The same strategy was used to incorporate 2 into the 5'-terminal position of the 12-mer homopolynucleotide methylphosphonate 14. A preliminary approach for solid-phase incorporation of the nucleosidic building block 1 into a preselected position of an oligonucleotide sequence to give 19 is presented, a reaction performed by means of a coupling strategy involving catalytic oxazaphospholidine-ring cleavage.

show abstract

The Preparation and Properties of Tervalent Phosphorus Acid Derivatives

Dahl

2009

Patai's Chemistry of Functional Groups

View full text Add to dashboard Cite

show abstract

N,N-diisopropyl-O-P-nitrophenyl-P-methylphosphonoamidite: novel difunctional PIII reagent in oligonucleoside methylphosphonate synthesis containing 4-nitrophenoxy group

Cited by 26 publications

References 9 publications

Novel Organophosphate Ligand O-(2-Fluoroethyl)-O-(p-Nitrophenyl)Methylphosphonate: Synthesis, Hydrolytic Stability and Analysis of the Inhibition and Reactivation of Cholinesterases

Novel Organophosphate Ligand O-(2-Fluoroethyl)-O-(p-Nitrophenyl)Methylphosphonate: Synthesis, Hydrolytic Stability and Analysis of the Inhibition and Reactivation of Cholinesterases

‘Ethylene‐Bis[phosphonate] Nucleic Acids’: Novel Monomeric Synthons for the Solid‐Phase Synthesis of (PCH₂CH₂P)‐Bridged Oligonucleotides

The Preparation and Properties of Tervalent Phosphorus Acid Derivatives

Contact Info

Product

Resources

About

N,N-diisopropyl-O-P-nitrophenyl-P-methylphosphonoamidite: novel difunctional PIII reagent in oligonucleoside methylphosphonate synthesis containing 4-nitrophenoxy group

Cited by 26 publications

References 9 publications

Novel Organophosphate Ligand O-(2-Fluoroethyl)-O-(p-Nitrophenyl)Methylphosphonate: Synthesis, Hydrolytic Stability and Analysis of the Inhibition and Reactivation of Cholinesterases

Novel Organophosphate Ligand O-(2-Fluoroethyl)-O-(p-Nitrophenyl)Methylphosphonate: Synthesis, Hydrolytic Stability and Analysis of the Inhibition and Reactivation of Cholinesterases

‘Ethylene‐Bis[phosphonate] Nucleic Acids’: Novel Monomeric Synthons for the Solid‐Phase Synthesis of (PCH2CH2P)‐Bridged Oligonucleotides

The Preparation and Properties of Tervalent Phosphorus Acid Derivatives

Contact Info

Product

Resources

About

‘Ethylene‐Bis[phosphonate] Nucleic Acids’: Novel Monomeric Synthons for the Solid‐Phase Synthesis of (PCH₂CH₂P)‐Bridged Oligonucleotides