A programmed five-membered cyclic phosphorylating reagent for the synthesis of oligonucleotides and its use

Richter, Wolfgang; Karl, R.; Ugi, lvar

doi:10.1016/s0040-4020(01)85456-9

Cited by 15 publications

(2 citation statements)

References 25 publications

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“…1. Reagents for the synthesis were as described by Hunsoh et al (1994) and Richter et al (1990). The general procedures are based on the methodology described by McGuigan et al (1990aMcGuigan et al ( ,b,c, 1991McGuigan et al ( , 1993b.…”

Section: Synthesis Of 5'-phosphate Derivatives Of Nucleoside Analoguesmentioning

confidence: 99%

The use of 5′-Phosphate Derivatives of Nucleoside Analogues as Inhibitors of HIV-1 Replication

Nillroth

Vrang

Ahlsén

et al. 1995

Antivir Chem Chemother

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A series of phosphate esters of nucleoside analogues was synthesized and tested for anti-HIV activity in cell culture. A number of these compounds were potent inhibitors of HIV-replication with ED50 ≥ 10 nM. The most potent compounds were phosphate esters of the most potent nucleosides, 3′-fluoro-3′-deoxythymidine (FLT) and 3′-azido-3′-deoxythymidine (AZT). In cell culture, the inhibition by one of these derivatives was shown to be reversed by thymidine. Also, the AZT analogue was less active against AZT-resistant virus. None of the compounds tested was directly inhibitory of HIV reverse transcriptase. The compounds were found to be labile; the rate of hydrolysis and the identity of the products varied depending on the substituents on the phosphorus atom. Activation of the most active analogue, FLT-5′-(methoxyglycinyl S-(N-methylcarbamoylmethyl))thiophosphate (JCA-304), involved a pH-dependent hydrolysis, which increased with increasing pH. The hydrolysis was not dependent on HIV proteinase, the presence of MT4 cells or enzymatic activity originating from the culture medium. The product of hydrolysis of JCA-304 was the free nucleoside (FLT); FLT-5′-monophosphate was not detected. The corresponding acyclovir analogue was not active against thymidine-kinase-deficient herpes simplex virus in Vero cells. Hydrolysis of FLT-5′-(S-(N-methylcarbamoylmethyl))thiophosphate (JCA-319) was observed in cell culture medium but not in buffer at the same pH. The product was identified as FLT-5′-monophosphate. Neither of these compounds was seen as an intermediate in the hydrolysis of JCA-304. The results suggest that the compounds are prodrugs activated by a non-enzymatic hydrolysis and a cytosolic phosphorylation yielding potent inhibitors of HIV reverse transcriptase. The cellular stability of substituted 5′-phosphate derivatives cannot be predicted from their behaviour in buffer or from the hydrolysis of closely related analogues.

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Section: Synthesis Of 5'-phosphate Derivatives Of Nucleoside Analoguesmentioning

confidence: 99%

The use of 5′-Phosphate Derivatives of Nucleoside Analogues as Inhibitors of HIV-1 Replication

Nillroth

Vrang

Ahlsén

et al. 1995

Antivir Chem Chemother

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“…Sie erhielten 5 zum einen bei der Umsetzung von 2,2,2-Trichlor-1,3-dimethyl-l ,3-diaza-2A5-phosphetidin-4-on mit Methylisocyanat, zum anderen bei der Umsetzung von 2,2,2,4,4,4-Hexachlor-l,3-dimethyl-2,4-diazadiphosphetidin mit Methylisocyanat. Von Ugi und M itarbeitern wurde die Umsetzung einer m ethoxysubstituierten A3-Phosphorverbindung mit Sulfurylchlorid beschrieben, bei der unter Entstehung von Methylchlorid und Schwefeldioxid eine 2-Chlor-2-oxo-A4-Phosphorverbindung erhal ten wurde [12,13]. D aher lag es nahe, die 2-methoxy-bzw.…”

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Zur Chemie der 1,3,5-Triaza-2-phosphorinan-4,6-dione. Teil VII⁺. Über die Synthese von 2-Methoxy- und 2-Trimethylsiloxy-1,3,5-trimethyI- 1.3.5-triaza-2λ3-phosphorinan-4,6-dion sowie 2-Chlor-1,3,5-trimethyl- 1.3.5-triaza-2-oxo-2λ⁴-phosphorinan-4,6-dion / Chemistry of the 1,3,5-Triaza-2-phosphorinane-4,6-diones. Part VII. Synthesis of 2-Methoxy- and 2-Trimethylsiloxy-1,3,5-trimethyl-1.3.5-triaza-2λ³-phosphorinane-4,6-dione and 2-Chloro-1,3,5-trimethyl- 1.3.5-triaza-2-oxo-2λ
Neda
¹
,
Farkens
²
,
Schmutzler
³

1994
Zeitschrift Für Naturforschung B
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0
0
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1.3.5-Trimethyl-substituted l,3,5-Triaza-2A3-phosphorinane-4,6-diones, 1.3.5-Triaza-2-oxo-2A4-phosphorinane-4,6-diones, NMR Spectra, Mass SpectraThe reactions of 1,3,5-trimethylbiuret with methyldichlorophosphite, and of 2-chloro-1.3.5-trimethyl-l,3,5-triaza-2A3-phosphorinane-4,6-dione 1 with methanol or methoxytrimethylsilane furnished the methoxy-substituted triazaphosphorinane-dione 3. In the reaction of 2-hydro-l,3,5-trimethyl-l,3,5-triaza-2-oxo-2A4-phosphorinane-4,6-dione 2 with diethylaminotrimethylsilane the corresponding trimethylsiloxy-substituted triazaphos phorinane-dione 4 was formed. The reactions of 3 and 4 with sulphuryl chloride gave 2-chloro-l,3,5-trimethyl-l,3,5-triaza-2-oxo-2A4-phosphorinane-4,6-dione 5, whose synthesis via another route was described previously [7]. In the reaction of 1 with 4 the A3P-0-A3P-bridged compound 6 and trimethylchlorosilane were formed. Condensation reactions of the P(:0)C1 compound 5 with 2-chloroethylamine hydrochloride and bis(2-chloroethyl)amine hydrochloride in the presence of triethylamine furnished the amide derivatives 7 and 8. Compounds 3-5, 7 and 8 were characterized via their JH, 13C, 31P NMR and mass spectra, compound 6 was characterized from its X H and 31P NMR spectra only.In letzter Zeit wurde eine große Anzahl cyclischer sechsgliedriger l,3,5-Triaza-2-phosphorinan-4,6-dion-Derivate mit Phosphor der Koordinations zahlen 3, 4 und 5 beschrieben [1][2][3][4][5][6]. Das A3-Phosphoratom war dabei jeweils halogen-, alkyl-, aryloder diorganoamino-substituiert. Die Darstellung dieser l,3,5-Triaza-2A3-phosphorinan-4,6-dione er folgte durch Kondensationsreaktionen von 1,3,5-Triorganobiureten mit den entsprechenden Dichlorphosphinen oder Phosphortrichlorid [1][2][3][4][5][6].Bisher nicht dargestellt wurden dagegen 1,3,5-Triaza-2A3-phosphorinan-4,6-dione mit einem Alkoxysubstituenten am Phosphor. In der vorlie genden A rbeit wird, ausgehend von verschiedenen Edukten, die Synthese der Verbindungen 3 und 4 + Teil I-V I siehe Lit. [1][2][3][4][5][6].

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Die computerunterstützte Lösung chemischer Probleme eine neue Disziplin der Chemie

et al. 1993

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A programmed five-membered cyclic phosphorylating reagent for the synthesis of oligonucleotides and its use

Cited by 15 publications

References 25 publications

The use of 5′-Phosphate Derivatives of Nucleoside Analogues as Inhibitors of HIV-1 Replication

The use of 5′-Phosphate Derivatives of Nucleoside Analogues as Inhibitors of HIV-1 Replication

Die computerunterstützte Lösung chemischer Probleme eine neue Disziplin der Chemie

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