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Design, synthesis, antiviral and cytotoxic evaluation of novel acyclic phosphonate nucleotide analogues with a 5,6-dihydro-1H-[1,2,3]triazolo[4,5-d]pyridazine-4,7-dione system.

Bankowska E, Balzarini J, Głowacka IE, Wróblewski AE - Monatsh. Chem. (2014)

Bottom Line: All compounds containing P-C-C-triazole or P-C-C-CH2-triazole moieties exist in single conformations in which the diethoxyphosphoryl and substituted 1,2,3-triazolyl or substituted (1,2,3-triazolyl)methyl groups are oriented anti.None of the compounds were endowed with antiviral activity.They were not cytostatic at 100 μM.

View Article: PubMed Central - PubMed

Affiliation: Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Łódź, Muszyńskiego 1, 90-151 Lodz, Poland.

ABSTRACT

Abstract: A series of diethyl 2-(4,5-dimethoxycarbonyl-1H-1,2,3-triazol-1-yl)alkylphosphonates was synthesised from ω-azidoalkylphosphonates and dimethyl acetylenedicarboxylate and was further transformed into the respective diamides, dihydrazides, and 5,6-dihydro-1H-[1,2,3]triazolo[4,5-d]pyridazine-4,7-diones as phosphonate analogues of acyclic nucleosides having nucleobases replaced with substituted 1,2,3-triazoles. All compounds containing P-C-C-triazole or P-C-C-CH2-triazole moieties exist in single conformations in which the diethoxyphosphoryl and substituted 1,2,3-triazolyl or substituted (1,2,3-triazolyl)methyl groups are oriented anti. All phosphonates were evaluated in vitro for activity against a variety of DNA and RNA viruses. None of the compounds were endowed with antiviral activity. They were not cytostatic at 100 μM.

No MeSH data available.


Related in: MedlinePlus

Compounds 12a and 13a
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Fig6: Compounds 12a and 13a

Mentions: The diesters 8a–8g were also converted to the corresponding dihydrazides 10a–10g with hydrazine hydrate (Scheme 1). Preliminary attempts at synthesising dihydrazide 10a followed the literature procedure [41] and showed that refluxing phosphonate 8a and hydrazine hydrate in ethanolic solution for 5 h led to the formation of several products. The 31P NMR spectrum of the reaction mixture revealed the presence of the expected phosphonate 10a (76 %), bicyclic 1,2,3-triazolopyridazinedione 11a (11 %) and their monodealkylated counterparts 12a and 13a (10 and 3 %, respectively) (Fig. 6). When hydrazinolysis of the diester 8a was conducted for 2 h only phosphonates 10a (79 %) and 11a (21 %) were produced. For this reason syntheses of dihydrazides 10b–10g were performed under the same conditions. However, it appeared that for compounds 8c and 8g significant dealkylation still occurred. In both cases the respective crude reaction mixtures contained almost 50 % of by-products. Purifications on silica gel columns and crystallisations gave dihydrazides 10a–10g in 28–66 % yields.Fig. 6


Design, synthesis, antiviral and cytotoxic evaluation of novel acyclic phosphonate nucleotide analogues with a 5,6-dihydro-1H-[1,2,3]triazolo[4,5-d]pyridazine-4,7-dione system.

Bankowska E, Balzarini J, Głowacka IE, Wróblewski AE - Monatsh. Chem. (2014)

Compounds 12a and 13a
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4494773&req=5

Fig6: Compounds 12a and 13a
Mentions: The diesters 8a–8g were also converted to the corresponding dihydrazides 10a–10g with hydrazine hydrate (Scheme 1). Preliminary attempts at synthesising dihydrazide 10a followed the literature procedure [41] and showed that refluxing phosphonate 8a and hydrazine hydrate in ethanolic solution for 5 h led to the formation of several products. The 31P NMR spectrum of the reaction mixture revealed the presence of the expected phosphonate 10a (76 %), bicyclic 1,2,3-triazolopyridazinedione 11a (11 %) and their monodealkylated counterparts 12a and 13a (10 and 3 %, respectively) (Fig. 6). When hydrazinolysis of the diester 8a was conducted for 2 h only phosphonates 10a (79 %) and 11a (21 %) were produced. For this reason syntheses of dihydrazides 10b–10g were performed under the same conditions. However, it appeared that for compounds 8c and 8g significant dealkylation still occurred. In both cases the respective crude reaction mixtures contained almost 50 % of by-products. Purifications on silica gel columns and crystallisations gave dihydrazides 10a–10g in 28–66 % yields.Fig. 6

Bottom Line: All compounds containing P-C-C-triazole or P-C-C-CH2-triazole moieties exist in single conformations in which the diethoxyphosphoryl and substituted 1,2,3-triazolyl or substituted (1,2,3-triazolyl)methyl groups are oriented anti.None of the compounds were endowed with antiviral activity.They were not cytostatic at 100 μM.

View Article: PubMed Central - PubMed

Affiliation: Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Łódź, Muszyńskiego 1, 90-151 Lodz, Poland.

ABSTRACT

Abstract: A series of diethyl 2-(4,5-dimethoxycarbonyl-1H-1,2,3-triazol-1-yl)alkylphosphonates was synthesised from ω-azidoalkylphosphonates and dimethyl acetylenedicarboxylate and was further transformed into the respective diamides, dihydrazides, and 5,6-dihydro-1H-[1,2,3]triazolo[4,5-d]pyridazine-4,7-diones as phosphonate analogues of acyclic nucleosides having nucleobases replaced with substituted 1,2,3-triazoles. All compounds containing P-C-C-triazole or P-C-C-CH2-triazole moieties exist in single conformations in which the diethoxyphosphoryl and substituted 1,2,3-triazolyl or substituted (1,2,3-triazolyl)methyl groups are oriented anti. All phosphonates were evaluated in vitro for activity against a variety of DNA and RNA viruses. None of the compounds were endowed with antiviral activity. They were not cytostatic at 100 μM.

No MeSH data available.


Related in: MedlinePlus