Design, synthesis, antiviral and cytostatic evaluation of novel isoxazolidine nucleotide analogues with a 1,2,3-triazole linker

Abstract

Azidation (TMSN(3), SnCl(4)) of a 9:1 mixture of trans- and cis-5-acetoxy-2-methylisoxazolidin-3-yl-3-phosphonates at the anomeric carbon atom led to the formation of the equimolar mixture of cis- and trans-5-azido-2-methylisoxazolidin-3-yl-3-phosphonates, which were efficiently separated. The 1,3-dipolar cycloaddition of pure trans- and cis-5-azidoisoxazolidin-3-yl-3-phosphonates with selected alkynes gave the respective nucleoside mimetics containing a 1,2,3-triazole linker. The (1,2,3-triazolyl)isoxazolidine phosphonates obtained herein were evaluated in vitro for activity against a variety of DNA and RNA viruses. None of the compounds were endowed with antiviral activity at subtoxic concentrations. Compounds 15f-j and 16f-j were cytostatic in the higher micromolar range.

Multicomponent Click Synthesis of New 1,2,3-Triazole Derivatives of Pyrimidine Nucleobases: Promising Acidic Corrosion Inhibitors for Steel

“…Monopropargyl pyrimidine nucleobases (uracil and thymine) are versatile building blocks for the synthesis of biologically relevant 1,2,3-triazoles [11]. They are generally used as starting material for the synthesis of triazole nucleosides [12][13][14][15][16][17][18][19], triazole nucleotides [20][21][22][23], oxiconazole analogues [24], nucleopeptides [25], inhibitors of human topoisomerase type II [26], and nucleoamino oxyacids [27]. Further, these propargyl nucleobases are also used in the synthesis of organogels [28], and as corrosion inhibitors [29].…”

Pronounced Inhibition Shift from HIV Reverse Transcriptase to Herpetic DNA Polymerases by Increasing the Flexibility of α-Carboxy Nucleoside Phosphonates

“…Phosphononucleosides linked with a 1,2,3-triazole group were reported to exhibit interesting antiviral activity. 21 The aim was to synthesize both the carboxyphosphonate moiety linked with an azide functionality 3f and N-1-propargyl thymine 4b, and subject these to Cu-catalyzed azide-alkyne cycloaddition. The Rh(II)-catalyzed reaction of 2-bromoethanol 1f with trimethyl phosphonodiazoacetate 2 followed by azidation of the O-H inserted compound furnished the azidocarboxyphosphonate 3f .…”

Design, synthesis, antiviral and cytostatic evaluation of novel isoxazolidine nucleotide analogues with a carbamoyl linker

“…Nucleoside analogue 1 [(À)-AdFU] having a fluorouracil residue attached to the isoxazolidine ring induces apoptosis on lymphoid and monocytoid cells and exhibits low level of cytotoxicity. 21 Synthesis and promising antiproliferative properties of isoxazolidines 4 have been reported by Bortolini et al 22 Recently, a series of 3,5-disubstituted isoxazolidine nucleosides 5 23,24 as well as their further modifications 6 with an 1,2,3-triazole spacer 25 have been obtained and their antiviral and cytotoxic properties were evaluated. 20 Furthermore, compounds of general formula 3 show high cytotoxic activity against several cancer cell lines comparable to the known anticancer drugs, namely, Mitomycin C, Paclitaxel and 5-Fluorouracil, used as positive controls.…”