Novel isoxazolidine analogues of homonucleosides and homonucleotides

Abstract

a b s t r a c tIsoxazolidine analogues of homonucleos(t)ides were synthesized from nucleobase-derived nitrones 20a-20e (uracil, 5-fluorouracil, 5-bromouracil, thymine, adenine) employing 1,3-dipolar cycloadditions with allyl alcohol as well as with alkenylphosphonates (allyl-, allyloxymethyl-and vinyloxymethyl-and vinylphosphonate). Besides reactions with vinylphosphonate the additions proceeded regioselectively to produce mixtures of major cis and minor trans 3,5-disubstituted isoxazolidines (d.e. 28e82%). From vinylphosphonate up to 10% of 3,4-disubstituted isoxazolidines was additionally produced. Vicinal couplings, shielding effects and 2D NOE correlations were employed in configurational assignments as well as in conformational analysis to find out preferred conformations for several isoxazolidines and to observe anomeric effects (pseudoaxial orientation of phosphonylmethoxy groups) for those obtained from vinyloxymethylphosphonate. None of the tested compounds were endowed in vitro with antiviral activity against a variety of DNA and RNA viruses at subtoxic concentrations (up to 250 mM) nor exhibited antiproliferative activity towards L1210, CEM, and HeLa cells (IC 50 ¼ !100 mM).

Pyrimidine 2,4-Diones in the Design of New HIV RT Inhibitors

“…Physical and spectroscopic data for compounds 7a , b are superimposable with that reported in literature [61].…”

“…Phosphonated reverse homo- N , O -nucleosides 7 have been described in literature and tested as antitumoral agents [61]. Here, we report a different synthetic route which proceeds with better yields and allows the obtainment of pure α and β anomers.…”

Novel Isoxazolidine and γ-Lactam Analogues of Homonucleosides

“…Nucleobase-derived nitrones 13 were synthesized from N-(2-oxoethyl)nucleobases and N -methylhydroxylamine, as described previously [45,46]. The 1,3-dipolar cycloadditions of the nucleobase-derived nitrones 13 to methyl acrylate were carried out at 60 °C in methanol for 24 h (Scheme 2, Table 1) and afforded mixtures of diastereoisomeric isoxazolidines cis - 14 and trans - 14 .…”

“…In the isoxazolidine nucleoside/nucleotide analogues described so far, a nucleobase is attached to C5; therefore, the 1,3-dipolar cycloaddition of nitrones and N -vinyl or N -allyl nucleobases has been found a convenient method for their preparation [44]. Recently, we designed isoxazolidine analogues of 1′-homonucleos(t)ides 12 (Figure 3), in which nucleobases were attached to C3 to underscore the fundamental difference to the already-described ones [45,46]. In the synthesis of homonucleosides 12 , the 1,3-dipolar cycloaddition was also employed, but in that case, nucleobase-derived nitrones and selected alkenes were applied [45,46].…”

“…Recently, we designed isoxazolidine analogues of 1′-homonucleos(t)ides 12 (Figure 3), in which nucleobases were attached to C3 to underscore the fundamental difference to the already-described ones [45,46]. In the synthesis of homonucleosides 12 , the 1,3-dipolar cycloaddition was also employed, but in that case, nucleobase-derived nitrones and selected alkenes were applied [45,46]. Since no significant activity of compounds 12 toward the viruses tested was noticed, we wondered whether the replacement of an isoxazolidine moiety with a γ-lactam ring would lead to an improvement of antiviral properties of newly-designed compounds 15 .…”