Enantioselective Syntheses and Cytotoxicity of N,O-Nucleosides

Abstract

Enantiomers of 4'-aza-2',3'-dideoxynucleosides have been prepared by two different synthetic approaches, on the basis of 1,3-dipolar cycloaddition of a chiral nitrone. Cytotoxicity and apoptotic activity have been investigated. (5'S)-5-Fluoro-1-isoxazolidin-5-yl-1H-pyrimidine-2,4-dione [(-)-AdFU], while showing low level of cytotoxicity, is a good inductor of apoptosis on lymphoid and monocytoid cells, acting as a strong potentiator of Fas-induced cell death.

Truncated phosphonated C-1′-branched N,O-nucleosides: A new class of antiviral agents

“…[17][18][19][20][21][22] Following intracellular phosphorylation to their 5 0 -triphosphate forms, they are able to serve as chain terminators, thus acting as inhibitors in the viral reverse transcription reaction. 18,19 Several strategies to overcome the initial selective phosphorylation step have been designed; 23 in particular, phosphonate analogues, 20 by miming the nucleoside monophosphates, overcome the instability of nucleotides towards phosphodiesterase and enhance the cellular uptake by bypassing the initial phosphorylation step.…”

Synthesis and biological evaluation of phosphonated dihydroisoxazole nucleosides

“…Nevertheless, the compounds generally showed a low level of toxicity. None of the compounds tested showed a CC 20 lower than the maximal concentration tested on Vero cells, while compounds 6b and c showed a certain degree of cytotoxicity on Molt-3 cells.…”

“…The two-step methodology previously reported, 20 based on the 1,3-dipolar cycloaddition of 9 with vinyl acetate and followed by Vorbrü ggen nucleosidation, always led to the expected diethyl(isoxazol-3-yl)methylphosphonate as an exclusive product.…”

“…The compounds were added to the wells to obtain final concentrations ranging from 1 to 400 lM. For compounds showing a CC 20 lower than 400 lM, the maximal concentration tested for anti-HSV activity was that immediately higher than the calculated CC 20 . The effective concentrations 50 (EC 50 ) were calculated as the concentrations of the compounds required to cause 50% reduction of plaque formation.…”

“…7 Some of the obtained compounds exhibit interesting biological features in vitro: in particular, (À)-ADFU 1 (B = 5-fluorouracil), while showing low levels of cytotoxicity, has been shown to be a good inductor of apoptosis on lymphoid and monocytoid cells, acting as a strong potentiator of Fas-induced cell death. 8 Also the dihydroisoxazole ring could constitute a suitable substrate for the synthesis of new antiviral compounds. Hydroxymethyl dihydroisoxazole nucleosides 4 have been reported to exhibit in vitro moderate anti-HIV activity and moderate cytotoxicity; thus representing the first example of potential antiviral agents which derive from dihydroisoxazole nucleus (Fig.…”