Synthesis of an Apionucleoside Family and Discovery of a Prodrug with Anti-HIV Activity

Abstract

We report the synthesis of a family of D- and L-furano-D-apionucleosides, their 3'-deoxy, as well as their 2',3'-dideoxy analogues with thymine and adenine nucleobases. Single carbon homologation of 1,2-O-isopropylidene-D-glycero-tetrafuranos-3-ulose (15) and optimized glycosylation conditions involving microwave irradiation were key to the successful synthesis of the target compounds. While all target nucleosides failed to show significant antiviral activity, we demonstrated that the triphosphate of 2',3'-deoxy-D-apio-D-furanoadenosine (1), in contrast to that of its D-apio-L-furanose epimer 2, was readily incorporated into a DNA template by HIV reverse transcriptase to act as a DNA chain terminator. This led us to convert adenine derivative 1 into two phosphoramidate prodrugs. ProTide 9b was found active against HIV-1 and HIV-2 (EC50 = 0.5-1.5 μM), indicating that the lack of activity of the parent nucleoside, and possibly also other members of the D-apio-D-furanose nucleoside family must be sought in the inefficient cellular conversion to the monophosphate.

Purine and Guanine Thioglycoside Analogs: Novel Synthesis of a New Class of Pyrazolo[1,5-a][1,3,5]Triazine-4-Thioglycoside Derivatives under Microwave Activation

“…The other sixglucose protons appear as a multiplet at δ 3.34-4.41, while the four hydroxy groups of glucose moiety resonated at δ 5.14-5.23 (exchangeable by D 2 O). Encouraged by these results, methylation of compounds 4a-e with methyl iodide in sodium ethoxide gave the 4-methylthiopyrazolo [1,5-a] [1,3,5]triazine …”

“…Compounds 2 are readily reacted with one equivalent of 5-aminopyrazoles 1a-e in the presence of acetic acid under microwave activation for 10 min to give the corresponding pyrazolo [1,5-a] [1,3,5]triazine-4-thiol derivatives 4a-e in good yields. The structures of 4a-e were established on the basis of its elemental analysis and spectral data (IR, 1 H NMR, and 13 C NMR).…”

“…The other six glucose protons resonated at δ 3.73-4.82 ppm. When glycosides 6a-j were treated with methanolic ammonia at room temperature for 10 min, the deprotected derivatives 7a-j were obtained in almost quantitative yields (Scheme 2), the structures of which were established SCHEME 1 Synthetic pathway for 4-(2 ,3 ,4 ,6 -Tetra-O-acetyl-β-D-glycopyranosylthio)-pyrazolo[1,5-a] [1,3,5]triazines 6a-j on the basis of elemental analysis and spectral data. Thus, the analytical data for 7a reveal the molecular formula C 17 H 20 N 8 O 5 S. The 1 H NMR spectrum shows the anomeric proton as a doublet at δ 4.52-4.54 (J 1,2 = 9.95 Hz), indicating the presence of only β-D configuration.…”

“…This means that it mimics the substance necessary in DNA synthesis. [1] In the body, 6-MP is converted into the corresponding ribonucleotide. 6-MP ribonucleotide is a potent inhibitor of the conversion of the compound called inosinic acid to adenylic acid.…”

“…The key step of this protocol is the formation of sodium pyrazolo [1,5-a] [1,3,5]triazine-4-thiolates via condensation of 5-amino-1H-pyrazoles with sodium cyanocarbonimidodithioate salt under microwave irradiation, followed by coupling with halo sugars to give the corresponding purine thioglycoside analogues. Further studies on the application of this method for the synthesis of other highly functionalized biologically active glycosides are underway.…”