Synthesis of Novel <scp>d</scp> ‐Glucopyranuronamide‐Based Nucleos(t)ide Analogs Bearing (Triazolyl)methyl Phosph(on)ate Motifs With Anticancer and Antibacterial Potential

The synthesis and evaluation of the antiproliferative and antibacterial potential of novel d ‐glucuronamide‐based nucleoside analogs and isonucleotides is reported. The synthesized molecules comprise an anomeric (triazolyl)methyl phosphonate or phosphate motif and a dodecyl chain or a (triazolyl)ethyl purine system at the amide moiety. Their synthesis involved a 1,3‐dipolar cycloaddition between N ‐propargyl or N ‐dodecyl glucuronamidyl azides with propargyl alcohol or propargyl bromide and further O ‐phosphorylation or Arbuzov reaction, respectively, to furnish glucuronamidyl (triazolyl)methyl phosphate/phosphonate derivatives. N ‐Propargyl glucuronamidyl derivatives were then engaged in cycloaddition with 9‐azidoethyl‐6‐chloropurine to afford 6‐chloropurine isonucleotides. Isonucleoside (triazolyl)methyl phosphonate/phosphates containing a 3‐ O ‐dodecyl moiety displayed significant antiproliferative activities in chronic myeloid leukemia (K562) and breast cancer (MCF‐7) cells with GI 50 values ranging from 20.4 to 11.8 μM and were shown to induce apoptosis. These isonucleotides also exhibited significant and selective antibacterial activities against Streptococcus pneumoniae D39, a clinical serotype 2 strain, with MIC values of 17.20 and 4.23 μM, with no activity against the Gram‐negative bacteria Escherichia coli . The most active compound was the (triazolyl)methyl phosphate‐containing isonucleotide with GI 50 values of 12.8 and 11.8 μM in K562 and MCF‐7 cells, respectively, and a MIC value of 4.23 μM in S. pneumoniae D39.