Synthesis of Novel d-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 GI50 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 GI50 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.