Synthesis and Antiproliferative Evaluation of d‐Glucuronamide‐Based Nucleosides and (Triazolyl)methyl Amide‐Linked Pseudodisaccharide Nucleosides**

Abstract

AbstractThe synthesis and antiproliferative evaluation of novel d‐glucopyranuronamide‐containing nucleosides is described. Based on our previously reported anticancer d‐glucuronamide‐based nucleosides, new analogues comprising N/O‐dodecyl or N‐propargyl substituents at the glucuronamide unit and anomerically‐N‐linked 2‐acetamido‐6‐chloropurine, 6‐chloropurine or 4‐(6‐chloropurinyl)methyl triazole motifs were synthesized in 4–6 steps starting from acetonide‐protected glucofuranurono‐6,3‐lactone. The methodologies were based on the access to N‐substituted glycopyranuronamide precursors, namely 1,2‐O‐acetyl derivatives or glucuronoamidyl azides for further nucleobase N‐glycosylation or 1,3‐dipolar cycloaddition with N9‐ and N7‐propargyl‐6‐chloropurines, respectively. N‐Propargyl glucuronamide‐based N9‐purine nucleosides were converted into (triazolyl)methyl amide‐6,6‐linked pseudodisaccharide nucleosides via cycloaddition with methyl 6‐azido‐glucopyranoside. A CuI/Amberlyst A‐21 catalytic system employed in the cycloaddition reactions also effected conversion into 6‐dimethylaminopurine nucleosides. Antiproliferative evaluation in chronic myeloid leukemia (K562) and breast cancer (MCF‐7) cells revealed significant effects exhibited by the synthesized monododecylated purine‐containing nucleosides. A N‐propargyl 3‐O‐dodecyl glucuronamide derivative comprising a N9‐β‐linked 6‐chloropurine moiety was the most active compound against MCF‐7 cells (GI50=11.9 μM) while a related α‐(purinyl)methyltriazole nucleoside comprising a N7‐linked 6‐chloropurine moiety exhibited the highest activity against K562 cells (GI50=8.0 μM). Flow cytometry and immunoblotting analysis of apoptosis‐related proteins in K562 cells treated with the N‐propargyl 3‐O‐dodecyl glucuronamide‐based N9‐linked 6‐chloropurine nucleoside indicated that it acts via apoptosis induction.