Synthesis and biological activity of novel N6-substituted and 2,N6-disubstituted adenine ribo- and 3′-C-methyl-ribonucleosides as antitumor agents

A series of N6-aminopurine-9-β-d-ribonucleosides and ribose-modified 3′-C-methyl analogues substituted at N6-position with a small group like hydroxy, methoxy or amino group or at C2(N6) position have been synthesized and tested against a panel of human leukemia and carcinoma cell lines. N6-Hydrazino-9-β-d-ribofuranosyl-purine (5) displayed the best antiproliferative activity in the low micromolar or submicromolar range against all tested tumor cell lines. The activity of this nucleoside is related in part to ribonucleotide reductase inhibition. C2-modification or 3′-C-methylation in N6-substituted adenosine analogues leads to a decrease or loss in activity.

Graphical abstractA series of N6-aminopurine-9-β-d-ribonucleosides and ribose-modified 3′-C-methyl analogues substituted at N6-position with a small group like hydroxy, methoxy or amino group or at C2(N6)-positions have been synthesized and tested against a panel of human leukemia and carcinoma cell lines. N6-Hydrazino-9-β-d-ribofuranosyl-purine (5) displayed the best antiproliferative activity in the low micromolar or submicromolar range against all tested tumor cell lines. Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► N6-amino-adenosine is a potent antiproliferative agent. ► N6-amino-adenosine is an inhibitor of ribonucleotide reductase. ► Antitumor agent N6-amino-adenosine has multi-target characteristics.