Synthesis and antitumor activity of new d-galactose-containing derivatives of doxorubicin Original Research Article

A general scheme of synthesis of antibiotic doxorubicin derivatives is based on the 13-dimethyl ketal of 14-bromodaunorubicin (4). The interaction of 4 with melibiose (5), lactose (6), 3-methoxy-4-O-(2,3,4,6-tetra-O-acetyl-β-d-galactopyranosyl)-4-oxybenzaldehyde (12) or 4-O-(2,3,4,6-tetra-O-acetyl-β-d-galactopyranosyl)-4-oxybenzaldehyde (13) by reductive alkylation followed by hydrolysis of the corresponding intermediate bromoketals produced 3′-N-[α-d-galactopyranosyl-(1→6)-O-1-deoxy-d-glucit-1-yl]doxorubicin (7), 3′-N-[β-d-galactopyranosyl-(1→4)-O-1-deoxy-d-glucit-1-yl]doxorubicin (8), 3′-N-[3″-methoxy-4″-O-(β-d-galactopyranosyl)-4″-oxybenzyl]doxorubicin (16), and 3′-N-[4″-O-(β-d-galactopyranosyl)-4″-oxybenzyl]doxorubicin (17). Cytotoxic and antitumor activity of the synthesized drug candidates compared to the parent doxorubicin was studied using various experimental models, in particular, on mice bearing lymphocyte leukemia P-388 at single and multiple i.v. injection regimens.