Synthesis and antitumor activity of new D-galactose-containing derivatives of doxorubicin.
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-beta-D-galactopyranosyl)-4-oxybenzaldehyde (12) or 4-O-(2,3,4,6-tetra-O-acetyl-beta-D-galactopyranosyl)-4-oxybenzaldehyde (13) by reductive alkylation followed by hydrolysis of the corresponding intermediate bromoketals produced 3'-N-[alpha-D-galactopyranosyl-(1-->6)-O-1-deoxy-D-glucit-1-yl]doxorubicin (7), 3'-N-[beta-D-galactopyranosyl-(1-->4)-O-1-deoxy-D-glucit-1-yl]doxorubicin (8), 3'-N-[3"-methoxy-4"-O-(beta-D-galactopyranosyl)-4"-oxybenzyl]doxorubicin (16), and 3'-N-[4"-O-(beta-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.
Olsufyeva
Eugenia N
EN
Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, B.Pirogovskaya 11, 119021, Moscow, Russia.
Tevyashova
Anna N
AN
Trestchalin
Ivan D
ID
Preobrazhenskaya
Maria N
MN
Platt
David
D
Klyosov
Anatole
A
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000031:analogs & derivatives*; D004354:Drug Screening Assays, Antitumor; D005690:Galactose / Q000737:chemistry*; D007939:Leukemia L1210 / Q000188:drug therapy / Q000473:pathology; D007941:Leukemia P388 / Q000188:drug therapy*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D004317:Doxorubicin; D005690:Galactose