Beta-galactoside prodrugs of doxorubicin for application in antibody directed enzyme prodrug therapy/prodrug monotherapy.
Anthracycline antibiotics, particularly doxorubicin and daunorubicin, have been used exten sively in the treatment of human malignancies. However cardiotoxicity and multidrug resistance are significant problems that limit the clinical efficacy of such agents. Rational design to avoid these side effects includes strategies such as drug targeting and prodrug synthesis. Described here are the synthesis and preliminary biological evaluation of the enzymatically activated two new prodrugs (6 & 11) of doxorubicin. These prodrugs were designed as potential candidates for selective chemotherapy in ADEPT or PMT strategies. They are constituted of a galactose moiety, a spacer and the cytotoxic drug and they differ by the type of spacer. The prodrugs were stable in a buffer, and the in vitro studies showed good detoxification and hydrolysis kinetics. As prodrug 11 was readily hydrolyzed, this could be a valuable candidate for further development.
Drug Metabolism, Pharmacokinetics, Cancer & Aging Research Division, University College of Pharmaceutical Sciences, Kakatiya University, Warangal-9, AP, India.
HariKrishna
H
Devalapally
Raghavendra Swamy
RS
Navath
Venkateshwarlu
V
Yenamandra
RaghuRam Rao
RR
Akkinepally
Rama Krishna
RK
Devarakonda
D000906:Antibodies / Q000737:chemistry*; D002021:Buffers; D002384:Catalysis; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004798:Enzymes / Q000737:chemistry*; D004926:Escherichia coli / Q000201:enzymology; D005697:Galactosides / Q000138:chemical synthesis* / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D007202:Indicators and Reagents; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology*; D012996:Solutions; D013055:Spectrophotometry, Infrared; D013056:Spectrophotometry, Ultraviolet; D001616:beta-Galactosidase / Q000378:metabolism
D000906:Antibodies; D002021:Buffers; D004798:Enzymes; D005697:Galactosides; D007202:Indicators and Reagents; D011355:Prodrugs; D012996:Solutions; C007816:beta-galactoside; D004317:Doxorubicin; D001616:beta-Galactosidase