1. Beta-galactoside prodrugs of doxorubicin for application in antibody directed enzyme prodrug therapy/prodrug monotherapy.
- Author
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Devalapally H, Navath RS, Yenamandra V, Akkinepally RR, and Devarakonda RK
- Subjects
- Buffers, Catalysis, Cell Line, Tumor, Escherichia coli enzymology, Half-Life, Humans, Indicators and Reagents, Kinetics, Magnetic Resonance Spectroscopy, Solutions, Spectrophotometry, Infrared, Spectrophotometry, Ultraviolet, beta-Galactosidase metabolism, Antibodies chemistry, Doxorubicin analogs & derivatives, Doxorubicin pharmacology, Enzymes chemistry, Galactosides chemical synthesis, Galactosides pharmacology, Prodrugs chemical synthesis, Prodrugs pharmacology
- Abstract
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.
- Published
- 2007
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