Abstract
New prodrugs consisting of a beta-D-glucuronic acid linked to a MDR reversal agent (verapamil, quinine or dipyridamole) through a self-immolative spacer were synthesized. Four of them were selected for their reduced cytoxicity and beta-glucuronidase enzymatic efficient hydrolysis. Combined use of these prodrugs with a beta-D-glucuronyl-spacer-doxorubicin (HMR1826) according to an ADEPT strategy restored in vitro the sensibility of a MDR resistant strain.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Chromatography, High Pressure Liquid
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Dipyridamole / chemistry
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Dipyridamole / pharmacology
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Doxorubicin / chemistry
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Drug Resistance, Multiple
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Drug Resistance, Neoplasm
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Drug Stability
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Escherichia coli / enzymology
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Glucuronates / chemistry
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Glucuronic Acid
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Glucuronidase / chemistry
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Humans
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Hydrolysis
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Leukemia L1210 / pathology
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Prodrugs / chemical synthesis*
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Prodrugs / chemistry
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Prodrugs / pharmacology
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Quinine / chemistry
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Quinine / pharmacology
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Spectrophotometry, Ultraviolet
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Structure-Activity Relationship
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Tumor Cells, Cultured
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Verapamil / chemistry
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Verapamil / pharmacology
Substances
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Antineoplastic Agents
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Glucuronates
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Prodrugs
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Dipyridamole
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Doxorubicin
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Glucuronic Acid
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Quinine
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Verapamil
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Glucuronidase