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Bioreductive heterosubstituted quinone antitumor drug delivery agents
Abstract
In an attempt to overcome the inherent problems of poor selectivity for tumor cells and toxicity to normal tissues which plague most current chemotherapeutic regimens, heterosubstituted quinone propanoic acid derivatives designed to be used as hypoxia-selective bioreductive drug delivery agents were prepared. It is believed that the heterosubstitution will provide both negative reduction potentials similar to that of the known antitumor agent mitomycin C and acceptable aqueous solubilities. Alkoxy- and aminoquinone propanoic acids were prepared initially and the quinone-drug conjugates were obtained as amides or thioesters by reaction of the corresponding in situ generated symmetric quinone acid anhydrides with the known cytotoxic agents bis(2-chloroethyl)amine, 4-(3-methyltriazeno) toluene, 4-(methyltriazeno)imidazole-5-carboxamide, 5-fluorouracil, and 6-mercaptopurine. These agents are designed to be selectively reduced at an oxygen deficient hypoxic tumor site to the transient hydroquinone amides or thioesters which then should cyclize to the related lactones with concurrent release of the cytotoxic drugs. The controlled release should result in the selective kill of tumor cells with minimal toxic effects in normal tissues. This approach is based upon studies of similar quinone-based antitumor compounds which are thought to operate via initial bioreductive activation. Tests on both model quinone amides and the quinone-drug conjugates show that under reductive conditions lactonization and drug release does indeed occur. Biological testing of the various quinone derivatives prepared is currently in progress in several laboratories.
Subject Area
Organic chemistry
Recommended Citation
Berglund, Richard Alan, "Bioreductive heterosubstituted quinone antitumor drug delivery agents" (1987). Doctoral Dissertations Available from Proquest. AAI8805895.
https://scholarworks.umass.edu/dissertations/AAI8805895