title: N-(2-hydroxypropyl)methacrylamide copolymers of a glutathione (GSH)-activated glyoxalase i inhibitor and DNA alkylating agent: synthesis, reaction kinetics with GSH, and in vitro antitumor activities.
abstract: The incorporation of anticancer prodrugs into polyacrylamide conjugates has been shown to improve tumor targeting via the so-called "enhanced permeability and retention" effect. This strategy has now been expanded to include two different classes of glutathione (GSH)-activated antitumor agents prepared by radical polymerization of N-(2-hydroxypropyl)methacrylamide (HPMA) with 2-methacryloyloxy-methyl-2-cyclohexenone (7) and/or with S-(N-4-chlorophenyl-N-hydroxycarbamoyl-thioethyl)methacrylamide (8), followed by treatment with 3-chloroperoxybenzoic acid, to give the HPMA copolymers of 7 and the 8-sulfoxide, respectively. In aqueous-buffered solution at pH 6.5, GSH reacts rapidly with poly-HPMA-8-sulfoxide (k approximately 2.3 mM(-1) min(-1)) to give S-(N-4-chlorophenyl-N-hydroxycarbamoyl)glutathione (1), a tight-binding transition state analogue inhibitor of the antitumor target enzyme glyoxalase I (K(i) = 46 nM), or with poly-HPMA-7 (k approximately 0.02 mM(-1) min(-1)) to give the electrophilic antitumor agent 3-glutathio-2-methylenecyclohexenone (4). Indeed, B16 melanotic melanoma in culture is inhibited by poly-HPMA-8-sulfoxide and by poly-HPMA-7 with IC(50) values of 168 +/- 8 and 284 +/- 5 microM, respectively. These values are significantly greater than those of the unpolymerized prodrugs suggesting that the cytotoxicity of the polymer prodrugs might be limited by slow cellular uptake via pinocytosis. This prodrug strategy should be applicable to a range of different GSH-based antitumor agents.
authors.affiliation: Department of Chemistry and Biochemistry, University of Maryland, Baltimore, Maryland 21250, USA.
authors.forename: Zhe-Bin
authors.initials: ZB
authors.lastname: Zheng
authors.forename: Guozhang
authors.initials: G
authors.lastname: Zhu
authors.forename: Heekyung
authors.initials: H
authors.lastname: Tak
authors.forename: Erin
authors.initials: E
authors.lastname: Joseph
authors.forename: Julie L
authors.initials: JL
authors.lastname: Eiseman
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Creighton
mesh_terms: D000178:Acrylamides / Q000737:chemistry*; D000477:Alkylating Agents / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000378:metabolism*; D004705:Endocytosis; D005978:Glutathione / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D007791:Lactoylglutathione Lyase / Q000037:antagonists & inhibitors*; D051379:Mice; D015394:Molecular Structure; D011108:Polymers / Q000737:chemistry*; D013057:Spectrum Analysis
chemical_list: D000178:Acrylamides; D000477:Alkylating Agents; D000970:Antineoplastic Agents; D011108:Polymers; D004247:DNA; D007791:Lactoylglutathione Lyase; D005978:Glutathione; C032976:N-(2-hydroxypropyl)methacrylamide