title: Bioreductively activatable prodrug conjugates of phenstatin designed to target tumor hypoxia.
abstract: A variety of solid tumor cancers contain significant regions of hypoxia, which provide unique challenges for targeting by potent anticancer agents. Bioreductively activatable prodrug conjugates (BAPCs) represent a promising strategy for therapeutic intervention. BAPCs are designed to be biologically inert until they come into contact with low oxygen tension, at which point reductase enzyme mediated cleavage releases the parent anticancer agent in a tumor-specific manner. Phenstatin is a potent inhibitor of tubulin polymerization, mimicking the chemical structure and biological activity of the natural product combretastatin A-4. Synthetic approaches have been established for nitrobenzyl, nitroimidazole, nitrofuranyl, and nitrothienyl prodrugs of phenstatin incorporating nor-methyl, mono-methyl, and gem-dimethyl variants of the attached nitro compounds. A series of BAPCs based on phenstatin have been prepared by chemical synthesis and evaluated against the tubulin-microtubule protein system. In a preliminary study using anaerobic conditions, the gem-dimethyl nitrothiophene and gem-dimethyl nitrofuran analogues were shown to undergo efficient enzymatic cleavage in the presence of NADPH cytochrome P450 oxidoreductase. Each of the eleven BAPCs evaluated in this study demonstrated significantly reduced inhibitory activity against tubulin in comparison to the parent anti-cancer agent phenstatin (IC50=1.0μM). In fact, the majority of the BAPCs (seven of the eleven analogues) were not inhibitors of tubulin polymerization (IC50>20μM), which represents an anticipated (and desirable) attribute for these prodrugs, since they are intended to be biologically inactive prior to enzyme-mediated cleavage to release phenstatin.
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, TX 76798-7348, United States.
authors.forename: Blake A
authors.initials: BA
authors.lastname: Winn
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, TX 76798-7348, United States.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Shi
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, TX 76798-7348, United States.
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Carlson
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, TX 76798-7348, United States.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, TX 76798-7348, United States.
authors.forename: Benson L
authors.initials: BL
authors.lastname: Nguyen
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, TX 76798-7348, United States.
authors.forename: Evan M
authors.initials: EM
authors.lastname: Kelly
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, TX 76798-7348, United States.
authors.forename: R David
authors.initials: RD
authors.lastname: Ross
authors.affiliation: Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, MD 21702, United States.
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, TX 76798-7348, United States; Mateon Therapeutics, Inc., 701 Gateway Boulevard, Suite 210, South San Francisco, CA 94080, United States.
authors.forename: David J
authors.initials: DJ
authors.lastname: Chaplin
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, TX 76798-7348, United States. Electronic address: Mary_Lynn_Trawick@baylor.edu.
authors.forename: Mary L
authors.initials: ML
authors.lastname: Trawick
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, TX 76798-7348, United States. Electronic address: Kevin_Pinney@baylor.edu.
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Pinney
mesh_terms: D001577:Benzophenones / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000072258:Tumor Hypoxia / Q000187:drug effects*
chemical_list: D001577:Benzophenones; D011355:Prodrugs; D014404:Tubulin; D050257:Tubulin Modulators; C000612885:phenstatin
keywords: Bioreductively activatable prodrug conjugates (BAPCs); Inhibitors of tubulin polymerization; Phenstatin; Prodrug synthesis; Tumor-associated hypoxia