title: Synthesis and biological properties of bioreductively targeted nitrothienyl prodrugs of combretastatin A-4.
abstract: Nitrothienylprop-2-yl ether formation on the 3'-phenolic position of combretastatin A-4 (1) abolishes the cytotoxicity and tubulin polymerization-inhibitory effects of the drug. 5-Nitrothiophene derivatives of 1 were synthesized following model kinetic studies with analogous coumarin derivatives, and of these, compound 13 represents a promising new lead in bioreductively targeted cytotoxic anticancer therapies. In this compound, optimized gem-dimethyl alpha-carbon substitution enhances both the aerobic metabolic stability and the efficiency of hypoxia-mediated drug release. Only the gem-substituted derivative 13 released 1 under anoxia in either in vitro whole-cell experiments or supersomal suspensions. The rate of release of 1 from the radical anions of these prodrugs is enhanced by greater methyl substitution on the alpha-carbon. Cellular and supersomal studies showed that this alpha-substitution pattern controls the useful range of oxygen concentrations over which 1 can be effectively released by the prodrug.
authors.affiliation: Gray Cancer Institute, University of Oxford, Mount Vernon Hospital, Northwood, Middlesex, United Kingdom. thomson@gci.ac.uk
authors.forename: Peter
authors.initials: P
authors.lastname: Thomson
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Naylor
authors.forename: Steven A
authors.initials: SA
authors.lastname: Everett
authors.forename: Michael R L
authors.initials: MR
authors.lastname: Stratford
authors.forename: Gemma
authors.initials: G
authors.lastname: Lewis
authors.forename: Sally
authors.initials: S
authors.lastname: Hill
authors.forename: Kantilal B
authors.initials: KB
authors.lastname: Patel
authors.forename: Peter
authors.initials: P
authors.lastname: Wardman
authors.forename: Peter D
authors.initials: PD
authors.lastname: Davis
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009574:Nitro Compounds / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D013267:Stilbenes / Q000737:chemistry* / Q000378:metabolism*; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry; D013997:Time Factors; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D009574:Nitro Compounds; D011355:Prodrugs; D013267:Stilbenes; D013876:Thiophenes; D014404:Tubulin; C058728:fosbretabulin