Synthesis and biological properties of bioreductively targeted nitrothienyl prodrugs of combretastatin A-4.
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.
Thomson
Peter
P
Gray Cancer Institute, University of Oxford, Mount Vernon Hospital, Northwood, Middlesex, United Kingdom. thomson@gci.ac.uk
Naylor
Matthew A
MA
Everett
Steven A
SA
Stratford
Michael R L
MR
Lewis
Gemma
G
Hill
Sally
S
Patel
Kantilal B
KB
Wardman
Peter
P
Davis
Peter D
PD
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
D000972:Antineoplastic Agents, Phytogenic; D009574:Nitro Compounds; D011355:Prodrugs; D013267:Stilbenes; D013876:Thiophenes; D014404:Tubulin; C058728:fosbretabulin