title: Development of synthetic methodology suitable for the radiosynthesis of combretastatin A-1 (CA1) and its corresponding prodrug CA1P.
abstract: Synthetic methodology has been established suitable for the preparation of combretastatin A-1 (CA1) and its corresponding phosphate prodrug salt (CA1P) in high specific activity radiolabeled form. Judicious selection of appropriate phenolic protecting groups to distinguish positions on the A-ring from the B-ring of the stilbenoid was paramount for the success of this project. Methylation of the C-4' phenolic moiety by removal of the tert-butyldimethylsilyl protecting group in the presence of methyl iodide was accomplished in excellent yield without significant Z to E isomerization. This step (carried out with (12)C-methyl iodide as proof of concept in this study) represents the process in which a (14)C radioisotope could be incorporated in an actual radiosynthesis. CA1 is a natural product isolated from the African bush willow tree (Combretum caffrum) that has important medicinal value due, in part, to its ability to inhibit tubulin assembly. As a prodrug, CA1P (OXi4503) is in human clinical trials as a vascular disrupting agent.
authors.affiliation: Department of Chemistry and Biochemistry, Baylor University, Waco, Texas 76798, USA.
authors.forename: Anupama
authors.initials: A
authors.lastname: Shirali
authors.forename: Madhavi
authors.initials: M
authors.lastname: Sriram
authors.forename: John J
authors.initials: JJ
authors.lastname: Hall
authors.forename: Benson L
authors.initials: BL
authors.lastname: Nguyen
authors.forename: Rajsekhar
authors.initials: R
authors.lastname: Guddneppanavar
authors.forename: Mallinath B
authors.initials: MB
authors.lastname: Hadimani
authors.forename: J Freeland
authors.initials: JF
authors.lastname: Ackley
authors.forename: Rogelio
authors.initials: R
authors.lastname: Siles
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Jelinek
authors.forename: Phyllis
authors.initials: P
authors.lastname: Arthasery
authors.forename: Rodney C
authors.initials: RC
authors.lastname: Brown
authors.forename: Victor Leon
authors.initials: VL
authors.lastname: Murrell
authors.forename: Austin
authors.initials: A
authors.lastname: McMordie
authors.forename: Suman
authors.initials: S
authors.lastname: Sharma
authors.forename: David J
authors.initials: DJ
authors.lastname: Chaplin
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Pinney
mesh_terms: D000818:Animals; D029765:Combretum / Q000737:chemistry; D011756:Diphosphates / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D010946:Plants, Medicinal / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013267:Stilbenes / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D011756:Diphosphates; C465018:Oxi 4503; D011355:Prodrugs; D013267:Stilbenes; C063690:combretastatin A-1