Development of synthetic methodology suitable for the radiosynthesis of combretastatin A-1 (CA1) and its corresponding prodrug CA1P.
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.
Shirali
Anupama
A
Department of Chemistry and Biochemistry, Baylor University, Waco, Texas 76798, USA.
Sriram
Madhavi
M
Hall
John J
JJ
Nguyen
Benson L
BL
Guddneppanavar
Rajsekhar
R
Hadimani
Mallinath B
MB
Ackley
J Freeland
JF
Siles
Rogelio
R
Jelinek
Christopher J
CJ
Arthasery
Phyllis
P
Brown
Rodney C
RC
Murrell
Victor Leon
VL
McMordie
Austin
A
Sharma
Suman
S
Chaplin
David J
DJ
Pinney
Kevin G
KG
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
D011756:Diphosphates; C465018:Oxi 4503; D011355:Prodrugs; D013267:Stilbenes; C063690:combretastatin A-1