Combretastatin A-3 prodrug
AssigneeArizona Board of Regents, A Body Corporate of the State of Arizona Acting for and On Behalf of Arizona State University
InventorsGeorge R. Pettit, Mathew D. Minardi
Life of this patent
Estimating the term…
Abstract
A new and more efficient synthesis of combretastatin A-3 (2a) was completed (8.4% overall yield) starting from methyl gallate and isovanillin with aldehyde 5 and phosphonium salt 8 as key intermediates. Conversion of combretastatin A-3 (2a) to a series of diphosphate prodrugs (lOa-lOl) containing selected anions was achieved. Both the diphosphate sodium (lOa) and potassium salts (lOc) displayed aqueous solubility in excess of 220 mg/ml at room temperature and good cancer cell line inhibitory activity.
Claims6
A method for preparing a Combretastatin A-3 diphosphate prodrug having the following structure:
- wherein Z is Na, said method comprising performing the reactions as set forth below in the following reaction scheme:
- Reagents and Conditions:
- (a) n-Bu-Li, THF, −78° C.;
- (b) 4-5-Dimethoxy-3-O-tert-butyldimethyl silyloxy-benzaldehyde in 20 mL THF;
- (c) 1M TBAF;
- (d) CCl4, DIPEA, DMAP, Dibenzyl phosphite, −10° C., ACN;
- (e) TMSBr, CH2Cl2;
- (f) sodium methoxide and ethanol.
A compound having the following structure:
- wherein Z is a cation selected from the group consisting of sodium, lithium, potassium, rubidium, calcium, zinc, manganese and magnesium or Z is an amine selected from the group consisting of quinine, quinidine, morpholine and nicotinamide.
Dependencies are inferred from the claim text.