Synthesis of potential prodrug systems for reductive activation. Prodrugs for anti-angiogenic isoflavones and VEGF receptor tyrosine kinase inhibitory oxindoles

A number of potential prodrug systems for reductive activation have been investigated. The prodrug systems chosen for the study were the 2-nitrophenylacetyl, 3-methyl-3-(3,6-dimethyl-1,4-benzoquinon-2-yl)butanoyl and 4-nitrobenzyl groups, readily attached to acidic OH or NH groups in drug molecules, and released upon bioreductive activation. The drug molecules studied were the naturally occurring isoflavone biochanin A, an inhibitor of VEGF-induced angiogenesis, and the pyrrolylmethylidenyl oxindole SU5416 (semaxanib) and its 6-hydroxy derivative, inhibitors of VEGF receptor tyrosine kinase. Following coupling the prodrug system to the drug, the compounds were evaluated chemically and biologically. Under chemical reducing conditions, the 3-methyl-3-(3,6-dimethyl-1,4-benzoquinon-2-yl)butanoic acid based prodrugs appear to fragment the most efficiently, followed by the 2-nitrophenylacetate esters with the 4-nitrobenzyl ethers being the least efficient. The potentially pro-anti-angiogenic compounds were also assayed for their ability to block VEGF-induced angiogenesis in HUVECS in comparison to the free agents. Control compounds that cannot be activated under bioreductive conditions are less potent than the free drug, whereas many of the potential prodrugs not only exhibit a dose response, but appear at least equipotent with the free drug.