Wu, Xinghua. Novel peptidylaminoarylmethyl phosphoramide mustards for activation by prostate-specific antigen. Retrieved from https://doi.org/doi:10.7282/T3B27VND
DescriptionA series of nitroarylmethyl phosphoramide mustards was designed, synthesized and evaluated as nitroreductase-targeted prodrugs in gene-directed enzyme-prodrug therapy. Among them, fluorinated prodrugs showed improved bystander effect, cytotoxicity and selectivity. Based on the similar drug release mechanism via 1,6-elimination, a series of peptidylaminoarylmethyl phosphoramide mustards was designed, targeting prostate-specific antigen (PSA) as a prodrug-converting enzyme. By design, the prodrugs would only be activated after proteolytic cleavage of the PSA-specific peptide by PSA and then selectively release the highly cytotoxic phosphoramide mustard at the prostate tumor site. Among the synthesized prodrugs, the 2-fluorinated derivative had over 19-fold selectivity against PSA-secreting cancer cells with an IC50 of 5.3 µM according to in vitro antiproliferative cell assays.
To overcome the difficulty of synthesizing the designed peptidylaminoarylmethyl phosphoramide mustards, a novel selenocarboxylate/azide amidation methodology was developed. This strategy not only played a crucial role in the success of this project but also provided an excellent solution to the acylation of highly electron-deficient amines. Selenocarboxylate/azide amidation has been successfully used to synthesize a series of amino acid-pNAs and amino acid-AMCs that are important synthons in the synthesis of chromogenic and fluorogenic protease substrates.