Design and synthesis of peptide conjugates of phosphoramide mustard as prodrugs activated by prostate-specific antigen. Issue 12 (15th June 2016)

• Record Type: Journal Article
• Authors: Wu, Xinghua; Hu, Longqin
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 12(2016)
• Page Start: 2697
• Page End: 2706
• Publication Date: 2016-06-15
• Subjects: Phosphoramide mustard prodrug -- Prostate-specific antigen -- Site-specific activation -- Self-immolative linker -- Structure–activity relationship; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.04.035
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: A series of Glutaryl-Hyp-Ala-Ser-Chg-Gln-4-aminobenzyl phosphoramide mustard conjugates (1a –e ) was designed and synthesized as potential prodrugs for site-specific activation by PSA in prostate cancer cells. All conjugates were found to be substrates of PSA with cleavage occurring between Gln and the para -aminobenzyl (PAB) linker. Structure–activity relationship studies on these conjugates indicated that introduction of electron-withdrawing fluorine(s) on the phenyl ring in the PAB linker uniformly improved the chemical stability of the conjugates while the position of substitution affected differently the self-immolative process of conjugates upon proteolysis. Introduction of a fluorine at ortho position to benzylic phosphoramide as in1b results in better stability of the conjugate prior to activation while maintaining its antiproliferative activity upon activation by PSA. The conjugate1b with 2-fluoro substitution was identified as a promising lead for further evaluation and optimization in the development of prostate cancer-targeted prodrugs.