title: Design and synthesis of phosphotyrosine peptidomimetic prodrugs.
abstract: A novel approach to the intracellular delivery of aryl phosphates has been developed that utilizes a phosphoramidate-based prodrug approach. The prodrugs contain an ester group that undergoes reductive activation intracellularly with concomitant expulsion of a phosphoramidate anion. This anion undergoes intramolecular cyclization and hydrolysis to generate aryl phosphate exclusively with a t(1/2) = approximately 20 min. Phosphoramidate prodrugs (8-10) of phosphate-containing peptidomimetics that target the SH2 domain were synthesized. Evaluation of these peptidomimetic prodrugs in a growth inhibition assay and in a cell-based transcriptional assay demonstrated that the prodrugs had IC50 values in the low micromolar range. Synthesis of phosphorodiamidate analogues containing a P-NH-Ar linker (16-18) was also carried out in the hope that the phosphoramidates released might be phosphatase-resistant. Comparable activation rates and cell-based activities were observed for these prodrugs, but the intermediate phosphoramidate dianion underwent spontaneous hydrolysis with a t(1/2) = approximately 30 min.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, and the Cancer Center, Purdue University, West Lafayette, Indiana 47907, USA.
authors.forename: Hugo
authors.initials: H
authors.lastname: Garrido-Hernandez
authors.forename: Kyung D
authors.initials: KD
authors.lastname: Moon
authors.forename: Robert L
authors.initials: RL
authors.lastname: Geahlen
authors.forename: Richard F
authors.initials: RF
authors.lastname: Borch
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology; D002463:Cell Membrane Permeability; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D006868:Hydrolysis; D019169:Jurkat Cells; D007700:Kinetics; D018716:Molecular Mimicry; D010755:Organophosphates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry*; D010756:Phosphoric Acids / Q000138:chemical synthesis / Q000494:pharmacology; D019000:Phosphotyrosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D018909:src Homology Domains
chemical_list: D000577:Amides; D010755:Organophosphates; D010455:Peptides; D010756:Phosphoric Acids; D011355:Prodrugs; D019000:Phosphotyrosine; C011067:phosphoramidic acid