title: Effect of aminomethyl (N-Mannich base) derivatization on the ability of S6-acetyloxymethyl-6-mercaptopurine prodrug to deliver 6-mercaptopurine through hairless mouse skin.
abstract: A series of 9-aminomethyl-S6-acetyloxymethyl-6-mercaptopurine (9-AM-6-AOM-6-MP) prodrugs have been synthesized and characterized, and their ability to deliver total 6-mercaptopurine (6-MP) through hairless mouse skin has been measured. The 9-AM-6-AOM-6-MP prodrugs are much more soluble in isopropyl myristate (IPM) than S6-acetyloxymethyl-6-MP (6-AOM-6-MP) itself or the corresponding 7-aminomethyl-6-MP (7-AM-6-MP) prodrugs. The 9-AM-6-AOM-6-MP prodrugs were all more effective (1.8-4 times) than 6-AOM-6-MP at delivering total 6-MP, except for the piperidylmethyl derivative which only gave a comparable rate of delivery. The 9-AM-6-AOM-6-MP prodrugs were also more effective (7-27 times) than the corresponding 7-AM-6-MP prodrugs at delivering 6-MP, except for the diethylaminomethyl derivative which only gave a comparable rate of delivery. In contrast to the 9-aminomethyl-S6-pivaloyloxymethyl-6-MP (9-AM-6-POM-6-MP) derivatives which generally delivered as much or more intact S6-pivaloyloxymethyl-6-MP (6-POM-6-MP) as 6-MP, the 9-AM-6-AOM-6-MP derivatives delivered mainly (80-95%) 6-MP from IPM. There was a direct correlation between log experimental permeability coefficients for delivery of total 6-MP (P sigma) and the calculated solubility parameter values for the 9-AM-6-AOM-6-MP prodrugs(delta j), with the P sigma generally decreasing as the value of delta j approached that of the vehicle, IPM.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Medicinal Chemistry, University of Florida, Gainesville 32610.
authors.forename: A N
authors.initials: AN
authors.lastname: Saab
authors.forename: K B
authors.initials: KB
authors.lastname: Sloan
authors.forename: H D
authors.initials: HD
authors.lastname: Beall
authors.forename: R
authors.initials: R
authors.lastname: Villaneuva
mesh_terms: D000818:Animals; D015122:Mercaptopurine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008812:Mice, Hairless; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D012869:Skin Absorption
chemical_list: D011355:Prodrugs; D015122:Mercaptopurine