title: Alkylation of 6-mercaptopurine (6-MP) with N-alkyl-N-alkoxycarbonylaminomethyl chlorides: S6-(N-alkyl-N-alkoxycarbonyl)aminomethyl-6-MP prodrug structure effect on the dermal delivery of 6-MP.
abstract: The S6-(N-alkyl-N-alkoxycarbonyl)aminomethyl-6-MP (6-CARB-6-MP) prodrugs 5-20 were synthesized from the reaction of 6-MP with N-alkyl-N-alkyoxycarbonylaminomethyl chlorides (4) in dimethyl sulfoxide in overall yields of 5-62%, depending on the N-alkyl and the alkoxy groups involved. The derivatives were fully characterized by spectral and microanalyses. The assignment of the substitution pattern as S6-alkyl was based on comparisons of the UV, 1H NMR and 13C NMR spectra with model compounds. A S6, 9-bis-alkyl derivative was obtained from the reaction of 2 equivalents of 4 with 6-MP but the product was unstable and decomposed on standing to a 9-alkyl derivative. The 6-CARB-6-MP prodrugs reverted to 6-MP in water by an SN1-type mechanism involving unimolecular charge separation in the transition state of the rate determining step. There was no effect of dermal enzymes on the rate of hydrolysis. The solubilities in isopropyl myristate (IPM) for all of the 6-CARB-6-MP prodrugs were significantly greater than the solubility of 6-MP in IPM but only one prodrug (5) was apparently even as soluble as 6-MP in water. Selected 6-CARB-6-MP prodrugs were examined in diffusion cell experiments. Only the N-methyl-N-methoxycarbonyl derivative 5 gave a steady-state rate of delivery of 6-MP from IPM that was significantly greater than the steady-state rate of delivery of 6-MP from 6-MP in IPM. All the other derivatives gave steady-state rates of delivery of 6-MP from IPM that were either not significantly different, or were significantly lower than the rate obtained from 6-MP in IPM. In all cases, the effect of the 6-CARB-6-MP:IPM suspensions on the permeability of the skin, as determined by the second application flux of theophylline:propylene glycol, was of the same magnitude as the effect of IPM alone.
authors.affiliation: Department of Medicinal Chemistry, University of Florida, Gainesville 32610.
authors.forename: K G
authors.initials: KG
authors.lastname: Siver
authors.forename: K B
authors.initials: KB
authors.lastname: Sloan
mesh_terms: D000287:Administration, Topical; D000478:Alkylation; D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004058:Diffusion; D004355:Drug Stability; D006207:Half-Life; D009682:Magnetic Resonance Spectroscopy; D015122:Mercaptopurine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D051379:Mice; D008812:Mice, Hairless; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis*; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet
chemical_list: D011355:Prodrugs; D015122:Mercaptopurine