alpha-Monofluoromethyl and alpha-difluoromethyl putrescine as ornithine decarboxylase inhibitors: in vitro and in vivo biochemical properties.
In vitro, 5-fluoropentane-1,4-diamine and 5,5-difluoropentane-1,4-diamine are potent enzyme-activated inhibitors of rat liver ornithine decarboxylase (EC 4.1.1.17). The two alpha-fluoromethyl derivatives of putrescine activate to different degrees S-adenosyl-L-methionine decarboxylase (EC 4.1.1.50). The difluoromethyl derivative differs from the monofluoromethyl derivative in that it is not a substrate of diamine oxidase (EC 1.4.3.6), but is a better substrate of mitochondrial monoamine oxidase (EC 1.4.3.4) than the monofluoromethyl derivative. In vivo, a single i.p. injection of 200 mg/kg of 5-fluoropentane-1,4-diamine to rats causes a marked decrease of the ornithine decarboxylase activity in the ventral prostate and to a lesser extent in the thymus, whereas 5,5-difluoropentane-1,4-diamine causes only a slight decrease of this enzyme activity in the prostate and does not affect it in the thymus. Both compounds produce a decrease of 4-aminobutyrate: 2-oxoglutarate aminotransferase (EC 2.6.1.19) activity in the brain. The differences observed between the biochemical properties of the two alpha-fluoromethyl derivatives of putrescine are discussed in relation to the pKa value of the alpha-amino group which decreases from 7.75 for 5-fluoropentane-1,4-diamine to 6.4 for 5,5-difluoropentane-1,4-diamine.
D000818:Animals; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors*; D055598:Chemical Phenomena; D002621:Chemistry; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008297:Male; D065108:Ornithine Decarboxylase Inhibitors; D011467:Prostate / Q000201:enzymology; D011700:Putrescine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013737:Testis / Q000201:enzymology; D013950:Thymus Gland / Q000201:enzymology; D013997:Time Factors
D065108:Ornithine Decarboxylase Inhibitors; C035578:alpha-monofluoromethylputrescine; C036845:alpha-difluoromethylputrescine; D002262:Carboxy-Lyases; D011700:Putrescine