Difluoromethyl 2- ornithine

Diethylenetriaminepentaacetic acid DFMO al-Difluoromethyl ornithine DFP Diisopropyl fluorophosphate DFX Desferrioxamine DGLA Dihomo-y-linolenic acid DH Delayed hypersensitivity DHA Docosahexaenoic acid DHBA Dihydroxybenzoic acid DHR Delayed hypersensitivity reaction... 

Eflornithine (difluoromethyl ornithine, Ornidyl) is a unique antiprotozoal agent in that its mode of action involves inhibition of a specific enzyme, ornifhine decarboxylase. In eukaryofes, decarboxylafion of ornifhine is required for biosynfhesis of polyamines, which are im-porfanf in cell division and differenfiafion. 

The ban of halogenofluoromethanes (halons) for environmental reasons may reduce the benefit of this straightforward method, at least on the industrial level. Difluoromethyl ornithine (DFMO) was prepared industrially by this path (alkylation with CHCIF2). New approaches are currently the focus of research in order to restart its production. 

Ornithine decarboxylase is specifically inhibited by the enzyme-activated inhibitor a-difluoromethyl-ornithine, which can cure human infection with Trypanosoma brucei (African sleeping sickness) by interfering with polyamine synthesis.243-2443 In combination with inhibitors of spermidine synthase or S-adenosylmethionine decarboxylase,245 it can reduce polyamine levels and growth rates of cells. Another powerful inhibitor that acts on both ornithine and adenosylmethionine decarboxylases is the hydroxy-lamine derivative l-aminooxy-3-aminopropane 246... 

Anonymous. d,l-alpha-Difluoromethyl ornithine. DFMO. Eflornithine. Drugs Future 1985 10 242. 

The cream contains 13.9% (139 mg/g) anhydrous eflomi-thine hydrochloride as eflornithine hydrochloride monohydrate (150 mg/g). Chemically, eflornithine hydrochloride is ( )-2-(difluoromethyl)ornithine monohydrochloride monohydrate, with the empirical formula C6H12F2N202 ... 

Metcalf et al. (23) reported the synthesis of efiornithine (difluoromethyl ornithine [DFMO]) in 1978. Their interest arose from the desire to prepare ornithine decarboxylase (ODC) inhibitors as tools for studying the role of polyamines as regulators of growth processes. Ornithine decarboxylase catalyzes the conversion of ornithine to putrescine (1,4-diaminobutane), which in turn leads to the formation of the polyamines, spermine, and spermidine. It was not until 1980 that Bacchi et al. (24) demonstrated the potential of DFMO in the treatment of trypanosomiasis. 

Difluoromethyl ornithine is a suicide inhibitor of ODC, a pyridoxal phosphate-dependent enzyme. 

Difluoromethyl ornithine 10% Azone Porcine 1.30 McCullough etal., 1985... 

McCullough, J.L., Peckham, P, Klein, J., Weinstein, G.D., and Jenkins, J.J. (1985). Regulation of epidermal proliferation in mouse epidermis by combination of difluoromethyl ornithine (DEMO) and methylglyoxal bis(guanylhydrazone) (MGBG), J. Invest. Dermatol, 85 518-521. 

The concept of inhibition via p elimination of fluoride ion has now been extended to the irreversible inhibition of a-amino acid decarboxylases. Ornithine decarboxylase (ODC), which catalyzes the decarboxylation of ornithine to putrescine is irreversibly inhibited by a-difluoromethylornithine (IX Fig. 9) (28). In this case, the carbanion formation which precedes P elimination is generated by loss of CO2, and not by proton abstraction (Fig. 9). Similarly, aromatic amino acid decarboxylase is irreversibly inhibited by C-difluoromethyl-3,4-dihydroxyphenylalanine (29) while histidine decarboxylase, ornithine decarboxylase and aromatic amino acid decarboxylase have been inhibited by the corresponding <=d-monof luoromethylanri.no acids, respectively (29). 

Tire difluoromethyl analog of the natural substrate ornithine acts as a mechanism-based inhibitor of ornithine decarboxylase (OD). The final stage ofthe process is formation of a covalently bound complex with the enzyme and the coenzyme pyridoxal phosphate (PLP) [10] (Scheme 4.36). 

Abbreviations ADC, arginine decarboxylase ODC, ornithine decarboxylase SAM, 5-adenosylmethionine DFMA, DL-a-difluoromethylaiginine DFMO, DL-a-difluoromethyl-omithine MGBG, methylglyoxal bis(guanylhydrazone) DCHA, dicyclohexylamine. 

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