Eflornithine

Metcalf et al.reported the synthesis of eflornithine (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. demonstrated the potential of DFMO in the treatment of trypanosomiasis.

Eflomithine Hydrochloride: C16 H12F2N2O2·HCl·H20. Crystallized from water-ethanol, melting point 183°C.

ChEBI: Eflornithine is a fluoroamino acid that is ornithine substituted by a difluoromethyl group at position 2. It has a role as a trypanocidal drug. It is a fluoroamino acid and an alpha-amino acid. It is functionally related to an ornithine.

15 THF was cooled to -80°C, 2.82 L of diisopropylamine was added under the protection of nitrogen, and then 12 L of 15% butyllithium in hexane was added at a rate to maintain the temperature of the reaction solution at -75 to -80°C. Then, a solution of N, N'-diphenylmethylene ornithine methyl ester (I) dissolved in 15 L of THF was added. After the addition is complete, slowly increase to 35~40°C, and replace nitrogen with bubbling with chlorodifluoromethane to carry out the reaction. 20L saturated sodium chloride solution and 75L isopropyl ether were added, the organic layer was separated, and the aqueous layer was extracted. The extract and the organic layer were combined, washed with saturated sodium chloride solution, and concentrated to a residual oil, which was Compound (II). The oily substance and 30 Llmol/L hydrochloric acid were reacted at room temperature for 3 hours for hydrolysis. After the reaction was completed, it was extracted with chloroform, and the extract was discarded. The extracted water layer was diluted with 6L of water, adjusted to Ph value of 3.3, heated, filtered, washed, and recrystallized to obtain eflunithine.

Labelled Eflornithine. Irreversible inhibitor of ornithine decarboxylase, an enzyme involved in polyamine biosynthesis. Antineoplastic; antipneumocystic; antiprotozoal (Trypanosoma). Used in the treatment of hirsutism.

Eflornithine is an irreversible inhibitor of ornithine decarboxylase that blocks putrescine biosynthesis in T. brucei in vitro and inhibits the growth and multiplication of the parasite in vivo. The drug, administered orally or parenterally, is relatively nontoxic and is effective in eliminating the parasite T. b. rhodesiense and, to a greater extent, T. b. gambiense. Eflornithine was approved for human use by the FDA in late 1990. Side effects associated with oral administration are diarrhea, nausea, and vomiting. There is a significant relapse rate. A mixture of eflornithine (5) and nifurtimox (6, C10H13N3O5S, Lampit, Bayer 2502) shows good activity against T. b. gambiense. The former compound is also reported to potentiate the effect of melarsoprol in infected mice.