α-(Fluoromethyl)dehydroornithine and α-(fluoromethyl)dehydroputrescine analogues as irreversible inhibitors of ornithine decarboxylase

Article abstract of DOI:10.1021/jm00365a002

(E)-Dehydro analogues of α-(fluoromethyl)putrescine and -ornithine derivatives were synthesized and evaluated in vitro as irreversible inhibitors of a preparation of ornithine decarboxylase (ODC, EC 4.1.1.17) obtained from rat liver. The key step in the synthesis of (E)-α-(fluoromethyl)dehydroornithine (17) and -putrescine (14) was the addition of propenylmagnesium bromide to fluoroacetonitrile. The resulting unstable conjugated imine salt was reduced regioselectively in situ with NaBH₄ or was quenched with a solution of NaCN to give the corresponding unsaturated α-(fluoromethyl) amine and α-amino nitrile, respectively. These were transformed into 17 and 14 via a four-step sequence involving (a) phthaloyation of the amine function; (b) allylic bromination of the methyl group; (c) Gabriel reaction; and (d) hydrolytic cleavage of the protective groups. (E)-α-(Difluoromethyl)dehydroornithine (10) and -putrescine (7) were prepared from ethyl tert-butyl 2-(difluoromethyl)-2-(2-propenyl)malonate and di-tert-butyl 2-(difluoromethyl)-2-(2-propenyl)malonate, respectively, via a sequence similar to that reported previously for the synthesis of the saturated analogues. Compounds 17, 14, 10, and 7 proved to be much more potent enzyme-activated irreversible inhibitors of ODC than the corresponding saturated analogues. The increase in potency is particularly marked in the α-fluoromethyl series. The apparent dissociation constants [K(I)] and the times of half-inactivation of enzyme (τ₅₀) at infinite concentration of inhibitors are 2.7 μM and 2.6 min for 17 and 42 μM and 0.2 min for 14. The K(I) and τ₅₀ of the corresponding saturated analogues are 75 μM and 1.6 min for the ornithine derivative and 56 μM and 4.4 min for the putrescine derived.