.alpha.-(Fluoromethyl)dehydroornithine and .alpha.-(fluoromethyl)dehydroputrescine analogs as irreversible inhibitors of ornithine decarboxylase

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Abstract
(E)-Dehydro analogs of .alpha.-(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)-.alpha.-(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 .alpha.-(fluoromethyl) amine and .alpha.-amino nitrile, respectively. These were transformed into 17 and 14 via a 4-step sequence involving the following: phthaloyation of the amine function; allylic bromination of the methyl group; Gabriel reaction; and hydrolytic cleavage of the protective groups. (E)-.alpha.-(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 analogs. Compounds 17, 14, 10 and 7 were much more potent enzyme-activated irreversible inhibitors of ODC than the corresponding saturated analogs. The increase in potency was particularly marked in the .alpha.-fluoromethyl series. The apparent dissociation constants (KI) and the times of half-inactivation of enzyme (.tau.50) at infinite concentration of inhibitors were 2.7 .mu.M and 2.6 min for 17 and 42 .mu.M and 0.2 min for 14. The KI and .tau.50 of the corresponding saturated analogs were 75 .mu.M and 1.6 min for the ornithine derivative and 56 .mu.M and 4.4 min for the putrescine derivative.