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A series of sulfonyl-containing 5-fluoro-2‘-deoxyuridine (FdU) phosphotriester and phosphoramidate analogues were designed and synthesized as anticancer prodrugs of FdUMP. Stability studies have demonstrated that these compounds underwent pH dependent β-elimination to liberate the corresponding nucleotide species with half-lives in the range of 0.33−12.23 h under model physiological conditions in 0.1 M phosphate buffer at pH 7.4 and 37 °C. Acceleration of the elimination was observed in the presence of human plasma. Compounds with an FdUMP moiety (4−9) were considerably more potent than those without (1−3) as well as 5-fluorouracil (5-FU) against Chinese hamster lung fibroblasts (V-79 cells) in vitro. Addition of thymidine (10 μM) reversed the growth inhibition activities of only 5-FU and the compounds with an FdUMP moiety, but had no effect on those without. These results are consistent with thymidylate synthase as the target of the prodrugs. Keywords: 5-FU; nucleotide prodrug; sulfonyl; β-elimination

A series of (S)-(+)-5-n-propyl-2-iminohydantoins with various N-1 substituents were synthesized and tested for anticonvulsant activity to better understand the structure–activity relationship (SAR) of 2-iminohydantoins. Compounds with N-1 phenoxycarbonyl (2), ethoxycarbonyl (6), t-butoxycarbonyl (7), propoxycarbonyl (12), and p-methyl phenoxycarbonyl (14) groups provided the most substantial anticonvulsant activity against the maximal electroshock seizure (MES) test with ED50 values in the range of 72–124 mg/kg. All of the above compounds except 7 also showed activity against the pentylenetetrazol (PTZ) test with ED50 values in the range of 65–178 mg/kg. Compound 6 provided the highest protective index (PI) value against the PTZ test, while 7 provided the highest PI value against the MES test. All significantly active compounds against the MES test (1, 2, 6, 7, 12, and 14) possessed aliphatic hydrocarbon chains of relatively small carbon length or aryl/arylalkyl groups not greater than benzyl in the carbamate moiety. Longer or larger than a benzyl group (3, 5, 8, 9, 10, and 11) or a saturated six-member ring (4) destroyed the activity. In addition, N-1 methoxycarbonyl substituted compound (13) was also devoid of significant activity. These results suggest that steric size of the substituent at N-1 oxycarbonyl sidechain in the 2-iminohydantoin molecule plays an important role in providing anticonvulsant activity, and that an alkyl substituent with a proper size further enhances PTZ anticonvulsant activity while maintaining MES activity. Drug Dev. Res. 47:17–26, 1999. © 1999 Wiley-Liss, Inc.

A series of (S)‐(+)‐5‐n‐propyl‐2‐iminohydantoins with various N‐1 substituents were synthesized and tested for anticonvulsant activity to better understand the structure–activity relationship (SAR) of 2‐iminohydantoins. Compounds with N‐1 phenoxycarbonyl (2), ethoxycarbonyl (6), t‐butoxycarbonyl (7), propoxycarbonyl (12), and p‐methyl phenoxycarbonyl (14) groups provided the most substantial anticonvulsant activity against the maximal electroshock seizure (MES) test with ED50values in the range of 72–124 mg/kg. All of the above compounds except 7also showed activity against the pentylenetetrazol (PTZ) test with ED50values in the range of 65–178 mg/kg. Compound 6provided the highest protective index (PI) value against the PTZ test, while 7provided the highest PI value against the MES test. All significantly active compounds against the MES test (1, 2, 6, 7, 12, and 14) possessed aliphatic hydrocarbon chains of relatively small carbon length or aryl/arylalkyl groups not greater than benzyl in the carbamate moiety. Longer or larger than a benzyl group (3, 5, 8, 9, 10, and 11) or a saturated six‐member ring (4) destroyed the activity. In addition, N‐1 methoxycarbonyl substituted compound (13) was also devoid of significant activity. These results suggest that steric size of the substituent at N‐1 oxycarbonyl sidechain in the 2‐iminohydantoin molecule plays an important role in providing anticonvulsant activity, and that an alkyl substituent with a proper size further enhances PTZ anticonvulsant activity while maintaining MES activity. Drug Dev. Res. 47:17–26, 1999. © 1999 Wiley‐Liss, Inc.

Studies on the metabolic fate of aromatic nitriles, in contrast to their aliphatic counterparts, have been minimal and the subject of controversy. Thein vitrometabolic fate of several aromatic nitriles with varying substituents was investigated by using rat liver subcellular fractions, with a particular emphasis on the nitrile moiety. Benzonitriles and 4‐cyanophenols underwent oxidative metabolism to produce ring‐hydroxy‐lated metabolites. On the other hand, 2‐cyanophenol was resistant to metabolism.o‐Tolunitrile was metabolized and producedo‐cyanobenzyl alcohol and phthalide. Phthalide, however, was chemically derived fromo‐cyanobenzyl alcohol, the initial metabolite. 4‐Nitrobenzonitrile was resistant to oxidation on the ring, but was readily reduced to the corresponding amine metabolite under both aerobic and anaerobic conditions. Nitroxynil (3‐iodo‐4‐hydroxy‐5‐nitrobenzonitrile) was metabolized to produce 3‐iodo‐4‐hydroxy‐5‐nitrobenzamide and 3‐iodo‐4‐hydroxy‐5‐nitrobenzoic acid. The enzyme(s) responsible for this hydrolytic metabolism was primarily localized in the cytosol. Among the nitriles tested,o‐tolunitrile and nitroxynil produced metabolites in which the nitrile moiety was modified. Nitroxynil, however, was the only compound that was directly metabolized on the nitrile moiety by the rat liver enzyme(s).

A practical method for the preparation of substituted 2-iminohydantoins by cyclization of N-alkoxycarbonyl-α-amino acyl cyanamides is described.

For Abstract see ChemInform Abstract in Full Text.