5'-(2-Nitrophenylalkanoyl)-2'-deoxy-5-fluorouridines as potential prodrugs of FUDR for reductive activation.
Four 5'-(2-nitrophenylalkanoyl)-2'-deoxy-5-fluorouridines (1a-d) were designed and synthesized as potential prodrugs of FUDR for reductive activation. Two methyl groups were introduced alpha to the ester carbonyl to increase both the rate of cyclization activation and the stability of the conjugates towards serum esterases. Chemical reduction of the nitro group into an amino leads to cyclization and release of the active FUDR. Kinetic analysis of the cyclization activation process indicates that the two methyl groups alpha to the ester carbonyl restrict the rotational freedom of ground state molecule and promote the cyclization reaction. However, the two methyl groups also were found to render the conjugates as poor substrates of E. coli B nitroreductase. Conjugate 1c, without the two methyl groups, was reduced by E. coli B nitroreductase (t(1/2)=8 h) to give two products, a N-hydroxyl lactam and the drug FUDR, suggesting that the enzymatic reduction and subsequent cyclization activation proceeded through the hydroxylamine intermediate. These results indicate that cyclization activation will occur once the nitro group is reduced either to an amino or to a hydroxylamino group. The fact that the amino intermediates cyclized easily to release the incorporated drug FUDR suggests the feasibility of using peptide-linked acyl 2-aminophenylalkanoic acid esters as potential prodrugs for proteolytic activation.
Liu
Bin
B
Department of Pharmaceutical Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA.
Hu
Longqin
L
D003500:Cyclization; D004789:Enzyme Activation; D004926:Escherichia coli / Q000201:enzymology; D004952:Esters / Q000737:chemistry; D005467:Floxuridine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006898:Hydroxylamines / Q000737:chemistry; D009243:NAD / Q000737:chemistry / Q000378:metabolism; D009601:Nitroreductases / Q000378:metabolism; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship
D004952:Esters; D006898:Hydroxylamines; D011355:Prodrugs; D005467:Floxuridine; D009243:NAD; D009601:Nitroreductases