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New insights regarding the potential of the pronucleotide approach in antiviral chemotherapy

100%

Gosselin G., Girardet J. L., Perigaud C., Benzaria S., Lefebvre I., Schlienger N., Pompon A., Imbach J. L.

Acta Biochimica Polonica

1996

tom 43

nr 1

The rationale for a pronucleotide approach based on the use of phosphotriesters which incorporate enzyme-mediated bio-labile protection is discussed in detail. Among the studied bio-labile phosphate protecting groups, the S-acyl-2-thioethyl (SATF.) groups appeared the most promising as exemplified in cell culture systems in the case of the pronucleotides of 3'-a7.ido-3'-deoxythymidine, 2',3'-didehydro- -3-deoxythymidine, 2'„3-dideoxyadenosine and acyclovir. 7m vivo implementations of such bis(SATE) pronucleotides have been planned for future animal studies.

Molecular mechanism of thymidylate synthase-catalysed reaction and interaction of the enzyme with 2- and-or 4-substituted analogues of dUMP and 5-fluoro-dUMP

63%

Rode W., Les A.

Acta Biochimica Polonica

1996

tom 43

nr 1

Thymidylate synthase is a target enzyme in anticancer, antiviral, antifungal and antiprotozoan chemotherapy. With two dUMP analogues, 5-fluoro-dUMP (FdUMP) and 5-(trifluoromethyl)-dUMP (CF3dUMP), strong thymidylate synthase inhibitors and active forms of drugs, the inhibition mechanism is based on the reaction mechanism. Recent comparative studies of new dUMP analogues, containing more than one substituent in the pyrimidine ring, showed that substitution of the pyrimidine ring Qd=0 group in FdUMP by either C(4)=N-OH group (in N4-hydroxy-FdCMP) or C(4)=S group (in 4-thio-FdUMP) preserves high inhibitory potency of the drug but may alter its specificity for thymidylate synthases from various sources, which differ in sensitivity to slow-binding inhibition by FdUMP. Informations suggesting mechanisms responsible for the foregoing have been reviewed, including results of molecular modeling studies suggesting interaction of the pyrimidine C(4)=0 group, or its modification, with the N4-methylene-

Ograniczanie wyników

2 Acta Biochimica Polonica

1 Benzaria S.

1 Girardet J. L.

1 Gosselin G.

1 Imbach J. L.

1 Lefebvre I.

1 Les A.

1 Perigaud C.

1 Pompon A.

1 Rode W.

1 Schlienger N.

2 1996

Wyniki wyszukiwania

New insights regarding the potential of the pronucleotide approach in antiviral chemotherapy

Molecular mechanism of thymidylate synthase-catalysed reaction and interaction of the enzyme with 2- and-or 4-substituted analogues of dUMP and 5-fluoro-dUMP