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Cyclic phosphates of some antiviral acyclonucleosides: relationship between conformation and substrate-inhibitor properties in some enzyme systems

100%

Ciesla J. M., Stolarski R., Shugar D.

Acta Biochimica Polonica

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1993

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tom 40

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nr 2

Solution conformations, and substrate/inhibitor properties towards several phosphodiesterases and other nucleolytic enzymes, have been investigated for the cyclic phosphates of various acyclonucleosides, some with known antiviral activity, including 9-[(l,3-dihydroxy-2-propoxy)methyl]guanine (DHPG) and its carbocyclic congener, 9-(3,4-dihydroxybutyl)guanine (DHBG), 9-[4-hydroxy-2-(hydroxymethyl)- butyl]-guanine (2HM-HBG), and 9-(2,3-dihydroxypropyl)guanine (HPG). Conformations of the cyclic phosphate rings were derived from analysis of the 1H-1H and 1H-31P vicinal coupling constants in the n.m.r. spectra, subsequently optimalized by minimalization of the internal energy. The resulting structures were examined with respect to their ability to recognize various specific phosphodiesterases and nucleases, and some structural parameters were delineated for acyclonucleotide interactions. Qualitative data are presented for inhibitory properties of the acyclonucleoside cyclic phosphates, and, in those instances where they were substrates, kinetic constants were evaluated. An unusual finding was the apparent ability of nuclease P1 to hydrolyse a five-membered cyclic phosphate ring of an acyclonucleoside.

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Crystal structures of some acyclonucleosides with antiviral activity and related compounds

86%

Birnbaum K. B.

Acta Biochimica Polonica

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1996

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tom 43

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nr 1

The crystal structure of the acyclonucleoside, 9-[4-hydroxy-2-(hydroxymethyl)- butyljguanine (2HM-HBG), has been compared with related acyclonucleosides, and that of the acyclonucleotide, 9-1(1,3-dihydroxy-2-propoxy)methyl]guanine-3',5'-cyclic phosphate (DlIPG-cMP), also with its parent second messenger cGMP and cyclic monophosphate nucleotides. There is considerable conformational flexibility in the acyclic chain of these compounds with several conformations coexisting in the solid state. This flexibility together with the narrow range of the glycosidic torsion angles (from 69° to 94°, with an average of 83(3)° for 11 molecules when the aglycon is guanine, and from 92° to 108° with an average of 103(3)° for 4 molecules when the aglycon is adenine) may be essential for the antiviral activity of these compounds and their ability to act as substrates. The mechanism of antiviral activity of, 9-1(1,3-dihydro- xy-2-propoxy)methyllguanine-3',5'-cyclic phosphate is different from that of the acyclonucleosides, and is discussed in the light of it being a close structural analogue to the second messenger cGMP.

3

In vivo phosphorylation of alloxymethyl purine and pyrymidine acyclonucleosides and the inhibitory effect of these compounds on thymidine and deoxyguanosine kinases

86%

Modrzejewska H., Greger J., Lewandowska U., Fidek W.

Acta Biochimica Polonica

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1994

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tom 41

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nr 2

Ograniczanie wyników

3 Acta Biochimica Polonica

1 Birnbaum K. B.

1 Ciesla J. M.

1 Fidek W.

1 Greger J.

1 Lewandowska U.

1 Modrzejewska H.

1 Shugar D.

1 Stolarski R.

1 1996

1 1994

1 1993

Cyclic phosphates of some antiviral acyclonucleosides: relationship between conformation and substrate-inhibitor properties in some enzyme systems

Crystal structures of some acyclonucleosides with antiviral activity and related compounds

In vivo phosphorylation of alloxymethyl purine and pyrymidine acyclonucleosides and the inhibitory effect of these compounds on thymidine and deoxyguanosine kinases