Conformation analysis of 3'-fluorinated A(2'-5')A(2'-5')A fragments. Relation between conformation and biological activity.
A one- and two-dimensional NMR study has been performed on seven A(2'-5')A(2'-5')A fragments containing 9-(3'-fluoro-3'-deoxy-beta-D-xylofuranosyl)-adenine (AF) or 3'-fluoro-3'-deoxyadenosine (AF) residues at different positions, and on the corresponding monomers. A(2'-5')A(2'-5')A served as a reference compound. The fluoro substituent governs the conformation of the sugar ring: an AF residue displays mainly N-type sugar and the ring is considerably flattened (phi N approximately 30 degrees) compared to AF residues (phi S approximately 40 degrees), which exhibit almost pure S-type conformation. Moreover, in AF moieties the rotamer distribution around torsion angle gamma (O5'-C5'-C4'-C3') and the base orientation are influenced to a large extent by the presence of the fluorine substituent. The sugar rings of nonfluorinated residues in the trimers appear rather flexible. A possible correlation between the conformational characteristics of the fluorinated fragments and their biological activity has been found: the fragments that meet the prerequisites for binding to RNase L indeed show enhanced binding to this endonuclease. Furthermore, substitution of the 3'-OH group of the second residue by hydrogen or of the 3'-OH group of the 2'-terminal residue by fluorine or hydrogen results in increased resistance towards 2'-5'-phosphodiesterase.
Van den Boogaart
J E
JE
Gorlaeus Laboratories, State University of Leiden, The Netherlands.
Kalinichenko
E N
EN
Podkopaeva
T L
TL
Mikhailopulo
I A
IA
Altona
C
C
D000227:Adenine Nucleotides / Q000737:chemistry* / Q000494:pharmacology; D003839:Deoxyadenosines / Q000737:chemistry* / Q000494:pharmacology; D004722:Endoribonucleases / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D011108:Polymers; D013329:Structure-Activity Relationship
D000227:Adenine Nucleotides; D003839:Deoxyadenosines; D011108:Polymers; C087172:9-(3'-fluoro-3'-deoxyxylofuranosyl)adenine; C031128:adenylyl-(2'-5')-adenylyl-(2'-5')adenosine; C062976:3'-fluoro-3'-deoxyadenosine; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease