The interactions of substituted pyrido[1,2-e]purines with oligonucleotides depend on the amphiphilic properties of their side chain.
Three pyrido[1,2-e]purines of increasing hydrophilicity have been synthesized to evaluate as anticancer agents. These drugs interact quite differently with a synthetic oligodeoxynucleotide d(CGATCG)2. [1] is very hydrophobic due to a phenyl residue in its side chain. It only shows limited interactions with the minihelix without any evidence of intercalation. [2] and [3], on the other hand, have one ([2]) or two ([3]) hydroxyl groups in their acyl chain and present rather amphiphilic properties. The result is a similar intercalation of these derivatives between C and G base pairs as revealed by intermolecular nOe, 1H and 31P chemical shift variations. Models for the intercalation of [2] are proposed using energy minimizations and molecular dynamics (MD) calculations subject to restraints from nOe connectivities. Simulations and experiments indicate weak stability and thus fast exchange of [2] in its intercalation site.
Debouzy
J C
JC
CRSSA, Unité de Biophysique Cellulaire et Moléculaire, 24 Av. des maquis du Grésivaudan, La Tronche cedex, 38702, France.
Crouzy
S
S
Dabouis
V
V
Gueiffier
A
A
Brasme
B
B
Bachelet
C
C
Favier
A
A
Simorre
J P
JP
Mazet
L
L
Peinnequin
A
A
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D002460:Cell Line; D007364:Intercalating Agents / Q000378:metabolism; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D018482:Muscle, Skeletal / Q000378:metabolism; D009152:Mutagenicity Tests; D009690:Nucleic Acid Conformation; D009841:Oligonucleotides / Q000378:metabolism*; D011522:Protons; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*
C120503:3-(pyrido(1,2-e)purin-4-ylsulfanyl)-2-propanol; D000970:Antineoplastic Agents; D007364:Intercalating Agents; D009841:Oligonucleotides; D011522:Protons; D011687:Purines; D013449:Sulfonamides