Modulation of intercalating properties of pyrido[1,2-e]purins via side-chain modifications: NMR and MD studies.
Two pyrido[1,2-e]purins with different side chain lengths have been synthesized to test their ability to intercalate inside DNA. The interactions of these drugs with synthetic oligodeoxy nucleotide d(CGATCG)2 have been studied with 1H and 31P NMR spectroscopy experiments. Molecule 1, rather amphiphilic (Log(P) = 1.3, due to its hydroxypropyl side chain) can intercalate GC sites of the mini helix, under a fast exchange mechanism and a 2:1 stoechiometry. The presence of a six methylen side chain in 2 (hydroxyhexyl side chain) is responsible for a relatively poor solubility of this molecule in water (log P = 2.3). Binding, rather than intercalation, of 2 to the external GC pairs is observed, severely limited by the formation of aggregates. Models for the intercalation of 1, are proposed using energy minimizations and Molecular Dynamics (MD) calculations subject to restraints from experimental nOe connectivities. Simulations and experiments both indicate fast exchange of 1 in its intercalation site.
Debouzy
J C
JC
Unité de Biophysique Cellulaire et moléculaire, Centre de Recherches du Service de Santé des Armées, La Tranche, France. jcdebouzy@compuserve.com
Dabouis
V
V
Crouzy
S
S
Bachelet
C
C
Favier
A
A
Peinnequin
A
A
Gueiffier
A
A
D004247:DNA / Q000187:drug effects; D006860:Hydrogen Bonding; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009841:Oligonucleotides / Q000138:chemical synthesis / Q000494:pharmacology; D011522:Protons; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry; D012997:Solvents
D007364:Intercalating Agents; D009841:Oligonucleotides; D011522:Protons; D011687:Purines; D012997:Solvents; D004247:DNA