2,3-Diarylimidazo[1,2-a]pyridines as potential inhibitors of UV-induced keratinocytes apoptosis: synthesis, pharmacological properties and interactions with model membranes and oligonucleotides by NMR.
Four 2,3-diarylimidazo[1,2-a]pyridines (I, 1a-c) were synthesized as inhibitors of UV-induced apoptosis and showed quite different properties. First, only the pyridinyl derivative I showed protection in molt cells. From the supposed intracellular target, phospholipid membrane models were studied by (1)H, (2)H and (31)P NMR spectroscopy. All these molecules can incorporate the membrane bilayer of small unilamellar vesicles of lecithin (SUV). However, I is clearly closed to the external polar head of the lipids, and is relatively mobile in the layer. Conversely, the other molecules are strongly immobilized in the deep part of the external layer. (31)P solid-state NMR spectra recorded on phospholipid dispersions (multilayers vesicles (MLV)) completely excluded any detergent effect or any modification of temperature transition. The only structural or dynamic effect observed was a homogeneous, but limited, reduction in the chemical shift anisotropy in the presence of I, in agreement with its superficial location. (2)H NMR experiment performed on the same model using perdeuterated phospholipids showed no significant fluidity reduction at the level of terminal CD(3) groups in the presence of 1a-c, according to their deep location. Finally, their interactions with synthetic oligonucleotide, d(CGATCG)(2) was studied showing non specific interactions of 1a on the external GC pair, while no interaction was observed with the other derivatives.
Enguehard-Gueiffier
Cécile
C
UPRES-EA 3247, Laboratoire de Chimie Thérapeutique, Faculté de Pharmacie, 31 Avenue Monge, 37200 Tours, France.
Fauvelle
Florence
F
Debouzy
Jean-Claude
JC
Peinnequin
André
A
Thery
Isabelle
I
Dabouis
Vincent
V
Gueiffier
Alain
A
D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D045744:Cell Line, Tumor; D002470:Cell Survival; D003854:Deoxyribonucleotides / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects / Q000528:radiation effects*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008567:Membranes, Artificial; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D014466:Ultraviolet Rays
D003854:Deoxyribonucleotides; D007093:Imidazoles; D008567:Membranes, Artificial; D011725:Pyridines