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-alpha]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 H-1, H-2 and P-31 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. P-31 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 1, in agreement with its superficial location. H-2 NMR experiment performed on the same model using perdeuterated phospholipids showed no significant fluidity reduction at the level of terminal CD3 groups in the presence of la-c, according to their deep location. Finaly, their interactions with synthetic oligonucleotide, d(CGATCG)(2) was studied showing non specific interactions of la on the external GC pair, while no interaction was observed with the other derivatives. (C) 2004 Elsevier B.V. All rights reserved.