Conformational and dynamical study of squalene derivatives. III: azasqualenes and solvated squalene

A detailed conformational analysis of six squalene derivatives (19-azasqualene 1, 19-azasqualene N-oxide 2, azasqualene alcohol 3, azasqualene alcohol N-oxide 4, squalene ethylendiamine 5 and 22,23-oxidoazasqualene N-oxide 6) is presented. Most of these compounds are potent inhibitors of 2,3-oxidosqualene cyclases, key enzymes in the biosynthesis of sterols, mimicking the different carbonium ion intermediates formed during the cyclization of 2,3-oxidosqualene. They were studied by mono- and bi-dimensional NMR methods (both 1H and 13C NMR) and by molecular mechanics and molecular dynamics techniques, in order to obtain some insight into the conformational and dynamical behavior of these molecules in chloroform solution. NMR data indicate that azasqualene derivatives 1–6 behave similarly to squalene itself and to other previously studied analogues: the mid portion of all these squalene derivatives appears to be comparatively stiff with respect to the rather mobile endings. Molecular dynamic calculations on squalene in chloroform solution at 300K were also performed, using explicit atomic representation of the solvent, which permits: (i) reproducing and explaining the increase of mobility of the individual torsion angles in going from the center to the end of the squalene chain, indicating that the solvent plays a major role in dictating the conformational properties of squalene and its derivatives; (ii) achieving direct evidence of relatively stable, solvent induced folded conformations. Finally, the chemical and biological implications of the results are discussed.