Conformational Variability of Cyclosporin C Dissolved in Dimethylformamide

Abstract

Action of biologically active compounds requires proper spatial structure, and sometimes controversial requirements should be fulfilled at the same time. Cyclosporin, widely used to prevent allograft rejection, is an example because it should cross through a cell membrane and form a complex with a target protein inside the cell. This difficulty is overcome by flexibility of the molecule. Cyclosporin A was widely studied, and it is known to have multiple conformations in polar media such as water and methanol. However, detailed characterization of all these conformers is difficult: their lifetime is too long for MD simulations, analysis of NMR spectra is hampered due to severe signal overlap, and IR spectroscopy gives parameters averaged over all conformers. This paper presents characterization of conformational equilibrium of cyclosporin C dissolved in dimethylformamide. High-resolution NMR spectra recorded at 700 MHz allowed distinguishing most of observed amide proton signals. Existence of several intramolecular hydrogen bonds over the whole set of conformers was supposed; in most cases, however, these bonds are disrupted. Kinetics of a conformational transition is evaluated. Obtained results are in agreement with what is known about cyclosporin A, but can give new information on the role of additional H-bond donors (there are six of them in CsC vs. five in CsA) in the observed chain flexibility.