Spatial structure of beta-cyclodextrin clathrates with 1,4-benzodiazepine derivatives

Understanding Me mechanisms of mutual recognition and complementary binding of molecules in guest-host complexes is based on analysis of their spatial structure. As guest-host complexes, we have synthesized inclusion compounds of 1,4-benzodiazepine anxiolytic agents gidazepam and cinazepam with beta-cyclodextrin, in which these anxiolytic agents manifest increased biological accessibility. The spatial structure of the complexes was determined from the two-dimensional NOESY spectra and analysis of the fragmentary mobility of Me guest and host molecules, characterized by spin-lattice relaxation times T-1 of the C-13 nuclei. An analysis of d-contacts showed thar the 5-phenyl ring is completely enclosed in the inner hydrophobic cavity of beta-CD [((CH)-H-2'-(CH)-H-4')-CIIH(CIVH), CVH (CIIIH, CVIH2) CVIOH]. For the 1:1 complex; intense d-contacts of (CH)-H-8 with CVIOH indicate that (CH)-H-8 is located in Me vicinity of both wide and narrow bases of the bracelet This is only possible for the 2:2 complex, in which both beta-CD molecules approach each other by their wide and narrow bases. A comparison between the schemes of d-contacts for Me 2:2 and 2:1 associates proves that the beta-CD molecules have the same spatial orientation in the dimer. The difference is in Me fact Mat Me hydrazinocarbonyl fragment of gidazepam and the hemisuccinate fragment of cinazepam penetrate into an. empty molecule of Me 2:I beta-CD complex (NH2-CIH contact). The intensities of Me cross peaks were measured, due to which the interatomic distances between the guest and host molecules were calculated and Me spatial structure of the clathrates was established. The benzodiazepine derivatives are embedded differently into the clathrate molecule, as shown by Me value of the angle between Me symmetry mis of beta-CD and Me mis through the centers of Me aromatic rings: 0 degrees for gidazepam and 60 degrees for cinazepam. This is a consequence of the fact Mat Me substituents forming hydrogen bonds with hydroxyl groups at the wide base of the beta-CD bracelet lie in different positions: the hydrazinocarbonylmethyl fragment of gidazepam lies at N-1, and Me hemisuccinate fragment of cinazepam is at C-3.