V. Ya. Gorbatyuk

Stabilization of the peptide conformation on the micellar surface.

The conformational mobility of peptide molecules plays a significant role in peptide-receptor interactions and quantitative structure-activity relationships. As a receptor mimetic system, bis(2-ethylhexyl) sodium succinate (AOT) reversed micelles containing an aqueous solution of one of the melanotrophine inhibiting factor analogues prolyltyrosyl-glycinamide hydrochloride in the inner cavity have been used. Two-dimensional nuclear magnetic resonance spectroscopy (NOESY) and 13C spin-lattice relaxation time measurements have been used to establish that the peptide molecule assumes the biologically active beta II turn conformation when it is adsorbed at the surfactant-water border. This conformation is stabilized by intramolecular H-bonding between the proline carbonyl oxygen atom and amide protons. Moreover, it has been shown that the phenyl ring of tyrosine was inserted into the AOT intermolecular cavity, which is located between the polar AOT groups and the branches of iso-octane fragments. By and large, the phenyl ring acts as a hydrophobic anchor. Reversed micelles can be regarded as providing a realistic model of the receptor.

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

Understanding the 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 β-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 the guest and host molecules, characterized by spin-lattice relaxation times T1 of the13C nuclei. An analysis of d-contacts showed that the 5-phenyl ring is completely enclosed in the inner hydrophobic cavity of β-CD [(C2′ H-C4′ H)-CIIH(CIVH), CVH (CIIIH, CVIH2), CVIOH]. For the 1:1 complex, intense d-contracts of C8H with CVIOH indicate that C8H is located in the vicinity of both wide and narrow bases of the bracelet. This is only possible for the 2:2 complex, in which both β-CD molecules approach each other by their wide and narrow bases. A comparison between the schemes of d-contacts for the 2:2 and 2:1 associates proves that the β-CD molecules have the same spatial orientation in the dimer. The difference is in the fact that the hydrazinocarbonyl fragment of gidazepam and the hemisuccinate fragment of cinazepam penetrate into an empty molecule of the 2:1 β-CD complex (NH2-CIH contact). The intensities of the cross peaks were measured, due to which the interatomic distances between the guest and host molecules were calculated and the spatial structure of the clathrates was established. The benzodiazepine derivatives are embedded differently into the clathrate molecule, as shown by the value of the angle between the symmetry axis of β-CD and the axis through the centers of the aromatic rings: 0° for gidazepam and 60° for cinazepam. This is a consequence of the fact that the substituents forming hydrogen bonds with hydroxyl groups at the wide base of the β-CD bracelet lie in different positions: the hydrazinocarbonylmethyl fragment of gidazepam lies at N1, and the hemisuccinate fragment of cinazepam is at C3.

Shape parameters of peptide molecules as descriptors for solving QSAR problems

A system of basic conformations (BC) is built by numerical harmonic analysis methods. The system allows one to classify the conformations of peptide molecules for solving QSAR problems. The contributions of BC to real conformations of melanostatin and analogous tripeptide molecules are used as descriptors in analysis of the structure-antidepressant activity relationship. The activity is correlated with BC contributions from different families of parameters using regression analysis methods. Due to this we assumed the presence of an active gap-like receptor center, which is capable of binding the peptide molecule at three fragments—C1O, C3O, and NH2, and predicted the structures of molecules possessing high antidepressant activity.

Influence of the second amino acid residue on the antidepressive activity of melanostatin analogs

It has been shown for melanostatin analogs that the energy of the HOMO, calculated by the CNDO/2 method for side substitutents of the second amino acid residue, is correlated with the antidepressive activity. The excessive electron density that appears in the peptide chain is delocalized on the MO of the substituent to which the AO of the first carbon atom makes the greatest contribution (LUMO).

Stabilization of the Pro-Tyr-Gly-NH2 melanostatin analog on micelles

Inversed AOT micelles have been used as a system to simulate peptide-receptor interaction; they encapsulate an aqueous solution of the melanostatin analog HCl·Pro-Tyr-Gy-NH2. NOESY indicates that adsorption at the phase boundary causes the peptide to acquire the biologically active βII conformation. The phenyl ring in Tyr is inserted into the cavity formed by the isooctyl moieties of the AOT molecules.

Structure and conformational mobility of substituted imidazodiazepinediones

Two-dimensional (NOESY) and dynamic IH NMR spectroscopy was used to determine the structure and conformational mobility of substituted 1,4,7-trimethyl-4,5,7,8-6H-imidazo[4,5-e][l,4]-diazpene-5,6-diones, which are cyclic homologs of caffeine, a natural alkaloid. 13C NMR spectroscopy was used to determine the activation energy for inversion of the seven-membered ring, which was related to the electronic effect of substituents. Computer models were obtained for the predominant conformations of the compounds studied.

Synthesis and some structural characteristics of caffeine and isocaffeine homologs

As a result of methylation and subsequent catalytic debenzylation, 1-benzylimidazo[4,5-e][1,4]diazepine was converted to the corresponding imidazo[5,4-e][1,4]diazepine. Thermodynamic parameters of inversion in isomeric imidazo[4,5-e]- and imidazo[5,4-e][1,4]diazepines were determined by dynamic 1HNMR. The total energy of the compounds being compared was calculated by molecular-mechanics methods.

CONFORMATION OF 4,5,6-SUBSTITUTED 2-ISOPROPYL-1,3,2-OXATHIOBORINANES

The configuration and predominant conformations of 2-isopropyl-4,5,6-alkylsubstituted 1,3,2-oxathioborinanes have been studied by 1H-NMR spectroscopy. 2,4-and 2,6-Dialkylsubstituted derivatives exist in near half-chair conformations, while 6,6-dimethyl-2-isopropyl-1,3,2-oxathioborinane exists in two energetically equivalent inverting forms. 2,5,6- and 2,4,6-Trialkylsubstituted 1,3,2-oxathioborinanes consist of mixtures of stereoisomers differing in the orientations of the alkyl groups at the C(6) and C(4) ring atoms.