N-Amino-imidazol-2-one (Nai) Residues as Tools for Peptide Mimicry: Synthesis, Conformational Analysis and Biomedical Applications

N-Amino-imidazol-2-one (Nai) residues are tools for studying peptide-backbone and side-chain conformation and function. Recent methods for substituted Nai residue synthesis, conformational analysis by X-ray crystallography and computation, and biomedical applications are reviewed, demonstrating the utility of this constrained residue to favor biologically active turn conformers with defined χ-dihedral angle orientations.1 Introduction2 Synthetic Methods3 Conformational Analysis4 Biomedical Applications5 Conclusions

MICE-PES: An Algorithm for Accurate Conformational Analysis and its Implementation to Natural Products

<p>Secondary metabolites from natural sources have revolutionized the modern drug industry by acting as lead compounds. Many commercial drugs have evolved originally from natural molecules before being synthesized in the laboratory for commercialization. Because of the importance of natural molecules, it is crucial to determine their structural properties carefully as it is essential for their synthesis and studying their pharmacological behaviour. Many natural molecules have flexible structures and can adopt many different conformations in solution at room temperature. Hence, the determination of their relative configuration is a challenging task with the available experimental techniques. For structural analysis of natural molecules and to study their properties, all conformers which might be responsible for their chemical properties have to be considered. Theoretical chemistry has been very helpful in absolute structure determination of complex and conformationally flexible natural molecules by calculating their theoretical nuclear magnetic resonance, ultraviolet, infra red, and circular dichroism spectra etc. There are a number of software tools that offer conformational analysis by utilizing different molecular mechanics approaches. They produce a large number of possible conformers and are not general purpose, thus compromising accuracy. Apart from that, different force fields available for conformational analysis and minimization have been designed for specific molecular classes and do not produce good results beyond their scope. In the past, there have been reports about a “build-up procedure” for predicting the low energy conformations of peptides by optimising smaller fragments of the molecule under study and then joining them while minimizing their energies using force fields. Later on, this method was extended to predict the structure of DNA from sequences. This method used force field methods and did not gain much popularity due to its various limitations. Here, MICE-PES (Method for the Incremental Construction and Exploration of the Potential Energy Surface) is presented, an algorithm which performs a conformational analysis using high level quantum chemical calculations by building the molecule incrementally from its smallest possible analogue whose conformational degrees of freedom are very well separated than the rest of the molecule. MICE-PES has been validated through studies on known biomolecule 3-epi-xestoaminol whose absolute configuration has been determined already by experimental and theoretical methods. MICE-PES has also been used to assign the relative configuration of a natural product (meroterphenol C) whose configuration could not be established experimentally. Overall, the development of MICE-PES will be very helpful in solving problems in the study of conformationally flexible systems, in all aspects of organic chemistry.</p>

MICE-PES: An Algorithm for Accurate Conformational Analysis and its Implementation to Natural Products

<p>Secondary metabolites from natural sources have revolutionized the modern drug industry by acting as lead compounds. Many commercial drugs have evolved originally from natural molecules before being synthesized in the laboratory for commercialization. Because of the importance of natural molecules, it is crucial to determine their structural properties carefully as it is essential for their synthesis and studying their pharmacological behaviour. Many natural molecules have flexible structures and can adopt many different conformations in solution at room temperature. Hence, the determination of their relative configuration is a challenging task with the available experimental techniques. For structural analysis of natural molecules and to study their properties, all conformers which might be responsible for their chemical properties have to be considered. Theoretical chemistry has been very helpful in absolute structure determination of complex and conformationally flexible natural molecules by calculating their theoretical nuclear magnetic resonance, ultraviolet, infra red, and circular dichroism spectra etc. There are a number of software tools that offer conformational analysis by utilizing different molecular mechanics approaches. They produce a large number of possible conformers and are not general purpose, thus compromising accuracy. Apart from that, different force fields available for conformational analysis and minimization have been designed for specific molecular classes and do not produce good results beyond their scope. In the past, there have been reports about a “build-up procedure” for predicting the low energy conformations of peptides by optimising smaller fragments of the molecule under study and then joining them while minimizing their energies using force fields. Later on, this method was extended to predict the structure of DNA from sequences. This method used force field methods and did not gain much popularity due to its various limitations. Here, MICE-PES (Method for the Incremental Construction and Exploration of the Potential Energy Surface) is presented, an algorithm which performs a conformational analysis using high level quantum chemical calculations by building the molecule incrementally from its smallest possible analogue whose conformational degrees of freedom are very well separated than the rest of the molecule. MICE-PES has been validated through studies on known biomolecule 3-epi-xestoaminol whose absolute configuration has been determined already by experimental and theoretical methods. MICE-PES has also been used to assign the relative configuration of a natural product (meroterphenol C) whose configuration could not be established experimentally. Overall, the development of MICE-PES will be very helpful in solving problems in the study of conformationally flexible systems, in all aspects of organic chemistry.</p>

Synthesis, X-ray Structure, Conformational Analysis, and DFT Studies of a Giant s-Triazine bis-Schiff Base

The current work involves the synthesis of 2,2′-(6-(piperidin-1-yl)-1,3,5-triazine-2,4-diyl)bis(hydrazin-2-yl-1-ylidene))bis(methanylylidene))diphenol 4, characterization, and the DFT studies of the reported compound. The crystal unit cell parameters of 4 are a = 8.1139(2) Å, b = 11.2637(2) Å, c = 45.7836(8) Å. The unit cell volume is 4184.28(15) Å3 and Z = 4. It crystallized in the orthorhombic crystal system and Pbca space group. The O…H, N…H, C…H, H…H and C…C intermolecular contacts which affect the crystal stability were quantitatively analyzed using Hirshfeld calculations. Their percentages were calculated to be 9.8, 15.8, 23.7, 46.4, and 1.6% from the whole contacts occurred in the crystal, respectively. Conformational analysis was performed using DFT calculations for 17 suggested conformers and the most stable conformer was found to be the one which is stabilized by two intramolecular O-H…N hydrogen bonding interactions. This conclusion was further revealed by natural bond orbital calculations.