Assessing Atropisomer Axial Chirality in Drug Discovery and Development Steven R. LaPlante,* Lee D. Fader, Keith R. Fandrick, Daniel R. Fandrick, Oliver Hucke, Ray Kemper, Stephen P. F. Miller, and Paul J. Edwards* Department of Chemistry, Boehringer Ingelheim (Canada) Ltd., 2100 Cunard Street, Laval, Quebec, H7S 2G5, Canada Chemical Development, Non-Clinical Drug Safety, Boehringer Ingelheim Pharmaceutical Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877, United States Office of New Drug Quality Assessment, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Building 22, Room 1446, Silver Spring, Maryland 20993, United States

Assessing Atropisomer Axial Chirality in Drug Discovery and Development

An often overlooked source of chirality is atropisomerism, which results from slow rotation along a bond axis due to steric hindrance and/or electronic factors. If undetected or not managed properly, this time-dependent chirality has the potential to lead to serious consequences, because atropisomers can be present as distinct enantiomers or diastereoisomers with their attendant different properties. Herein we introduce a strategy to reveal and classify compounds that have atropisomeric chirality. Energy barriers to axial rotation were calculated using quantum mechanics, from which predicted high barriers could be experimentally validated. A calculated rotational energy barrier of 20 kcal mol(-1) was established as a suitable threshold to distinguish between atropisomers and non-atropisomers with a prediction accuracy of 86%. This methodology was applied to subsets of drug databases in the course of which atropisomeric drugs were identified. In addition, some drugs were exposed that were not yet known to have this chiral attribute. The most valuable utility of this tool will be to predict atropisomerism along the drug discovery pathway. When used in concert with our compound classification scheme, decisions can be made during early discovery stages such as "hit-to-lead" and "lead optimization," to foresee and validate the presence of atropisomers and to exercise options of removing, further stabilizing, or rendering the chiral axis of interest more freely rotatable via SAR design, thereby decreasing this potential liability within a compound series. The strategy can also improve drug development plans, such as determining whether a drug or series should be developed as a racemic mixture or as an isolated single compound. Moreover, the work described herein can be extended to other chemical fields that require the assessment of potential chiral axes.

Revealing Atropisomer Axial Chirality in Drug Discovery

Raman spectroscopy has advanced considerably in the last several years due to rapid developments in instrumentation and the availability of theoretical methods for accurate calculation of Raman spectra, thus enormously facilitating the interpretation of Raman data. This review is restricted to cover papers mainly published in the Journal of Raman Spectroscopy, which serve to give a fast overview of recent advances in this research field as well as to provide readers of this journal a quick introduction to the various subfields of Raman spectroscopy. It also reflects the current research interests of the Raman community. Similar reviews of highly active areas of Raman spectroscopy will appear in future issues of this journal. Copyright © 2007 John Wiley & Sons, Ltd.

Recent Advances in linear and nonlinear Raman spectroscopy I

An efficient and simple approach for the synthesis of pyranopyrazoles using imidazole (catalytic) in aqueous medium, and the vibrational spectroscopic studies on 6-amino-4-(4'-methoxyphenyl)-5-cyano-3-methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole using density functional theory.

Synthesis and antimicrobial activity of copper(II) and silver(I) complexes of hydroxynitrocoumarins: X-ray crystal structures of [Cu(hnc)2(H2O)2] · 2H2O and [Ag(hnc)] (hncH = 4-hydroxy-3-nitro-2H-chromen-2-one)

https://publik.tuwien.ac.at/files/PubDat_135967.pdf

DFT modeling and spectroscopic study of metal-ligand bonding in La(III) complex of coumarin-3-carboxylic acid

Density functional calculations with Becke's three parameter hybrid method using the correlation functional of Lee, Yang and Parr (B3LYP) were carried out for 3,3′-benzylidenebis(4-hydroxycoumarin) (phenyldicoumarol, PhDC), 3,3′-methylenebis(4-hydroxycoumarin) (dicoumarol, DC) and the parent compound, 4-hydroxycoumarin (4-HC). Different basis sets were tested in the course of the calculations: 6-31G*, 6-31+G** and 6-311G*. In full agreement with available X-ray data, B3LYP/6-31G* calculations of the lowest-energy conformer, PhDC showed two O–H⋯O asymmetrical intramolecular hydrogen bonds with O⋯O distances 2.638 and 2.696 A. The HB energies in PhDC were estimated of −55.46 and −52.32 kJ/mol, respectively. The values obtained correlated with the calculated and experimental O⋯O distances and predicted difference in the hydrogen bonding strengths in PhDC. The total HB energy in PhDC was calculated of −107.73 kJ/mol. At the same level of theory, both O⋯O intramolecular distances in DC were calculated identical (2.696 A) and thus two symmetrical hydrogen bondings were obtained. The single HB strength was estimated of −50.89 kJ/mol and the total one of −101.79 kJ/mol. The electron density (ρb) and Laplacian (∇2ρb) properties, estimated by AIM calculations, showed that both O⋯H bonds have low ρb and positive ∇2ρb values (consistent with electrostatic character of the HBs), whereas both O–H bonds have covalent character (∇2ρb

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DFT and AIM studies of intramolecular hydrogen bonds in dicoumarols

Spectroscopic and theoretical study of Cu(II), Zn(II), Ni(II), Co(II) and Cd(II) complexes of glyoxilic acid oxime.

Vibrational spectra of ortho-, meta- and para-pyridinomethylene substituted di(4-hydroxycoumarin) (o-, m-, p-PyDC, (PyDCs)) and their Ce(III), La(III) and Nd(III) complexes were studied by Raman and Fourier transform infrared (FT-IR) spectroscopies. Density functional theory (DFT) at B3LYP/6-31G(d) level was used to determine the geometrical and vibrational characteristics of the neutral PyDC isomers and their dianionic forms. The experimental IR and Raman bands of PyDCs were assigned to the corresponding normal modes on the basis of DFT calculations. The effect of the intramolecular H-bonds in PyDCs as well as of the PyDCs deprotonation on the vibrational mode positions was estimated by comparison with the molecular vibrations of the H-bonding-free 4-hydroxycoumarin and PyDC dianionic forms. The characteristic IR and Raman bands of o-, m- and p-PyDC were specified and discussed. The comparative vibrational analysis of the neutral and the dianionic PyDCs and their Ln(III) complexes gave evidence that the PyDC ligands bound the lanthanide(III) through the carbonylic oxygens and the deprotonated hydroxylic oxygens. Copyright © 2006 John Wiley & Sons, Ltd.

Raman, FT-IR and DFT studies of ortho-, meta- and para-pyridinomethylene substituted di(4-hydroxy-coumarin) and their Ce(III), La(III) and Nd(III) complexes

G Bauer

Papers

DFT modeling and spectroscopic study of metal-ligand bonding in La(III) complex of coumarin-3-carboxylic acid

DFT and AIM studies of intramolecular hydrogen bonds in dicoumarols

Spectroscopic and theoretical study of Cu(II), Zn(II), Ni(II), Co(II) and Cd(II) complexes of glyoxilic acid oxime.

Raman, FT-IR and DFT studies of ortho-, meta- and para-pyridinomethylene substituted di(4-hydroxy-coumarin) and their Ce(III), La(III) and Nd(III) complexes

IR and Raman study of Pt(II) and Pd(II) complexes of amino substituted phosphine oxides: Normal coordinate analysis