Georg Uray

X-Ray Structure, Conformational Analysis, Enantioseparation, and Determination of Absolute Configuration of the Mitotic Kinesin Eg5 Inhibitor Monastrol

Abstract The conformational features of the mitotic kinesin Eg5 inhibitor monastrol were investigated by computational (AM1, HF/3-21G∗), X-ray diffraction, and NMR studies showing that monastrol is a conformationally highly flexible molecule. Racemic monastrol was resolved by direct enantioselective HPLC and the absolute configuration of the first eluting (S)-(+) enantiomer was established by CD spectroscopy.

Liquid chromatographic separation of enantiomeric alkanolamines via diastereomeric tartaric acid monoesters

Abstract A new resolution method for the analytical and preparative separation of enantiomeric alkanolamines into their antipodes is presented. It involves formation of the monoesters of the alkanolamines with optically pure and symmetrically O,O- disubstituted ( R,R )- or ( S,S )-tartaric acids. The derivatization reactions are carried out in aprotic media by reaction with the tartaric acid anhydrides. The amine functions are ionically blocked via ion-pair formation with strong acids, e.g. trichloro-acetic acid. The resulting diastereomeric monoesters are easily separable into their antipodes by reversed-phase liquid chromatographic technique. Relative retention factors,α, up to 4 can be obtained, depending on the structural parameters of the alkanolamines and reagents, as well as on the mobile phase conditions (pH). The monoesters are zwitterions, possibly capable of forming intramolecular ion pairs via a ring structure favoured for ethanolamines.

Substituent effects on absorption and fluorescence spectra of carbostyrils

Abstract Absorption and fluorescence spectra as well as quantum yields of a series of differently substituted carbostyrils (quinolin-2(1H)-ones) are reported. Especially for compounds containing donor substituents in position 6, substantial bathochromic shifts (comparable to analogous coumarins) of both absorption as well as fluorescence transitions are obtained. High absorption intensities and quantum yields are found for 7-donor substituted isomers. Semiempirical molecular orbital calculations (AM1 for structures, ZINDO for electronic transition energies) prove to be a suitable tool for the prediction of absorption and fluorescence properties of these compounds. Ab initio and density functional calculations establish the lactam form as the dominant tautomer of the parent quinolin-2(1H)-one.

Quantitative structure-enantioselective retention relationships for chromatographic separation of arylalkylcarbinols on Pirkle type chiral stationary phases.

Quantitative structure-retention (QSRR, retention factors log k1 and log k2 for the first and second eluted enantiomer) as well as enantioselective retention relationships (QSERR, separation factor log a) for a series of 42 chiral arylalkylcarbinols on four brush-type chiral stationary phases are derived by multiple linear regression analyses and artificial neuronal network calculations using 2D and 3D molecular descriptors including those obtained by quantum chemical calculations. Separation factors are in addition modeled by the 3D-QSAR method of comparative molecular field analysis (CoMFA). For the retention factors the LUMO energy turns out to be the most important descriptor, whereas for log a it is the hydrophobicity of the analytes. With CoMFA both the steric and electrostatic field are found to be of almost comparable significance.

Synthesis and reactions of biginelli compounds −5. Facile preparation and resolution of a stable 5-dihydropyrimidinecarboxylic acid. ☆

Abstract The synthesis of enantiomerically pure 5-dihydropyrimidinecarboxylic acids 7a,b is described. Condensation of benzyl acetoacetate with methylurea and 2-naphthaldehyde gave Biginelli compound 3b, which after methylation and removal of the benzyl group led to racemic acid 5b. Fractional crystallization of diastereomeric α-methylbenzylammonium salts 6a,b followed by acidification provided the desired optically pure carboxylic acids 7a,b. Conversion of 7a,b to carboxylic acid azides 8a,b followed by Curtius rearrangement and reaction with 10-undecenol led to chiral urethanes 10a,b. The absolute stereochemistry of acids 7a,b was established by X-ray analysis of diastereomeric α-methylbenzylammonium-carboxylate 6c.

LONG-WAVELENGTH-ABSORBING AND -EMITTING CARBOSTYRILS WITH HIGH FLUORESCENCE QUANTUM YIELDS

Synthesis, absorption and fluorescence spectra, as well as quantum yields of a series of donor-acceptorsubstituted carbostyrils (a quinolin-2(1H )-ones), are reported. Unprecedented strong absorption maxima (ea 10000 ‐ 20000) close to the visible spectrum, large Stokes shifts up to 130 nm, and quantum yields up to 0.7 are obtained with derivatives containing donor substituents at C(6) and C(7), and either one Ph substituent at C(3) or one CF 3 residue at C(4). For analytical applications in biochemistry and medicine, N(1)-functionalization, or amidoacylation at C(3) in the case of the CF 3 derivatives, is possible without a concomitant hypsochromic shift of their absorption and emission maxima. Semiempirical molecular-orbital calculations ( AM1 for structures, ZINDO for electronic transition energies) prove to be a suitable tool for the prediction of absorption properties of these compounds. The crystal-structure analysis of 6,7-dimethoxy-1-methyl-3-nitro-4-(trifluoromethyl)quinolin-2-(1H )-one (7 )( C 13H11F 3N2O5, monoclinic, P21/c, aa 12.372(2), ba 12.154(2), ca 10.119(2)a, ba 112.95(2)8) shows that the NO2 group, squeezed between the CF 3 and the CaO group, is oriented almost perpendicularly (87.8(4)8) to the ring plane. The intramolecular F ··· N distance between the CF 3 and the NO2 group is only 2.513(4)a.

Diphenylethanediamine derivatives as chiral selectors V1. Efficient normal-phase high-performance liquid chromatographic enantioseparation of underivatized chiral arylalcohols on four differently linked 3,5-dinitrobenzoyldiphenylethanediamine-derived chiral stationary phases☆

Abstract Four brush-type chiral stationary phases (CSPs) have been prepared, via immobilization of ( R , R )-3,5-dinitrobenzoyl-1,2-diphenylethane-1,2-diamine (DNB-DPEDA) with structurally different anchoring groups. These phases separate at normal-phase HPLC conditions the enantiomers of numerous underivatized chiral aromatic alcohols, including ArCH(OH)R, ArCH 2 CH(OH)R, Ar(CH) 2 CH(OH)R, simple tertiary arylalkylcarbinols and trans -2-arylcyclohexanols. In mobile phases of low polarity separations are characterized by considerate levels of enantioselectivity ( α = 1.1–2.7), excellent band shapes and short elution times. The hydroxyl group of the analytes is shown to be essential for stereodiscrimination, while π-basicity and steric bulkiness determine the magnitude of enantioselectivity. For simple structured arylalkylcarbinols a correlation is found between elution order and absolute configuration of the analyte. A rationale for molecular recognition of carbinol type analytes on DNB-DPEDA-derived CSPs is advanced. Their general applicability is demonstrated for a number of chiral auxiliaries, solvating agents and drug intermediates of carbinol structure.

Diphenylethanediamine derivatives as chiral selectors VIII. Influence of the second amido function on the high- performance liquid chromatographic enantioseparation characteristics of (N-3,5-dinitrobenzoyl)-diphenylethanediamine based chiral stationary phases

Abstract The effect of the second amido group in ( R , R )- and ( R , S )-3,5-dinitrobenzoylated 1,2-diphenylethane-1,2-diamine (DPEDA) derived chiral selectors was investigated. Structurally related mono-amidic (“deaza”) model compounds were synthesized and immobilized. The HPLC performance of the resultant two new chiral stationary phases (CSPs) was compared with the broadly applicable diamidic analogues. On the “deaza” CSPs special enantioseparation capabilities for underivatized alcohols and carboxylic acids were significantly reduced whereas separation of amides, ureas and carbamates and also analytes containing ester functions were substantially improved.

Enantioselective drug monitoring of (R)- and (S)-propranolol in human plasma via derivatization with optically active (R,R)-O,O-diacetyl tartaric acid anhydride

A sensitive high-performance liquid chromatographic method was developed for the stereoselective assay of (R)- and (S)-propranolol in human plasma. The method involves diethyl ether extraction of the drugs and a racemic internal standard, N-tert.-butylpropranolol, followed by derivatization of the compounds with the chiral reagent (R,R)-O,O-diacetyl tartaric acid anhydride. The resulting diastereomeric derivatives were separated isocratically on a reversed-phase column. Quantitation was achieved by the peak-height ratio method with reference to the internal standard. The assay was accurate and reproducible in the concentration range 1-100 ng of (R)- and (S)-propranolol per ml plasma, using fluorescence detection at lambda ex 290 nm and lambda em 335 nm. The applicability of this method was demonstrated for the determination of concentration-time profiles of propranolol enantiomers in the course of comparative pharmacokinetic studies.

Structure–Activity Relationships and Molecular Docking of Novel Dihydropyrimidine-Based Mitotic Eg5 Inhibitors

Dihydropyrimidine‐based compounds belong to the first discovered inhibitors of the human mitotic kinesin Eg5. Although they are used by many research groups as model compounds for chemical genetics, considerably less emphasis has been placed on the improvement of this type of inhibitor, with the exception of two recent studies. Dihydropyrimidines can be divided into class I (analogues that bind in the S configuration) and class II type inhibitors, which bind in the R configuration. Herein we report the synthesis and optimization of novel class II type dihydropyrimidines using a combination of in vitro and docking techniques.