Giancarlo Bettoni

Enantiomers of clofibric acid analogs have opposite actions on rat skeletal muscle chloride channels

The S-(−) isomers of a series of clofibric acid analogs produced only a block of chloride conductance of rat skeletal muscle fibers with increasing concentrations until block was nearly complete. The R-(+) isomers, on the other hand, at low concentrations increased chloride conductance by as much as 9% to 39% and at higher concentrations decreased chloride conductance, but never by more than 27% of the control value. The actions of the enantiomeric pairs to either produce or inhibit myotonic excitability paralleled their ability to block or increase chloride conductance, respectively.

Synthesis and absolute configuration of substituted morpholines

Abstract We studied methods of stereospecific synthesis that enabled us to obtain variously substituted morpholinic compounds and to determine their absolute configuration. From a study of the chiroptical properties of synthetic N-[2-pyridyl-N-oxide] derivatives of optically active morpholines, it was possible to correlate the sign of the Cotton effect with the absolute configuration. This correlation agrees with that previously established for derivatives of the piperidine type. By evaluating the various contributions to the Cotton effect of substituents in positions 2 and 3, we established the absolute configuration of bicyclic compounds condensed in the two positions mentioned above.

LFER and CoMFA studies on optical resolution of α-alkyl α-aryloxy acetic acid methyl esters on DACH-DNB chiral stationary phase

SummaryThe HPLC resolution of a series of racemic α-substituted α-aryloxy acetic acid methyl esters I on a π-acid chiral stationary phase containing N,N′-(3,5-dinitrobenzoyl)-trans-1,2-diaminocyclohexane as chiral selector was modelled by linear free energy-related (LFER) equations and comparative molecular field analysis (CoMFA). Our results indicate that the retention process mainly depends on solute lipophilicity and steric properties, whereas enantioselectivity is primarily influenced by electrostatic and steric interactions. CoMFA provided additional information with respect to the LFER study, allowed the mixing of different subsets of I and led to a quantitative 3D model of steric and electrostatic factors responsible for chiral recognition.

Synthesis and Biological Evaluation of 2-Heteroarylthioalkanoic Acid Analogues of Clofibric Acid as Peroxisome Proliferator-Activated Receptor α Agonists

A series of 2-heteroarylthioalkanoic acids were synthesized through systematic structural modifications of clofibric acid and evaluated for human peroxisome proliferator-activated receptor alpha (PPARalpha) transactivation activity, with the aim of obtaining new hypolipidemic compounds. Some thiophene and benzothiazole derivatives showing a good activation of the receptor alpha were screened for activity against the PPARgamma isoform. The gene induction of selected compounds was also investigated in the human hepatoma cell line.

Oxidation of tertiary polycycl1c amines by RuO4

Abstract The reactions of certain tertiary polycyclic amines such as N-benzyl-9-azabicy-clo- [3,3,1]-nonane, N-benzyl-5, 6-dihydro-11H-dibenz [b,e] azepine, and N-benzyl-1,2,3,4-tetrahydroisoquinoline with ruthenium tetroxide, taking place in both heterogeneous and homogeneous systems, have made it possible to establish the order of reactivity of the various methylene groups adjacent to the nitrogen with respect to this oxidizing agent.

Optical properties of dimedonyl derivative of aromatic amines and amino acids

Abstract It is shown that the Cotton effect associated with the dimedone condensates of amino compounds depends on the relative position of the vinylogous amide group and other chromophores present in the molecule. The chirality of the homoconjugated chromophore, in these partially rigid structures, strongly affects the sign of their ORD curves which are opposite in the derivatives of aromatic and aliphatic amino acids having the same configuration at the asymmetric C atom. On this assumption, some results published previously have been corrected. The inversion of the Cotton effect observed in the derivatives of secondary amines has been explained by means of a conformational change.

Direct resolution of α-monoalkyl-α-aryloxyacetic acids via ester or imide derivatives

Abstract This paper describes a simple procedure for the resolution of racemic α-monoalkyl α-aryloxyacetic acids, using the chromatographic separation of theircovalent derivatives. (R)-Ethyl mandelate, (R)-pantolactone and (S)-4-(1-methylethyl)-2-oxazolidinone are the resolving agents involved in the formation of equimolecular diastereomeric mixtures of esters or imides. Chromatographic resolutions were performed by means of gas chromatography (GC), thin-layer chromatography (TLC) and flash chromatography. Successive hydrolysis of separated diastereomers provided optically pure aryloxyacetic acids.

Synthesis and antiplatelet activity of gemfibrozil chiral analogues

The chiral analogues of gemfibrozil 5-(2,5-dimethylphenoxy)-2-methylpentanoic acid and 5-(2,5-dimethylphenoxy)-2-ethylpentanoic acid were synthesized in optically active form using (S)-4-(1-methylethyl)-2-oxazolidinone as chiral auxiliary. All compounds inhibit human platelet aggregation. From these data, one can surmise that all tested compounds and gemfibrozil act at the platelet level with different mechanism than that of ASA, even if with a different potency.

NMR investigation on the conformational properties of N-[2-pyridyl-N-oxide]-amino derivatives

Abstract The proton NMR spectra of N-[2-pyridyl-N-oxide]-derivatives of primary and secondary ethylamines, containing a substituent R on the C atom bearing the amino function, have been completely analysed in terms of the fundamental NMR parameters. The preferred conformations of the compounds investigated were established by the indications from NOE experiments as well as: (1) the long range coupling across the five bond between the aminic hydrogen and the proton in 4-position of the pyridine-N-oxide ring (5JmH,NH ∼ 0·5 c/s), (2) the value of the vicinal coupling constant in the fragment CHNH (3JNHCH ∼ 7–9 c/s), (3) the large deshielding (Δτ ∼ 1–1·5 ppm) observed for the resonance position of the proton on the asymmetric C atom in secondary amine derivatives with respect to the corresponding primary ones, and (4) the diamagnetic shielding produced on protons in position 3 and 4 of the pyridine-N-oxide ring by different aromatic groups introduced in the R substituent. The NMR data confirmed the preferred rotamers previously suggested on the basis of ORD and CD measurements.

On the chiroptical properties of ketimine structures derived from 5-chloro-2-hydroxybenzophenone

Abstract The CD curves of several ketimines derived from condensation of 5-chloro-2-hydroxybenzophenone with optically active amino compounds have been measured. The geometric relationship between the chromophoric groups in the amino moiety and the 5-chloro-2-hydroxybenzophenone chromophore, which depends on the absolute configuration and conformation of the molecule, is more important than chirality at the asymmetric C atom in determining the chiroptical properties of these compounds.