Assignment of the absolute configuration at the sulfur atom of thioridazine metabolites by the analysis of their chiroptical properties: the case of thioridazine 2-sulfoxide.
Thioridazine (THD) is a commonly prescribed phenotiazine neuroleptic drug, which is extensively biotransformed in the organism producing as main metabolites sulfoxides and a sulfone by sulfur oxidation. Significant differences have been observed in the activity of the THD enantiomers as well as for its main metabolites, and enantioselectivity phenomena have been proved in the metabolic pathway. Here the assignment of the absolute configuration at the sulfur atom of enantiomeric THD-2-sulfoxide (THD-2-SO) has been carried out by circular dichroism (CD) spectroscopy. The stereoisomers were separated by HPLC on Chiralpak AS column, recording the CD spectra for the two collected enantiomeric fractions. The theoretical electronic CD spectrum has been obtained by the TDDFT/B3LYP/6-31G*, as Boltzmann averaging of the contributions calculated for the most stable conformations of the drug. The comparison of the simulated and experimental spectra allowed the absolute configuration at the sulfur atom of the four THD-2-SO stereoisomers to be assigned. The developed method should be useful for a reliable correlation between stereochemistry and activity and/or toxicity.
Bertucci
Carlo
C
Dipartimento Scienze Farmaceutiche, Università di Bologna, via Belmeloro 6, 40126 Bologna, Italy. carlo.bertucci@unibo.it
Guimarães
Luiz Fernando Lopes
LF
Bonato
Pierina Sueli
PS
Borges
Keyller Bastos
KB
Okano
Laura Tiemi
LT
Mazzeo
Giuseppe
G
Rosini
Carlo
C
D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism; D013881:Thioridazine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism
C529599:thioridazine-2-sulfoxide; D013881:Thioridazine