Novel Enantiopure Sigma Receptor Modulators: Quick (Semi-)Preparative Chiral Resolution via HPLC and Absolute Configuration Assignment.
The identification of novel pan-sigma receptor (SR) modulators, potentially useful in cancer treatment, represents a new goal of our research. Here, we report on the preparation of novel chiral compounds characterized by a 3-C alkyl chain bridging an aromatic portion to a 4-benzyl-piperidine moiety. All of the studied compounds have been prepared both in racemic and enantiomerically-pure form, with the final aim to address the role of chirality in the SR interaction. To isolate and characterize enantiomeric compounds, high-performance liquid chromatography (HPLC) procedures were set up. A systematic analytical screening, involving several combinations of chiral stationary and mobile phases, allowed us to optimize the analytical resolution and to set up the (semi-)preparative chromatographic conditions. Applying the optimized procedure, the enantiomeric resolution of the studied compounds was successfully achieved, obtaining all of the compounds with an enantiomeric excess higher than 95%. Lastly, the absolute configuration has been empirically assigned to enantiopure compounds, combining the electronic circular dichroism (ECD) technique to the elution order study.
Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, Viale Taramelli 12, Pavia 27100, Italy. marta.rui01@universitadipavia.it.|Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, Vienna 1090, Austria. marta.rui01@universitadipavia.it.
Marta
M
Rui
Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, Viale Taramelli 12, Pavia 27100, Italy. annamaria.marra@unipv.it.
Annamaria
A
Marra
Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, Vienna 1090, Austria. vittorio.pace@univie.ac.at.
Vittorio
V
Pace
Corden Pharma Switzerland LLC, Eichenweg 1, Liestal 4410, Switzerland. markus.juza@cordenpharma.com.
Markus
M
Juza
Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, Viale Taramelli 12, Pavia 27100, Italy. daniela.rossi@unipv.it.
Daniela
D
Rossi
Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, Viale Taramelli 12, Pavia 27100, Italy. simona.collina@unipv.it.
Simona
S
Collina
D002851:Chromatography, High Pressure Liquid; D006801:Humans; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification; D017480:Receptors, sigma / Q000819:agonists*
D010880:Piperidines; D017480:Receptors, sigma
amylose- and cellulose-derived CSPs; chiral resolution; electronic circular dichroism (ECD); enantioselective HPLC; sigma receptor (SR) modulators