Abstract
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.
Highlights
Sigma receptors (SRs) are involved in different pharmacological and pathological pathways.They modulate cell survival and excitability and sub-serve many critical functions in the human body
S1Rs are overexpressed in the central nervous system (CNS), while Sigma 2 receptors (S2R) are overexpressed in tumor cells and tissues in proliferation [1]
S1R modulators could be useful for the treatment of several CNS diseases, such as anxiety, depression, schizophrenia, drug addiction, Parkinson’s and Alzheimer’s diseases [2], whereas S2R ligands could have a relevant role in cancer diagnosis and therapy [3]
Summary
Sigma receptors (SRs) are involved in different pharmacological and pathological pathways. RC-34, characterized by the that small changes in the ligand (the structure markedly influence the with abilityrespect of SRs to discriminate the case, the of an electronegative element only structural difference to RC-33). In this presence of an electronegative element (the only structural difference with respect to RC-33). Racemic and enantiomeric RC-33 (Figure 1) interact in a non(S)-configured enantiomer resulted resulted in beinginthe eutomer, with the following eudismic ratio ratio (ER, case, the (S)-configured enantiomer being the eutomer, with the following eudismic stereoselective manner with SRs, both enantiomers showing a similar affinity toward both S1R and distomer eutomer. Of the potential chiral SR modulators 1–6, characterized by an alkyl or alcoholic spacer bridging an aromatic moiety to the 4-benzyl-piperidine portion (Table 1). Biological investigation, in order to study the intriguing aspect of the influence of chirality in
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