Studies on the Enantiomers of RC-33 as Neuroprotective Agents: Isolation, Configurational Assignment, and Preliminary Biological Profile

Abstract

In this study we addressed the role of chirality in the biological activity of RC-33, recently studied by us in its racemic form. An asymmetric synthesis procedure was the first experiment, leading to the desired enantioenriched RC-33 but with an enantiomeric excess (ee) not good enough for supporting the in vitro investigation. An enantioselective high-performance liquid chromatography (HPLC) procedure was then successfully carried out, yielding both RC-33 enantiomers in amounts and optical purity suitable for the pharmacological study. The absolute configuration of pure enantiomers was easily assigned exploiting the asymmetric synthesis previously devised. As emerged in the preliminary in vitro biological investigation, (S)- and (R)-RC-33 possess a comparable affinity towards the σ1 receptor and a very a similar behavior in the calcium influx assay, resulting in an equally effective σ1 receptor agonist. Overall, the results obtained so far suggest that the interaction with the biological target is nonstereoselective and leads us to hypothesize that there is a lack of stereoselectivity in the biological activity of RC-33.

Enantiomeric 4‐Acylamino‐6‐alkyloxy‐2 Alkylthiopyrimidines As Potential A3Adenosine Receptor Antagonists: HPLC Chiral Resolution and Absolute Configuration Assignment by a Full Set of Chiroptical Spectroscopy

“…Moreover, the design of the experiments took into account the good solubility of 1 , 2 , 3 in alcohols. For this reason the first set of experiments was performed on the considered columns, eluting with just methanol …”

“…For this reason the first set of experiments was performed on the considered columns, eluting with just methanol. 14 As a result of a first screening with pure methanol, it was found that Chiralcel OJ-H (4.6 mm × 150 mm, 5 μm) lead to relatively short retention times, high enantioselectivity, and high resolution for compound 2 (α = 3.3, R s = 6.7) and 3 (α = 1.9, R s = 4.1). Accordingly, these experimental conditions were selected for the scale-up to (semi)-preparative scale.…”

“…These tasks were achieved by using chiral high‐performance liquid chromatography (HPLC) and chiroptical spectroscopy methods combined with Density Functional Theory (DFT) calculations. In detail, on the basis of our previous experience we resolved enantiomeric 1 , 2 , 3 via enantioselective HPLC on chiral stationary phases (CSPs), this approach being an effective way for both the analytical and the preparative separations of chiral compounds . We carried out the absolute configuration (AC) assignment study of 1 , 2 , 3 resolved enantiomers by a full set of chiroptical spectroscopies and comparison with calculated spectra obtained by ab initio methods (DFT‐) .…”

“…In detail, on the basis of our previous experience we resolved enantiomeric 1-3 via enantioselective HPLC on chiral stationary phases (CSPs), this approach being an effective way for both the analytical and the preparative separations of chiral compounds. [12][13][14] We carried out the absolute configuration (AC) assignment study of 1-3 resolved enantiomers by a full set of chiroptical spectroscopies and comparison with calculated spectra obtained by ab initio methods (DFT-). [15][16][17] Thus, optical rotatory dispersion (ORD), electronic circular dichroism (ECD), and vibrational circular dichroism (VCD) spectra were recorded and compared to the calculated ones.…”

Dual-Functioning Scaffolds for the Treatment of Spinal Cord Injury: Alginate Nanofibers Loaded with the Sigma 1 Receptor (S1R) Agonist RC-33 in Chitosan Films

“…In particular, accumulating evidence highlighted the potential role of S1R agonists in exerting neuroprotective and/or restorative effects, by reducing excitotoxicity and oxidative damage [7][8][9][10][11]. Along the years, Rossi et al designed and synthetized a S1R modulator compound library, belonging to the common arylalkyl(alkenyl) aminic scaffold, which led the identification of 1-[3-(1,1 -biphen)-4-yl]butylpiperidine (henceforth , as a molecule endowed with the most promising pharmacological profile and able in promoting nerve growth factor(NGF)-induced neurite outgrowth in PC-12 cells [12][13][14][15]. In the light of these properties, RC-33 was selected as a neuroprotective agent to further investigate the role of S1R agonists in treating SCI.…”