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

Abstract

The chiral separation of enantiomeric couples of three potential A 3 adenosine receptor antagonists: (R/S)-N-(6-(1-phenylethoxy)-2-(propylthio)pyrimidin-4-yl)acetamide (1), (R/ S)-N-(2-(1-phenylethylthio)-6-propoxypyrimidin-4-yl)acetamide (2), and (R/S)-N-(2-(benzylthio)-6-sec-butoxypyrimidin-4-yl)acetamide (3) was achieved by high-performance liquid chromatography (HPLC). Three types of chiroptical spectroscopies, namely, optical rotatory dispersion (ORD), electronic circular dichroism (ECD), and vibrational circular dichroism (VCD), were applied to enantiomeric compounds. Through comparison with Density Functional Theory (DFT) calculations, encompassing extensive conformational analysis, full assignment of the absolute configuration (AC) for the three sets of compounds was obtained. Chirality 28: 434-440, 2016.

(R)-(−)-Aloesaponol III 8-Methyl Ether from Eremurus persicus: A Novel Compound against Leishmaniosis

“…The absolute configuration of (−)-ASME ( Figure 3 ) was unambiguously assigned through VCD (vibrational circular dichroism) and ECD (electronic circular dichroism) spectroscopies and DFT (density functional theory) calculations, through the approach reported in renowned literature [ 13 , 14 , 15 ] and also already employed in instances relevant to the present case [ 16 , 17 , 18 , 19 ]. In Figure 4 , we report the comparison of the spectra obtained with the computations performed for the assumed ( R ) configuration.…”

Insight into GEBR-32a: Chiral Resolution, Absolute Configuration and Enantiopreference in PDE4D Inhibition

“…Considering that both enantiomers are needed for biological testing, we synthesized racemic GEBR-32a first (according to the previously reported procedure, Scheme SI) [7] and solved the enantiomers by chiral liquid chromatography, a time-and cost-effective approach for enantiomer resolution at the discovery stage, commonly used both in Academia and the pharmaceutical industry [7,11]. To find easily scalable chiral resolution analytical methods, our standard approach to the analysis and separation of new chiral compounds consisted in the screening of polysaccharide-based chiral stationary phases (CSPs) immobilized on silica gel chiral columns characterized by wide solvent compatibility, versatility and robustness [11][12][13][14][15][16][17][18]. First, we tested a Regispack IA column containing a dimethylphenyl-derivative of amylose.…”

Studies on enantioselectivity of chiral 4-acetylamino-6-alkyloxy-2-alkylthiopyrimidines acting as antagonists of the human A3 adenosine receptor

“…As recently reported, 12 the resolution of racemic 1-3 by semi-preparative HPLC using chiral stationary phases was performed to isolate each enantiomer in small amounts suitable for configurational assignment and biological investigations. Briefly, a standard screening protocol was firstly applied by using an analytical Chiralcel OJ-H column (4.6 mm × 150 mm, 5 μm), whose chiral selector is cellulose tris-(4methylbenzoate) coated on a silica gel substrate.…”

“…The results of these studies have been recently published. 12 In the present work, racemic mixtures and the pure enantiomers of 1-3 were assayed in competition binding experiments to measure their affinities for the human A 3 AR and their selectivity trend towards the other AR subtypes. Cell-based functional experiments were carried out on the most potent enantiomers to confirm the expected antagonist efficacy profile.…”