A new C2-symmetric atropisomeric thiophene-based monomer for inherently chiral electroactive materials: synthesis, HPLC resolution, and absolute configuration assignment

Herein, we report on the synthesis and high-performance liquid chromatography (HPLC) resolution of a new atropisomeric C2-symmetry chiral monomer based on the 3,3′-bithiophene core, which was developed to produce novel, inherently oligomeric chiral electroactive materials. The analytical enantioseparation was optimized using the cellulose-type Chiralpak IB-3 column and a mixture of n-hexane–methanol–dichloromethane 90:5:5 (v/v/v) as the mobile phase. During the scale-up of the enantioseparation analytical conditions to a semipreparative level, remarkable deformations in the HPLC profile, such as peak splitting and plateau zones between enantiomeric peaks, were observed. We demonstrate the effects of sample diluent as they relate to distorted peak profiles, as well as provide experimental solutions to prevent the disturbing phenomenon. The optimized chromatographic conditions were exploited to collect milligram amounts of the enantiopure sample, which was submitted to chiroptical and stereochemical characterization studies

Direct HPLC enantioseparation of chemopreventive chiral isothiocyanates sulforaphane and iberin on immobilized amylose-based chiral stationary phases under normal-phase, polar organic and aqueous conditions

Sulforaphane and iberin are promising chemopreventive chiral phytochemicals. The chirality of these organic isothiocyanates is due to the presence of a stereogenic sulfur atom. Investigations of the effectiveness of single enantiomers as chemoprotective agents highlight the key role played by sulfur chirality on biological activity. The predominant native (R)-enantiomer is active whereas the (S)-counterpart is inactive or poorly active. Here, we provide an enantioselective method for the direct and complete resolution of both chiral sulfoxides by high-performance liquid chromatography on immobilized amylose-derived chiral stationary phases. A set of five different columns was investigated utilizing normal-phase, polar organic and aqueous conditions. The effect of the composition of mobile phase on enantioselectivity and retention was carefully evaluated. U-shape retention maps, which are indicative of a double and competitive hydrophilic interaction liquid chromatography and reversed-phase liquid chromatography retention mechanism, were established by recording the retention factors of the enantiomers of sulforaphane on the Chiralpak IA-3 and Chiralpak IG-3 chiral stationary phases varying progressively the water content in the water-acetonitrile mobile phases

Comparison of Coated and Immobilized Chiral Stationary Phases Based on Amylose tris-[(S)-α-Methylbenzylcarbamate] for the HPLC Enantiomer Separation of α-Lipoic Acid and Its Reduced Form

The couple of chiral sulfur compounds α-lipoic acid (ALA)/α-dihydrolipoic acid (DHALA) has attracted considerable attention in recent years owing to its remarkable anti-inflammatory and antioxidant properties. It is well known that the chirality of the C6 plays a key role in determining the biological activity of ALA. The natural occurring (R)-ALA enantiomer is an essential cofactor for key oxidative metabolism enzyme complexes and, after oral administration of the racemic mixture, it shows higher plasma concentration than (S)-ALA. Differently, the in vivo enantioselective action difference between the enantiomers of DHALA has not yet been studied. This lacking is perhaps due to the unavailability of analytical methods capable of determining the enantiomeric composition of biological samples during pharmacokinetic and pharmacodynamic events. In the present work, the direct and baseline enantioresolution of both chiral acids by HPLC on two amylose-derived chiral stationary phases is presented. The proposed chiral enantioselective protocol, therefore, does not require pre- or on-column derivatization. The performance of the coated Chiralpak AS-H CSP and the new immobilized Chiralpak IH-3 CSP, which have the same chiral selector amylose tris-[(S)-α-methylbenzylcarbamate], were compared using conventional normal-phase mobile phases containing ethanol or 2-propanol as alcoholic solvents and a fixed percentage of trifluoroacetic acid. Nonconventional eluents containing dichloromethane, ethyl acetate, and 2-methyltetrahydrofuran as organic cosolvents were applied in the separation of the enantiomers of two carboxylic acids on the immobilized Chiralpak IH-3 CSP. The effect of the column temperature was carefully evaluated in order to improve enantioselectivity. Adequate amounts of enantiomers were isolated by an analytical-size Chiralpak IH-3 column and submitted to chiroptical measurements. The absolute configuration assignment of the isolated enantiomers was determined by a multidisciplinary procedure based on the comparison of the experimental and calculated chiroptical properties

A New C2-Symmetric Atropisomeric Thiophene-Based Monomer for Inherently Chiral Electroactive Materials: Synthesis, HPLC Resolution, and Absolute Configuration Assignment

Herein, we report on the synthesis and high-performance liquid chromatography (HPLC) resolution of a new atropisomeric C2-symmetry chiral monomer based on the 3,3′-bithiophene core, which was developed to produce novel, inherently oligomeric chiral electroactive materials. The analytical enantioseparation was optimized using the cellulose-type Chiralpak IB-3 column and a mixture of n-hexane–methanol–dichloromethane 90:5:5 (v/v/v) as the mobile phase. During the scale-up of the enantioseparation analytical conditions to a semipreparative level, remarkable deformations in the HPLC profile, such as peak splitting and plateau zones between enantiomeric peaks, were observed. We demonstrate the effects of sample diluent as they relate to distorted peak profiles, as well as provide experimental solutions to prevent the disturbing phenomenon. The optimized chromatographic conditions were exploited to collect milligram amounts of the enantiopure sample, which was submitted to chiroptical and stereochemical characterization studies

Heterocyclic pharmacochemistry of new rhinovirus antiviral agents: A combined computational and experimental study

Rhinovirus (RV), member of the Enterovirus genus, is known to be involved in more than half of the common colds. Through advances in molecular biology, rhinoviruses have also been associated with exacerbations of chronic pulmonary diseases (e.g. asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis). In the current investigation, we develop a novel series of 4,5-dimethoxybenzyl derivatives that potently inhibits rhinovirus replication. Compound (S)-7f blocks RV-B14 replication with an EC50 value of 0.25 μM and shows a low toxicity in HeLa cells (CC50 > 271 μM). Enantioseparation followed by an absolute configuration determination by a Mosher's method revealed the interest of enantiopure compounds. Molecular docking studies permitted the identification of key biological interactions within the drug-binding pocket and an in silico drug-like study revealed a good potential for the development of these derivatives.status: publishe

Heterocyclic pharmacochemistry of new rhinovirus antiviral agents: a combined computational and experimental study

Rhinovirus (RV)​, member of the Enterovirus genus, is known to be involved in more than half of the common colds. Through advances in mol. biol., rhinoviruses have also been assocd. with exacerbations of chronic pulmonary diseases (e.g., asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis)​. In the current investigation, the authors develop a novel series of 4,​5-​dimethoxybenzyl derivs. that potently inhibits rhinovirus replication. Compd. (S)​-​7f ((S)​-​1-​(4-​(1H-​pyrazol-​4-​yl)​phenyl)​-​2-​(4,​5-​dimethoxy-​2-​nitrophenyl)​ethanol) blocks RV-​B14 replication with an EC50 value of 0.25 μM and shows a low toxicity in HeLa cells (CC50 > 271 μM)​. Enantiosepn. followed by an abs. configuration detn. by a Mosher's method revealed the interest of enantiopure compds. Mol. docking studies permitted the identification of key biol. interactions within the drug-​binding pocket and an in silico drug-​like study revealed a good potential for the development of these derivs

Structure-Based Drug Design of Potent Pyrazole Derivatives against Rhinovirus Replication

International audienceRhinoviruses (RVs) have been linked to exacerbations of many pulmonary diseases, thus increasing morbidity and/or mortality in subjects at risk. Unfortunately, the wide variety of RV genotypes constitutes a major hindrance for the development of Rhinovirus replication inhibitors. In the current investigation, we have developed a novel series of pyrazole derivatives that potently inhibit the Rhinovirus replication. Compounds 10e and 10h behave as early stage inhibitors of Rhinovirus infection with a broad-spectrum activity against RV-A and RV-B species (EC 50 < 0.1 μM). We also evaluate the dynamics of the emerging resistance of these promising compounds and their in vitro genotoxicity. Molecular docking experiments shed light on the pharmacophoric elements interacting with residues of the drug-binding pocket

Breakthrough Cancer Pain: Preliminary Data of The Italian Oncologic Pain Multisetting Multicentric Survey (IOPS-MS)

Introduction: An ongoing national multicenter survey [Italian Oncologic Pain multiSetting Multicentric Survey (IOPS-MS)] is evaluating the characteristics of breakthrough cancer pain (BTP) in different clinical settings. Preliminary data from the first 1500 cancer patients with BTP enrolled in this study are presented here. Methods: Thirty-two clinical centers are involved in the survey. A diagnosis of BTP was performed by a standard algorithm. Epidemiological data, Karnofsky index, stage of disease, presence and sites of metastases, ongoing oncologic treatment, and characteristics of background pain and BTP and their treatments were recorded. Background pain and BTP intensity were measured. Patients were also questioned about BTP predictability, BTP onset (≤10 or >10 min), BTP duration, background and BTP medications and their doses, time to meaningful pain relief after BTP medication, and satisfaction with BTP medication. The occurrence of adverse reactions was also assessed, as well as mucosal toxicity. Results: Background pain was well controlled with opioid treatment (numerical rating scale 3.0 ± 1.1). Patients reported 2.5 ± 1.6 BTP episodes/day with a mean intensity of 7.5 ± 1.4 and duration of 43 ± 40 min; 977 patients (65.1%) reported non-predictable BTP, and 1076 patients (71.7%) reported a rapid onset of BTP (≤10 min). Higher patient satisfaction was reported by patients treated with fast onset opioids. Conclusions: These preliminary data underline that the standard algorithm used is a valid tool for a proper diagnosis of BTP in cancer patients. Moreover, rapid relief of pain is crucial for patients’ satisfaction. The final IOPS-MS data are necessary to understand relationships between BTP characteristics and other clinical variables in oncologic patients. Funding: Molteni Farmaceutici, Italy