100568-03-4Relevant articles and documents
Truly-Biocompatible Gold Catalysis Enables Vivo-Orthogonal Intra-CNS Release of Anxiolytics
Adam, Catherine,Becker, Catherina G.,Hamilton, Lloyd,Ortega-Liebana, M. Carmen,Porter, Nicola J.,Sieger, Dirk,Unciti-Broceta, Asier,Valero, Teresa
supporting information, (2021/11/22)
Being recognized as the best-tolerated of all metals, the catalytic potential of gold (Au) has thus far been hindered by the ubiquitous presence of thiols in organisms. Herein we report the development of a truly-catalytic Au-polymer composite by assembling ultrasmall Au-nanoparticles at the protein-repelling outer layer of a co-polymer scaffold via electrostatic loading. Illustrating the in vivo-compatibility of the novel catalysts, we show their capacity to uncage the anxiolytic agent fluoxetine at the central nervous system (CNS) of developing zebrafish, influencing their swim pattern. This bioorthogonal strategy has enabled -for the first time- modification of cognitive activity by releasing a neuroactive agent directly in the brain of an animal.
Tuning the activity of known drugs via the introduction of halogen atoms, a case study of SERT ligands – Fluoxetine and fluvoxamine
Bojarski, Andrzej J.,Bugno, Ryszard,Duszyńska, Beata,Hogendorf, Adam S.,Hogendorf, Agata,Kurczab, Rafa?,Lenda, Tomasz,Pietru?, Wojciech,Sata?a, Grzegorz,Staroń, Jakub,Wantuch, Anna,Warszycki, Dawid
supporting information, (2021/06/02)
The selective serotonin reuptake inhibitors (SSRIs), acting at the serotonin transporter (SERT), are one of the most widely prescribed antidepressant medications. All five approved SSRIs possess either fluorine or chlorine atoms, and there is a limited number of reports describing their analogs with heavier halogens, i.e., bromine and iodine. To elucidate the role of halogen atoms in the binding of SSRIs to SERT, we designed a series of 22 fluoxetine and fluvoxamine analogs substituted with fluorine, chlorine, bromine, and iodine atoms, differently arranged on the phenyl ring. The obtained biological activity data, supported by a thorough in silico binding mode analysis, allowed the identification of two partners for halogen bond interactions: the backbone carbonyl oxygen atoms of E493 and T497. Additionally, compounds with heavier halogen atoms were found to bind with the SERT via a distinctly different binding mode, a result not presented elsewhere. The subsequent analysis of the prepared XSAR sets showed that E493 and T497 participated in the largest number of formed halogen bonds. The XSAR library analysis led to the synthesis of two of the most active compounds (3,4-diCl-fluoxetine 42, SERT Ki = 5 nM and 3,4-diCl-fluvoxamine 46, SERT Ki = 9 nM, fluoxetine SERT Ki = 31 nM, fluvoxamine SERT Ki = 458 nM). We present an example of the successful use of a rational methodology to analyze binding and design more active compounds by halogen atom introduction. ‘XSAR library analysis’, a new tool in medicinal chemistry, was instrumental in identifying optimal halogen atom substitution.
Method for synthesizing chiral secondary alcohol compound
-
Paragraph 0160-0166, (2021/05/29)
The invention discloses a method for synthesizing a chiral secondary alcohol compound. The method comprises the following step of: reacting a ketone compound in an aprotic organic solvent at room temperature and inert gas atmosphere under the action of a chiral cobalt catalyst and an activating agent by taking a combination of bis(pinacolato)diboron and alcohol or water as a reducing agent to obtain the chiral secondary alcohol compound. According to the method disclosed by the invention, a combination of pinacol diborate and alcohol or water which are cheap, stable and easy to obtain is taken as a reducing agent, and a ketone compound is efficiently reduced to synthesize a corresponding chiral secondary alcohol compound in an aprotic organic solvent under the action of a chiral cobalt catalyst; in a chiral cobalt catalyst adopted by the method, when a chiral ligand is PAOR, an activating agent is NaBHEt3 or NaOtBu and an adopted raw material is aromatic ketone, the yield is 80% or above, and the optical purity is 90% or above; and when the adopted raw material is alkane ketone, the yield can reach 70% or above, and the optical purity can reach 80% or above.
Systems and methods for synthesizing chemical products, including active pharmaceutical ingredients
-
Page/Page column 37-39, (2020/12/14)
Systems and methods for synthesizing chemical products, including active pharmaceutical ingredients, are provided. Certain of the systems and methods described herein are capable of manufacturing multiple chemical products without the need to fluidically connect or disconnect unit operations when switching from one making chemical product to making another chemical product.
Copper-catalyzed and additive free decarboxylative trifluoromethylation of aromatic and heteroaromatic iodides
Johansen, Martin B.,Lindhardt, Anders T.
, p. 1417 - 1425 (2020/03/03)
A copper-catalyzed decarboxylative trifluoromethylation of (hetero)aromatic iodides has been developed. Importantly, this new copper-catalyzed reaction operates in the absence of any ligands and metal additives. The protocol shows good functional group tolerance and is compatible with heteroaromatic systems. The reaction proved scalable to a 15 mmol scale with increased yield. Finally, late-stage installation of the trifluoromethyl functionality afforded the N-trifluoroacetamide variant of the antidepressant agent, Prozac, demonstrating the applicability of the developed method.
Enantioselective Heck Arylation of Acyclic Alkenol Aryl Ethers: Synthetic Applications and DFT Investigation of the Stereoselectivity
Polo, Ellen Christine,Wang, Martí Fernández,Angnes, Ricardo Almir,Braga, Ataualpa A. C.,Correia, Carlos Roque Duarte
supporting information, p. 884 - 892 (2019/12/30)
Herein we report the enantioselective Heck-Matsuda arylation of acyclic E and Z-alkenyl aryl ethers. The reactions were carried out under mild conditions affording the enantioenriched benzyl ethers in a regioselective manner, moderate to good yields (up to 73%), and in good to excellent enantiomeric ratios (up to 97:3). The enantioselective Heck-Matsuda arylation has shown a broad scope (25 examples), and some key Heck-Matsuda adducts were further converted into more complex and valuable scaffolds including their synthetic application in the synthesis of (R)-Fluoxetine, (R)-Atomoxetine, and in the synthesis of an enantioenriched benzo[c]chromene. Finally, in silico mechanistic investigations into the reaction's enantioselectivity were performed using density functional theory. (Figure presented.).
Enantioseparation of chiral pharmaceuticals by vancomycin-bonded stationary phase and analysis of chiral recognition mechanism
Li, Jiaxi,Liu, Ruixia,Wang, Liyang,Liu, Xiaoling,Gao, Hongjie
, p. 236 - 247 (2019/02/01)
The drug chirality is attracting increasing attention because of different biological activities, metabolic pathways, and toxicities of chiral enantiomers. The chiral separation has been a great challenge. Optimized high-performance liquid chromatography (HPLC) methods based on vancomycin chiral stationary phase (CSP) were developed for the enantioseparation of propranolol, atenolol, metoprolol, venlafaxine, fluoxetine, and amlodipine. The retention and enantioseparation properties of these analytes were investigated in the variety of mobile phase additives, flow rate, and column temperature. As a result, the optimal chromatographic condition was achieved using methanol as a main mobile phase with triethylamine (TEA) and glacial acetic acid (HOAc) added as modifiers in a volume ratio of 0.01% at a flow rate of 0.3?mL/minute and at a column temperature of 5°C. The thermodynamic parameters (eg, ΔH, ΔΔH, and ΔΔS) from linear van 't Hoff plots revealed that the retention of investigated pharmaceuticals on vancomycin CSP was an exothermic process. The nonlinear behavior of lnk′ against 1/T for propranolol, atenolol, and metoprolol suggested the presence of multiple binding mechanisms for these analytes on CSP with variation of temperature. The simulated interaction processes between vancomycin and pharmaceutical enantiomers using molecular docking technique and binding energy calculations indicated that the calculated magnitudes of steady combination energy (ΔG) coincided with experimental elution order for most of these enantiomers.
Simultaneous enantioselective determination of seven psychoactive drugs enantiomers in multi-specie animal tissues with chiral liquid chromatography coupled with tandem mass spectrometry
Zhu,Li, Shuang,Zhou, Li,Li, Qing,Guo, Xingjie
, (2019/07/31)
In stock farming, illegal use of antipsychotics has caused the food safety problem. This paper presents for the first time, a multi-residues method for the simultaneous enantioselective determination of seven antipsychotics in pork, beef and lamb muscles. The behaviors of Chiralpak AGP toward changes in pH and organic modifier in mobile phase were studied, and all analytes were rapidly separated within 30 min. The calibration curves of all enantiomers were linear in the range of 1–250 ng g?1, with correlation coefficient above 0.9931. The recoveries of the targeted compounds were higher than 82.1%, with repeatability and intermediate precision lower than 18.2% and 17.4%, respectively. In three matrices, the limit of detection and limit of quantification ranged from 0.20 to 0.65 ng g?1 and from 0.40 to 1.00 ng g?1, respectively. The proposed method can be used to provide additional information for the reliable risk assessment of chiral antipsychotics.
Evaluation of the Edman degradation product of vancomycin bonded to core-shell particles as a new HPLC chiral stationary phase
Hellinghausen, Garrett,Lopez, Diego A.,Lee, Jauh T.,Wang, Yadi,Weatherly, Choyce A.,Portillo, Abiud E.,Berthod, Alain,Armstrong, Daniel W.
, p. 1067 - 1078 (2018/08/01)
A modified macrocyclic glycopeptide-based chiral stationary phase (CSP), prepared via Edman degradation of vancomycin, was evaluated as a chiral selector for the first time. Its applicability was compared with other macrocyclic glycopeptide-based CSPs: TeicoShell and VancoShell. In addition, another modified macrocyclic glycopeptide-based CSP, NicoShell, was further examined. Initial evaluation was focused on the complementary behavior with these glycopeptides. A screening procedure was used based on previous work for the enantiomeric separation of 50 chiral compounds including amino acids, pesticides, stimulants, and a variety of pharmaceuticals. Fast and efficient chiral separations resulted by using superficially porous (core-shell) particle supports. Overall, the vancomycin Edman degradation product (EDP) resembled TeicoShell with high enantioselectivity for acidic compounds in the polar ionic mode. The simultaneous enantiomeric separation of 5 racemic profens using liquid chromatography-mass spectrometry with EDP was performed in approximately 3?minutes. Other highlights include simultaneous liquid chromatography separations of rac-amphetamine and rac-methamphetamine with VancoShell, rac-pseudoephedrine and rac-ephedrine with NicoShell, and rac-dichlorprop and rac-haloxyfop with TeicoShell.
Determination of fluoxetine hydrochloride via ion-pair complexation with alizarin red S
Constantinescu, Ioana Clementina,Neagu, Alexandra Filareta,Uivarosi, Valentina
, p. 1293 - 1303 (2019/01/04)
Two UV-Vis spectrophotometric methods and one fluorimetric method have been developed for the quantitative determination of fluoxetine hydrochloride in bulk and pharmaceutical formulations. These methods are based on the ion-pair complex formation between alizarin red S and fluoxetine hydrochloride. In the first method (method A), the yellow-colored complex obtained in acidic medium was extracted with chloroform and the absorbance of the chloroformic solution was measured at 425 nm. Beerís law limits (9.5 ? 48 μg/mL), the molar absorptivity (5256 L ∑ mol-1 ∑ cm-1), and the complex composition (1: 1) were determined. In the second method (method B), the yellow complex fluoxetine ? alizarin red S extracted in chloroform was broken in alkaline medium, and the absorbance of the resulting violet-colored free dye was measured at 524 nm. A linear relationship was observed in the range of 9.0 ? 54 μg/mL. In the third method (method C) the fluorescence intensity of the fluoxetine ? alizarin red S complex, obtained in the same manner as for method A, was measured at 594 nm after excitation at 425 nm. The fluorescence intensity was proportional to the drug concentration in the linear range of 2.7-10.2 μg/mL. The limits of detection and quantification have also been calculated. Furthermore, the proposed methods have been successfully applied for the assay of the drug in pharmaceutical dosage forms.
