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Aim: Cinchonine (CN) and its isomer cinchonidine (CD), two of the common cinchona alkaloids, are wildly used as antimalarial drugs. However, the effects of CN and CD on the auditory system are unknown., Methods: Molecular docking and molecular dynamics (MD) simulation were used for predicting effective drugs. The CCK-8 assay was conducted for assessing cell viability in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells. MitoSox Red staining revealed reactive oxygen species (ROS) amounts. TMRM staining was used to assess the mitochondrial membrane potential (ΔΨm). Immunofluorescence staining of myosin 7a was used to examine hair cells (HCs) in cisplatin-treated neonatal mouse cochlear explants, while TUJ-1 immunostaining was used for the detection of spiral ganglion neurons (SGNs). Cleaved caspase-3 and TUNEL immunostaining were utilized for apoptosis assessment. Immunoblot was carried out to detect PI3K-AKT signaling effectors., Results: Pretreatment with CN or CD significantly increased cell viability and reduced mitochondrial dysfunction and ROS accumulation in cisplatin-treated HEI-OC1 cells. Immunofluorescent staining of cochlear explants showed that CN and CD attenuated cisplatin-induced damage to SGNs and HCs. Immunoblot revealed that CN and CD downregulated the expression of cleaved caspase-3 and activated PI3K-AKT signaling in cisplatin-injured HEI-OC1 cells., Conclusion: CD and CN can reduce ototoxicity caused by cisplatin and might help treat cisplatin-associated hearing loss., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Renocardiac syndromes are a critical concern among patients with chronic kidney disease (CKD). High level of indoxyl sulfate (IS), a protein-bound uremic toxin, in plasma is known to promote the pathogenesis of cardiovascular diseases by impairing endothelial function. However, the therapeutic effects of the adsorbent of indole, a precursor of IS, on renocardiac syndromes is still debated. Therefore, novel therapeutic approaches should be developed to treat IS-associated endothelial dysfunction. In the present study, we have found that cinchonidine, a major Cinchona alkaloid, exhibited superior cell-protective effects among the 131 test compounds in IS-stimulated human umbilical vein endothelial cells (HUVECs). IS-induced cell death, cellular senescence, and impairment of tube formation in HUVECs were substantially reversed after treatment with cinchonidine. Despite the cinchonidine did not alter reactive oxygen species formation, cellular uptake of IS and OAT3 activity, RNA-Seq analysis showed that the cinchonidine treatment downregulated p53-modulated gene expression and substantially reversed IS-caused G0/G1 cell cycle arrest. Although the mRNA levels of p53 were not considerably downregulated by cinchonidine in IS-treated HUVECs, the treatment of cinchonidine promoted the degradation of p53 and the cytoplasmic-nuclear shuttling of MDM2. Cinchonidine exhibited cell-protective effects against the IS-induced cell death, cellular senescence, and impairment of vasculogenic activity in HUVECs through the downregulation of p53 signaling pathway. Collectively, cinchonidine may be a potential cell-protective agent to rescue IS-induced endothelial cell damage., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Alpha-lipoic acid is a natural product that possesses distinct pharmacological properties. Lipoic acid is a short-chain fatty acid containing an asymmetric carbon at five bonds of distance to the organic function. Herein, we developed a nuclear magnetic resonance protocol to access the chiral recognition of lipoic acid in a simple and rapid procedure employing cinchonidine as a cheap chiral solvation agent in deuterated chloroform. To optimize this method, a statistical design of the experimental model was performed to produce a clear understanding of the optimal concentration, temperature, and molar ratio parameters. Based on the obtained spectra, the cinchonidine H 8 -H 9 scalar coupling indicated a conformational preference in the chiral discrimination procedure. Density functional theory calculations established a proximity between the asymmetric center of lipoic acid and the aromatic moiety of cinchonidine, clarifying possible conformations in this ion-pair interaction. The described protocol demonstrates how far is far enough to chiral discrimination using a chiral solvation agent, expanding the method to compounds that contain a remote stereocenter., (© 2022 Wiley Periodicals LLC.)

The cobalt oxide-vanadium oxide (Co 3 O 4 -V 2 O 5 ) combined with reduced graphene oxide (rGO) having band gap of ∼ 3.3 eV appeared as a suitable photocatalyst for selective oxidation of 2-naphthol to BINOL. C2-symmetric BINOL was achieved with good yield using hydrogen peroxide as the oxidant under UV-light irradiation. The same catalyst was chirally modified with cinchonidine and a newly synthesized chiral Schiff base ligand having a sigma-hole center. The strong interaction of the chiral modifiers with the cobalt-vanadium oxide was truly evident from various spectroscopic studies and DFT calculations. The chirally modified mixed metal oxide transformed the oxidative CC coupling reaction with high enantioselectivity. High enantiomeric excess upto 92 % of R-BINOL was obtained in acetonitrile solvent and hydrogen peroxide as the oxidant. A significant achievement was the formation of S-BINOL in the case of the cinchonidine modified catalyst and R-BINOL with the Schiff base ligand anchored chiral catalyst. The UV-light induced catalytic reaction was found to involve hydroxyl radical as the active reactive species. The spin trapping ESR and fluorescence experiment provided relevant evidence for the formation of such species through photodecomposition of hydrogen peroxide on the catalyst surface. The chiral induction to the resultant product was found to induce through supramolecular interaction like OH…π, H…Br interaction. The presence of sigma hole center was believed to play significant role in naphtholate ion recognition during the catalytic cycle., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

β-thalassemias are among the most common inherited hemoglobinopathies worldwide and are the result of autosomal mutations in the gene encoding β-globin, causing an absence or low-level production of adult hemoglobin (HbA). Induction of fetal hemoglobin (HbF) is considered to be of key importance for the development of therapeutic protocols for β-thalassemia and novel HbF inducers need to be proposed for pre-clinical development. The main purpose on this study was to analyze Cinchona alkaloids (cinchonidine, quinidine and cinchonine) as natural HbF-inducing agents in human erythroid cells. The analytical methods employed were Reverse Transcription quantitative real-time PCR (RT-qPCR) (for quantification of γ-globin mRNA) and High Performance Liquid Chromatography (HPLC) (for analysis of the hemoglobin pattern). After an initial analysis using the K562 cell line as an experimental model system, showing induction of hemoglobin and γ-globin mRNA, we verified whether the two more active compounds, cinchonidine and quinidine, were able to induce HbF in erythroid progenitor cells isolated from β-thalassemia patients. The data obtained demonstrate that cinchonidine and quinidine are potent inducers of γ-globin mRNA and HbF in erythroid progenitor cells isolated from nine β-thalassemia patients. In addition, both compounds were found to synergize with the HbF inducer sirolimus for maximal production of HbF. The data obtained strongly indicate that these compounds deserve consideration in the development of pre-clinical approaches for therapeutic protocols of β-thalassemia.

Endeavor to discover biorational natural products-based insecticides, two series (27) of novel 9 R/S -acyloxy derivatives of cinchonidine and cinchonine were prepared and assessed for their insecticidal activity against Mythimna separata in vivo by the leaf-dipping method at 1 mg/mL. Among all the compounds, especially derivatives 6l and 6o exhibited the best insecticidal activity with final mortality rates of 75.0% and 71.4%, respectively. Overall, a free 9-hydroxyl group is not a prerequisite for insecticidal activity and C9-substitution is well tolerated; the configuration of C8/9 position is important for insecticidal activity, and 9 S -configuration is optimal; 6'-OCH 3 moiety is not necessary, removal of it is also acceptable. [Formula: see text].

New efficient catalysts based on electrophilic N-fluoro quaternary ammonium salts are reported for catalytic allylation of (E)-N,1-diphenylmethanimine. The chiral version of the catalyst based on cinchonidine (F-CD-BF 4 ) shows high catalytic activity with approximately 94% ee and TOF (>800 h -1 ). The F-CD-BF 4 is prepared from cinchonidine and Selectfluor by one-step transfer fluorination., (© 2018 Wiley Periodicals, Inc.)

Major Cinchona alkaloids quinine, quinidine, cinchonine, and cinchonidine are available chiral natural compounds (chiral pool). Unlike many other natural products, these alkaloids are available in multiple diastereomeric forms which are separated on an industrial scale. The introduction discusses in short conformational equilibria, traditional separation scheme, biosynthesis, and de novo chemical syntheses. The second section concerns useful chemical applications of the alkaloids as chiral recognition agents and effective chiral catalysts. Besides the Sharpless ethers and quaternary ammonium salts (chiral PTC), the most successful bifunctional organocatalysts are based on 9-amino derivatives: thioureas and squaramides. The third section reports the main transformations of Cinchona alkaloids. This covers reactions of the 9-hydroxyl group with the retention or inversion of configuration. Specific Cinchona rearrangements enlarging [2.2.2]bicycle of quinuclidine to [3.2.2] products are connected to the 9-OH substitution. The syntheses of numerous esterification and etherification products are described, including many examples of bi-Cinchona alkaloid ethers. Further derivatives comprise 9-N-substituted compounds. The amino group is introduced via an azido function with the inversion of configuration at the stereogenic center C9. The 9-epi-amino-alkaloids provide imines, amides, imides, thioureas, and squaramides. The syntheses of 9-carbon-, 9-sulfur-, and 9-selenium-substituted derivatives are discussed. Oxidation of the hydroxyl group of any alkaloid gives ketones, which can be selectively reduced, reacted with Grignard reagents, or subjected to the Corey-Chaykovsky reaction. The alkaloids were also partially degraded by splitting C4'-C9 or N1-C8 bonds. In order to immobilize Cinchona alkaloids the transformations of the 3-vinyl group were often exploited. Finally, miscellaneous functionalizations of quinuclidine, quinoline, and examples of various metal complexes of the alkaloids are considered., (© 2019 Elsevier Inc. All rights reserved.)

In order to prepare asymmetrically ( R )-(+)-1-(5-bromopentyl)-1-methyl-7-methoxy-2-tetralone ( 3a ), a key intermediate of dezocine, 17 cinchona alkaloid-derived catalysts were prepared and screened for the enantioselective alkylation of 1-methyl-7-methoxy-2-tetralone with 1,5-dibromopentane, and the best catalyst ( C7 ) was identified. In addition, optimizations of the alkylation were carried out so that the process became practical and effective.

Cinchonidine and Theophylline vitrification abilities have been investigated by differential and fast scanning calorimetry. These active pharmaceutical compounds are known in the literature to have a very high tendency to crystallize which has been confirmed by classical differential scanning calorimetry. Due to the growing interest in amorphous pharmaceutical compounds, their possible vitrifications have been investigated by fast scanning calorimetry. This work shows the high potential of this advanced thermal analysis technique to investigate the vitrification of active pharmaceutical compounds by melt-quenching protocol. For the first time, glass transitions of Cinchonidine and Theophylline were measured. From Cinchonidine, it has been shown that complete glassy state can be obtained by cooling from the melt at 2000K/s. Crystallization has also been suppressed by cooling down from the melt at 2K/s. However, such rate does not avoid the formation of nuclei. Theophylline crystallization process has been suppressed by a melt-quenching protocol carried out with a cooling rate of 4000K/s. However, the phenomenon of nuclei formation upon cooling seems unavoidable at this cooling rate. For both active pharmaceutical compounds, physical aging has been observed to play a role on the nuclei formation below the glass transition leading to modify the subsequent crystallization., (Copyright © 2017 Elsevier B.V. All rights reserved.)