Biology of quinoline and quinazoline alkaloids

Shang, Xiaofei; Morris‐Natschke, Susan L.; Liu, Ying‐Qian; Li, Xiuhui; Zhang, Jiyu; Lee, Kuo‐Hsiung

doi:10.1016/bs.alkal.2021.08.002

Cited by 10 publications

(6 citation statements)

References 243 publications

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“…In a wider perspective, RCD405 could have the potential of reducing the need for ICS and more important, oral corticosteroids in asthma and COPD. Quinolines are a large group of N-based heterocyclic aromatic compounds, with many having bioactive properties including pharmacological effects in several diseases [ 34 ]. Some alkaloids of this group have shown inhibitory activities of the proinflammatory transcription factors nuclear factor of activated T-cells (NFAT) and NF-κB [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

A novel quinoline with airway relaxant effects and anti-inflammatory properties

Bergwik,

Liu,

Padra

et al. 2024

Respir Res

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Background In chronic pulmonary diseases characterized by inflammation and airway obstruction, such as asthma and COPD, there are unmet needs for improved treatment. Quinolines is a group of small heterocyclic compounds that have a broad range of pharmacological properties. Here, we investigated the airway relaxant and anti-inflammatory properties of a novel quinoline (RCD405). Methods The airway relaxant effect of RCD405 was examined in isolated airways from humans, dogs, rats and mice. Murine models of ovalbumin (OVA)-induced allergic asthma and LPS-induced airway inflammation were used to study the effects in vivo. RCD405 (10 mg/kg) or, for comparisons in selected studies, budesonide (3 mg/kg), were administered intratracheally 1 h prior to each challenge. Airway responsiveness was determined using methacholine provocation. Immune cell recruitment to bronchi was measured using flow cytometry and histological analyses were applied to investigate cell influx and goblet cell hyperplasia of the airways. Furthermore, production of cytokines and chemokines was measured using a multiplex immunoassay. The expression levels of asthma-related genes in murine lung tissue were determined by PCR. The involvement of NF-κB and metabolic activity was measured in the human monocytic cell line THP-1. Results RCD405 demonstrated a relaxant effect on carbachol precontracted airways in all four species investigated (potency ranking: human = rat > dog = mouse). The OVA-specific IgE and airway hyperresponsiveness (AHR) were significantly reduced by intratracheal treatment with RCD405, while no significant changes were observed for budesonide. In addition, administration of RCD405 to mice significantly decreased the expression of proinflammatory cytokines and chemokines as well as recruitment of immune cells to the lungs in both OVA- and LPS-induced airway inflammation, with a similar effect as for budesonide (in the OVA-model). However, the effect on gene expression of Il-4, IL-5 and Il-13 was more pronounced for RCD405 as compared to budesonide. Finally, in vitro, RCD405 reduced the LPS-induced NF-κB activation and by itself reduced cellular metabolism. Conclusions RCD405 has airway relaxant effects, and it reduces AHR as well as airway inflammation in the models used, suggesting that it could be a clinically relevant compound to treat inflammatory airway diseases. Possible targets of this compound are complexes of mitochondrial oxidative phosphorylation, resulting in decreased metabolic activity of targeted cells as well as through pathways associated to NF-κB. However, further studies are needed to elucidate the mode of action.

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Section: Discussionmentioning

confidence: 99%

A novel quinoline with airway relaxant effects and anti-inflammatory properties

Bergwik,

Liu,

Padra

et al. 2024

Respir Res

View full text Add to dashboard Cite

show abstract

“…In a wider perspective, RCD405 could have the potential of reducing the need for ICS and more important, oral corticosteroids in asthma and COPD. Quinolines are a large group of N-based heterocyclic aromatic compounds, with many having bioactive properties including pharmacological effects in several disease (23). Some alkaloids of this group have shown inhibitory activities of the proin ammatory transcription factors nuclear factor of activated T-cells (NFAT) and NF-kB (24).…”

Section: Discussionmentioning

confidence: 99%

A Novel Quinoline With Airway Relaxant Effects and Anti-Inflammatory Properties

Bergwik,

Liu,

Padra

et al. 2023

Preprint

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Background In chronic pulmonary diseases characterized by inflammation and airway obstruction, such as asthma and COPD, there are unmet needs for improved treatment. Here, we investigated the relaxant and anti-inflammatory properties in the airways of a novel quinoline (RCD405). Methods The airway relaxant effect of RCD405 was examined in isolated airways from humans, dogs, rats and mice. Murine models of ovalbumin (OVA)-induced allergic asthma and LPS-induced airway inflammation were used to study the effects in vivo. Airway responsiveness was determined using methacholine provocation. Immune cell recruitment to bronchi was measured using flow cytometry and histological analyses were applied to investigate immune cell influx and goblet cell hyperplasia of the airways. The inflammatory response, as reflected by the production of cytokines and chemokines, was measured using a multiplex immunoassay. The expression levels of asthma-related genes in murine lung tissue were determined by PCR. The involvement of NF-κB and metabolic activity was measured in the human monocytic cell line THP-1. Results RCD405 demonstrated a relaxant effect on carbachol precontracted airways in all four species investigated. The OVA- specific IgE and airway hyperresponsiveness (AHR) were significantly reduced by intratracheal treatment with RCD405. In addition, administration of RCD405 to mice significantly decreased the expression of proinflammatory cytokines and chemokines as well as recruitment of immune cells to the lungs in both OVA- and LPS-induced airway inflammation. In vitro, RCD405 reduced the LPS-induced NF-κB activation and by itself reduced cellular metabolism. Conclusions RCD405 has airway relaxant effects and it reduces AHR as well as airway inflammation in the models used, suggesting that it could be a clinically relevant compound to treat inflammatory airway diseases. Possible targets of this compound are complexes of mitochondrial oxidative phosphorylation, resulting in decreased metabolic activity of targeted cells as well as through pathways associated to NF-κB. However, further studies are needed to elucidate the mode of action.

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“…Quinolines are an important class of heterocycles that are widely represented in natural products, 1 pharmaceuticals, biologically active substances, 2 agrochemicals, 3 functional materials, 4 organocatalysts or ligands, 5 and valuable intermediates. 6 Several quinoline derivatives such as chloroquine and cryptolepine (anti-malarial), 7 ciprofloxacin (antibacterial), 8 topotecan and camptothecin (anticancer), 9 dibucaine (local anesthetic), 10 and bedaquiline (anti-tubercular) 11 are widely used in clinics (Fig.…”

Section: Introductionmentioning

confidence: 99%