Synthesis and In Vitro Evaluation of Novel Liver X Receptor Agonists Based on Naphthoquinone Derivatives

Nishioka, Tatsuma; Endo-Umeda, Kaori; Ito, Yuki; Shimoda, Akane; Takeuchi, Atsuko; Tode, Chisato; Hirota, Yoshio; Osakabe, Naomi; Makishima, Makoto; Suhara, Yoshitomo

doi:10.3390/molecules24234316

Cited by 9 publications

(5 citation statements)

References 19 publications

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“…In addition to steric hindrance, the greater nucleophilicity associated with the nitrogen atom compared to oxygen promotes a greater probability of an N -substitution product than an O -substitution product [ 6 ]. In this context, the Michael addition product 1,4-NQ-CS was proposed for the reaction between 2,3-dichloronaphthoquinone and CS, whereas the amino-1,2-naphthoquinone (1,2-NQ-CS) was proposed for the reaction between sodium 1,2-naphthoquinone-4-sulfonate and CS, based on similar reactions reported in the literature [ 20 , 37 , 38 , 39 , 40 , 41 ].…”

Section: Resultsmentioning

confidence: 96%

Exploring the Antimicrobial and Antitumoral Activities of Naphthoquinone-Grafted Chitosans

et al. 2023

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Biopolymers obtained from natural macromolecules are noteworthy among materials presenting high biocompatibility and adequate biodegradability, as is the case of chitosan (CS), making this biopolymeric compound a suitable drug delivery system. Herein, chemically-modified CS were synthetized using 2,3-dichloro-1,4-naphthoquinone (1,4-NQ) and the sodium salt of 1,2-naphthoquinone-4-sulfonic acid (1,2-NQ), producing 1,4-NQ-CS and 1,2-NQ-CS by three different methods, employing an ethanol and water mixture (EtOH:H2O), EtOH:H2O plus triethylamine and dimethylformamide. The highest substitution degree (SD) of 0.12 was achieved using water/ethanol and triethylamine as the base for 1,4-NQ-CS and 0.54 for 1,2-NQ-CS. All synthesized products were characterized by FTIR, elemental analysis, SEM, TGA, DSC, Raman, and solid-state NMR, confirming the CS modification with 1,4-NQ and 1,2-NQ. Chitosan grafting to 1,4-NQ displayed superior antimicrobial activities against Staphylococcus aureus and Staphylococcus epidermidis associated with improved cytotoxicity and efficacy, indicated by high therapeutic indices, ensuring safe application to human tissue. Although 1,4-NQ-CS inhibited the growth of human mammary adenocarcinoma cells (MDA-MB-231), it is accompanied by cytotoxicity and should be considered with caution. The findings reported herein emphasize that 1,4-NQ-grafted CS may be useful in protecting injured tissue against bacteria, commonly found in skin infections, until complete tissue recovery.

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Section: Resultsmentioning

confidence: 96%

Exploring the Antimicrobial and Antitumoral Activities of Naphthoquinone-Grafted Chitosans

et al. 2023

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“…The docking studies were conducted using Glide in Extra Precision (XP) employed by Schrödinger (version 2023-4). LXRα structures were acquired from the Protein Data Bank (PDB) with codes 1UHL and 2ACL [ 42 ]. The 2D structures of the compounds were obtained in .sdf file format using CS ChemDraw (version 20) and were subsequently converted into 3D structures.…”

Section: Methodsmentioning

confidence: 99%

Microwave-Promoted Total Synthesis of Puniceloid D for Modulating the Liver X Receptor

Jung,

Hosseininasab,

Park

et al. 2024

Molecules

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A growing global health concern is metabolic syndrome, which is defined by low HDL, diabetes, hypertension, and abdominal obesity. Nuclear receptors are attractive targets for treatment of diseases associated with metabolic syndrome. Liver X receptors (LXRs) have become one of the most significant pharmacological targets among nuclear receptors. Multiple research studies emphasize the essential function of the liver X receptor (LXR) in the pathophysiology of metabolic syndrome. Puniceloid D, among natural products, demonstrated promising effects on LXRα. However, attempts at the total synthesis of natural products were faced with challenges, including long synthetic steps and low yields, requiring a more efficient approach. In this study, for the first time, we successfully synthesized puniceloid D through a seven-step process and conducted docking studies to gain a comprehensive understanding of the interactions involved in the binding of puniceloid D to LXR within different heterodimeric contexts. Our understanding of the pathophysiology of metabolic syndrome could be improved by these findings, which might assist with the development of novel treatment strategies.

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“…Recently, the introduction of piperidine, morpholine, and phenylsulfide substituents into the naphthoquinone structures gave rise to several powerful LXR agonists, from LXRα/β dual agonists to selective LXRα agonists (Nishioka et al, 2019). In the same way, another series of naphthoquinone derivative have been synthetized…”

Section: Other Potential Lxr Agonistsmentioning

confidence: 99%

Screening for liver X receptor modulators: Where are we and for what use?

Buñay

Fouache

Trousson

et al. 2020

British J Pharmacology

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Liver X receptors (LXRs) are members of the nuclear receptor superfamily that are canonically activated by oxidized derivatives of cholesterol. Since the mid-90s, numerous groups have identified LXRs as endocrine receptors that are involved in the regulation of various physiological functions. As a result, when their expression is genetically modified in mice, phenotypic analyses reveal endocrine disorders ranging from infertility to diabetes and obesity, nervous system pathologies such Alzheimer's or Parkinson's disease, immunological disturbances, inflammatory response, and enhancement of tumour development. Based on such findings, it appears that LXRs could constitute good pharmacological targets to prevent and/or to treat these diseases. This review discusses the various aspects of LXR drug discovery, from the tools available for the screening of potential LXR modulators to the current situational analysis of the drugs in development.

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Synthesis and In Vitro Evaluation of Novel Liver X Receptor Agonists Based on Naphthoquinone Derivatives

Cited by 9 publications

References 19 publications

Exploring the Antimicrobial and Antitumoral Activities of Naphthoquinone-Grafted Chitosans

Exploring the Antimicrobial and Antitumoral Activities of Naphthoquinone-Grafted Chitosans

Microwave-Promoted Total Synthesis of Puniceloid D for Modulating the Liver X Receptor

Screening for liver X receptor modulators: Where are we and for what use?

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