5-Demethylnobiletin: Insights into its pharmacological activity, mechanisms, pharmacokinetics and toxicity

Abstract

Background

5-Demethylnobiletin (5DN) is a polymethoxyflavone (PMF) primarily found in citrus fruits. It has various health-promoting properties and hence has attracted significant attention from scholars worldwide.

Purpose

This review is the first to systematically summarize the recent research progress of 5DN, including its pharmacological activity, mechanism of action, pharmacokinetics, and toxicological effects. In addition, the pharmacological mechanism of action of 5DN has been discussed from a molecular biological perspective, and data from in vivo and in vitro animal studies have been compiled to provide a more thorough understanding of 5DN as a potential lead drug.

Methods

Data were extracted from SciFinder, PubMed, ScienceDirect and China National Knowledge Infrastructure (CNKI) from database inception to January 2022.

Results

5DN has broad pharmacological activities. It exerts anti-inflammatory effects, promotes apoptosis and autophagy, and induces melanogenesis mainly by regulating the JAK2/STAT3, caspase-dependent apoptosis, ROS–AKT/mTOR, MAPK and PKA–CREB signaling pathways. 5DN can be used for treating diseases such as cancer, inflammation-related diseases, rheumatoid arthritis, and neurodegenerative diseases. To date, there have been only a few toxicological studies on 5DN, and both in vitro and in vivo on 5DN have not revealed significant toxic side effects. Pharmacokinetic studies have revealed that the metabolites of 5DN are mainly 5,3′-didemethylnobiletin (M1); 5,4′-didemethylnobiletin (M2) and 5,3′,4′-tridemethylnobiletin (M3), in either, glucuronide-conjugated or monomeric form. The pharmacokinetic products of 5DN, especially M1, possess better activity than 5DN for the treatment of cancer.

Conclusion

The anticancer effects of 5DN and its metabolites warrant further investigation as potential drug candidates, especially through in vivo studies. In addition, the therapeutic effects of 5DN in neurodegenerative diseases should be examined in more experimental models, and the absorption and metabolism of 5DN should be further investigated in vivo.

Introduction

5-Demethylnobiletin (5DN) is a polymethoxyflavone (PMF) known as 4H-1-benzopyran-4-one,2-(3,4-dimethoxyphenyl)-5-hydroxy‑6,7,8-trimethoxy. Its flavone skeleton is substituted by methoxy groups at positions 6, 7, 8, 3′ and 4′ and a hydroxyl group at position 5. The formula is C₂₀H₂₀O₈ with a molecular weight of 388.37 g/mol. Fig. 1 shows the chemical structure of 5DN. 5DN is a bioactive component found in citrus peels, which have been used in traditional Chinese medicine for treating ailments such as constipation, cramps, colic, diarrhea, bronchitis, tuberculosis, cough, cold, obesity, menstrual disorders, angina, hypertension, anxiety, depression, and stress (Milind and Dev, 2012).

The plant source for the extraction and isolation of 5DN is mostly Citrus reticulata, with Citrus reticulata Blanco being the most abundant source. In a study by Liu et al. (2012) 1.5 mg of 5DN was obtained from 100 g of citrus peels using high-speed counter-current chromatography for separation. On comparing the flavonoid content of different parts of citrus, Zhang et al. (2014) found that 5DN was present only in the peel, which was extracted using ultrasonic extraction and separated using High-speed counter-current chromatography to obtain approximately 0.7 mg of 5DN from 100 g of citrus peels. In addition to Citrus reticulata, other citrus species have been used as well, Kim et al. (1999) used silica gel elution and chromatography for purification on a Sephadex LH-20 column to obtain 14 mg of 5DN from 300 g of Citrus unshiu peels. Iwase et al. used column chromatography to extract and isolate 12.2 mg of 5DN from 955 g of Citrus sinensis Osbeck peels (Iwase et al., 2000). The amount of 5DN obtained from other plants is smaller than that obtained from Citrus spp. Nur-e-Alam et al. used a reversed-phase column and semi-preparative high performance liquid chromatography to isolate 5DN from the crude fraction of Scoparia dulcis L, and only 1.5 mg of 5DN was obtained from 2.07 kg of the herb (Nur-e-Alam et al., 2020). Lee et al. used activity-guided column chromatography to isolate Belamcanda chinensis (L.) DC and extracted 4 mg of 5DN from 3 kg of dried herb (Lee et al., 2015) In addition, 5DN has been extracted and isolated from Murraya paniculate (Wu et al., 2016),Euryops arabicus (Abdel-Lateff et al., 2020), and Gardenia lucida (Trivedi et al., 2017). These studies indicate that 5DN is widely present in plants, and its content is highest in the peel of citrus plants is the highest, which is of great value for exploitation. 5DN can be synthesized from nobiletin (NOB) under Node's conditions via selective demethylation at position 5 (Asakawa et al., 2019). In addition, NOB can be efficiently prepared as a hydroxylated product (position 5) by exposing it to hydrochloric acid or other acidic conditions (Li et al., 2007). 5DN is also found in the in vivo metabolites of NOB, which may be related to the medicinal value of NOB (Huang et al., 2016). Therefore, 5DN is a natural compound that can be synthesized or extracted from plants and has rich pharmacological activity. In this review, we summarized the pharmacological activity, mechanisms of action, pharmacokinetics, and toxicity of 5DN to provide a basis for the study of 5DN as a novel therapeutic agent.