Review articleQuinolizidine alkaloids derivatives from Sophora alopecuroides Linn: Bioactivities, structure-activity relationships and preliminary molecular mechanisms
Graphical abstract
Introduction
Sophora alopecuroides Linn, commonly known as Kudouzi, mainly grows in Western and central Asia. As a traditional Chinese medicine, S. alopecuroides L. has been long-term applied for treating cancer, skin diseases and hepatitis [1]. To date, active components, including saponins, polyohenols, flavonoids, glucosides and alkaloids extracted from S. alopecuroides L. have been widely analyzed for their potential biological activities. Specially, quinolizidine alkaloids, as the major active ingredients in S. alopecuroides L., are chemically divided into matrine-type alkaloids and aloperine-type alkaloids. The former type can be further divided into matrine, oxymatrine, sophocarpine, sophoridine. They are peculiar tetracyclo-quinolizindine alkaloids, which were first isolated and identified in 1958 [2]. The latter type, such as aloperine is commonly purified from S. alopecuroides L. (chemical structures are shown in Fig. 1) [3]. It is reported that the aforementioned alkaloids exhibit many biological activities and possess a wide range of pharmacological effects, such as anti-cancer [4], anti-inflammation [5], anti-virus [6], anti-fibrosis [7], pain relieving [8], anti-arrhythmia [9] and immunosuppression [10]. Hence, they have been extensively applied for the treatment of viral hepatitis, live fibrosis, cardiac arrhythmia, lupus erythematosus and autoimmune diseases in China. Particularly, the oxymatrine injection prepared from S. alopecuroides L., which contains oxymatrine, matrine, and sophoridine, has been successfully used for the treatment of chronic hepatitis B (CHB) in China [11].
Matrine-type and aloperine-type alkaloids are favorable to the development of total synthesis strategies and structure modification. Owing to the specific structures, many semi-synthesis studies on matrine-type and aloperine-type alkaloids have been reported. As a result, many synthesized quinolizindine derivatives have been subjected to phenotype-based screening or targeted based screening. Accordingly, biological activities and health benefits of quinolizindine derivatives can provide paramount information for future pharmaceutical researches. In this review, we will focus on the fruitful achievements on: (i) pharmacological activities and molecular mechanisms, (ii) structural modifications of quinolizidine and its derivatives, and (iii) relationship between pharmacological activities and structure-activity relationship (SAR) of quinolizidine alkaloids extracted from S. alopecuroides L.. We believe this review would be beneficial to provide constructive suggestions for further study of Sophora alopecuroides alkaloids.
Section snippets
Anti-cancer activities
It has been reported that matrine-type alkaloids could suppress cancer cell growth with a generally half-maximal inhibitory concentration (IC50) values higher than 0.5 mM [[12], [13], [14]]. Anti-cancer activities of aloperine (ALO) have also been reported in colon, esophagus, lung and liver cancer [15]. Growing researches have suggested that most of matrine-type and aloperine-type alkaloids can inhibit proliferative ability, induce apoptosis, arrest cell cycle arrest, restrain angiogenesis,
Anti-inflammation activities
Inflammation is a sophisticated physiological response of body tissue to noxious stimuli, such as pathogens, damaged cells and irritants, involving the participation of immune cells, blood vessels and molecular mediators [149]. Inflammatory response aims to eliminate external stimuli, clear damaged cells and tissues, and trigger the self-repair process [150]. Generally, inflammation is an automatic defense response. Nevertheless, inflammation also induces allergies in the body’s own immune
Anti-fibrosis activities
The formation of excess fibrous connective tissues in a reparative or reactive process is known as fibrosis, which has a high mortality [204]. Fibrosis occurs in various organs, including lung, heart, liver and kidney. EMT is a reversible terminal differentiation process that cell polarity and adhesion features of epithelial cells are lost, and then they acquire phenotypes of mesenchymal cells [205]. It is worth noting that EMT occurs during the progression of both tissue fibrosis and tumors,
Molecular mechanisms of matrine
Hepatitis B virus (HBV) infection caused by a hepatotropic DNA virus is a serious global health problem. HBV infection would result in chronic hepatitis and advanced liver diseases, including liver cirrhosis and HCC [238]. Virological studies have shown that HBV is an enveloped double-stranded DNA virus containing a 3.2 kb genome with four overlapping open reading frames (ORFs), which encode a core protein (Cp), surface protein (S), polymerase (P), and X protein (X). The HBV surface antigens
Anti-arrhythmic activities
Cardiac arrhythmia is a disease that is caused by a disturbance in the normal electrical activity of heart. Electrical activity changes lead to abnormal heath rhythm either too fast, too slow, or erratically. Furthermore, nearly 90% of acute cardiac deaths are caused by cardiac arrhythmia [257]. Notably, pharmacological studies demonstrated the anti-arrhythmia activities of matrine-type alkaloids [258]. In this chapter, we summarized updated information on the anti-arrhythmia activities of
Molecular mechanisms of matrine
Alzheimer’s disease (AD) is a popular neurodegenerative disease in the world. Neuro-inflammatory process is associated with AD. It has been shown that the activation of glial cells and the release of pro-inflammatory mediators are key pathogenesis of AD. Herein, some drugs that can improve AD by suppressing the over-production of inflammatory cytokines have been explored [273]. Zhang YF et al. demonstrated that MT could dose-dependently restore the relative balance of Th17/Treg cytokines and
Conclusion and future perspectives
S. alopecuroides is a well-known traditional Chinese medicine used in the treatment of cancer, inflammation, chronic hepatic disease, etc. Five alkaloids (MT, OMT, SCA, SRI and ALO) are its main active components, which have many pharmacological effects, such as anti-cancer, anti-inflammation, anti-fibrosis, antivirus and anti-arrhythmia. Great strides have been made on the synthesis of relevant derivatives with high selectivity, excellent pharmacological activities and few adverse reactions.
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.
Acknowledgement
We are grateful to the National Natural Science Foundation of China (No. 81922064, 81874290, 81673290, 81573290 and U1603123) and Sichuan Science and Technology Program (2019JDRC0091) for financial support.
References (284)
- et al.
Separation and enrichment of major quinolizidine type alkaloids from sophora alopecuroides using macroporous resins
J. Chromatogr. B Anal. Technol. Biomed. Life Sci.
(2014) - et al.
Indolizidine and quinolizidine alkaloids: structure and bioactivity
ChemInform
(2002) - et al.
Identification of compounds in an anti-fibrosis Chinese medicine (fufang biejia ruangan pill) and its absorbed components in rat biofluids and liver by uplc-ms
J. Chromatogr. B Anal. Technol. Biomed. Life Sci.
(2016) - et al.
Anti-nociceptive and anti-inflammatory activity of sophocarpine
J. Ethnopharmacol.
(2009) - et al.
Sophocarpine displays anti-inflammatory effect via inhibiting TLR4 and TLR4 downstream pathways on LPS-induced mastitis in the mammary gland of mice
Int. Immunopharmacol.
(2016) - et al.
Sophocarpine alleviates hepatocyte steatosis through activating AMPK signaling pathway
Toxicol. In Vitro
(2013) - et al.
Matrine promotes liver cancer cell apoptosis by inhibiting mitophagy and PINK1/Parkin pathways
Cell Stress Chaperones
(2018) - et al.
Drugs targeting mitochondrial functions to control tumor cell growth
Biochem. Pharmacol.
(2005) Mitophagy: link to cancer development and therapy
Biochem. Biophys. Res. Commun.
(2017)- et al.
Matrine promotes liver cancer cell apoptosis by inhibiting mitophagy and PINK1/Parkin pathways
Cell Stress Chaperones
(2018)