Bioactivities and Structure–Activity Relationships of Natural Tetrahydroanthraquinone Compounds: A Review

Tetrahydroanthraquinones are a kind of important microbial secondary metabolites with promising biological activities. Most of them were found in microorganisms, a few were derived from Chinese herbal medicine. In this review, aiming to provide basis for the further research and development of tetrahydroanthraquinone compounds, we summarized the physiological activities of natural tetrahydroanthraquinone compounds, including anti-cancer, anti-microbial, and antidiabetic activities. The source, structure, and action mechanisms of active tetrahydroanthraquinones are described in detail. Furthermore, this review firstly analyzed the structure–activity relationship of tetrahydroanthraquinones. Our study will serve as a valuable guideline for further research on the structural optimization, mechanism study, and development of tetrahydroanthraquinone as novel drugs. Aiming to provide references for further studies and development of tetrahydroanthraquinone compounds.


INTRODUCTION
Anthraquinones characterized by an anthraquinone scaffold structure, are widely distributed in plant as secondary metabolites. Modern pharmacological researcher showed that anthraquinones have various potent activities, including anticancer, anti-inflammatory, anti-injury, antibacterial, anti-osteoporosis, antioxidant, etc. (Li and Jiang, 2018).
Tetrahydroanthraquinone is a class of derivatives of anthraquinone in which the unsaturated double-bonds on the benzene ring A are hydrogenated by four hydrogens (Figure 1). Most of them were found in microorganisms, while a little were derived from Chinese herbal medicine. To date, about 60 different tetrahydroanthraquinones are found, of which only nine are from plants . Because of some of tetrahydroanthraquinones showing good pharmacological activity, such as anticancer, antibacterial, anti-malarial, and anti-viral, more and more researchers are being focused on the exploration of their pharmacological activity, mechanism, and structure activity relationships.
Structurally, tetrahydroanthraquinones are generally classified into tetrahydro-9,10-anthraquinones, hydroxyphenanthrenes, tetrahydro-1,4-anthraquinones, and bi-tetrahydroanthraquinone, and according to their sources, tetrahydroanthraquinones can be divided into the ones from microorganisms and the ones from plants. In this paper, we focus on the pharmacological activities and related structure-activity relationships of active tetrahydroanthraquinones, aiming to provide references for further studies and development of tetrahydroanthraquinone compounds.
There are ten hydroxyphenanthrenes that has been isolated and identified. Their detailed source and structure information were displayed in Table 2 and Figure 3.
The detailed source and structure information was displayed in Table 3 and Figure 4.

Anti-Tumor Activity
Anti-Tumor Activity of Tetrahydro-9,10-Anthraquinones Some natural anthraquinones have been proven to have anti-tumor effects, such as rhein and emodin (Li and Jiang, 2018;Han et al., 2018). Tetrahydroanthraquinones, a class of anthraquinones, can also exhibit anti-cancer activity such as inhibiting cell proliferation, invasion, metastasis, and angiogenesis by inducing cell apoptosis, arresting cell cycle or suppressing the relevant enzymes. Altersolanol A, one of the most researched tetrahydroanthraquinone, exhibits antitumor activities against broad spectrum cancers (bladder, colon, gastric cancers, etc.) (Zhang N. et al., 2016). It can inhibit the proliferation and migration of both adherent cells K562 and nonadherent cells A549, whereas leave non-cancer cells (PBMCs cells) unaffected (Teiten et al., 2013). The anti-tumor activity of Altersolanol A is correlated with its pro-apoptotic and antiinvasive effect due to the inhibition of NF-kB transcription (Teiten et al., 2013). Another study also showed Altersolanol A exerted anti-cancer activity by inhibiting angiogenesis at low concentration in vitro and in vivo, and suppress the proliferation, tube formation, and migration of endothelial cells (Phunlap et al.,  (Xuekui et al., 2011;Cong et al., 2013;Huang et al., 2014)

Bostrycin
Xylaria sp. 2508 Antitumor activity; Antibacterial activity (Dongni et al., 2013;Huang et al., 2014) FIGURE 4 | The structure of tetrahydro-5,8-anthraquinones compounds (39-43).  (Uzor et al., 2015). Altersolanol N and alterporriol G were also cytotoxic towards the murine cancer cell line L5178Y (Aly et al., 2008). SZ-685C, isolated from Halorosellinia sp. (No. 1403), exhibits broad spectrum of antitumor activity. A study showed it inhibits the growth of human glioma, hepatoma, prostate cancer, and breast cancer cells with IC 50 values ranging from 3.0 to 9.6 mM (Xie et al., 2010). In vivo experiment indicated that SZ-685C could suppress the tumor growth in nude mice by inducing apoptosis through the Akt/FOXO pathway (Xie et al., 2010). In addition, SZ-685C was reported to induce apoptosis in primary human nonfunctioning pituitary adenoma cells and adriamycin-resistant human breast cancer cells by inhibition of the Akt Pathway . Moreover, recent studies found that it may play antitumor function through regulating the expression of micro RNAs. Chen et al. (2013) reported that SZ-685C inhibited the proliferation of rat pituitary adenoma MMQ cells and induced cell apoptosis through downregulating the expression of miR-200c. Dujuan Wang et al. (2013) suggested that SZ-685C abrogated the radio resistance of human nasopharyngeal carcinoma CNE2 cells through the miR-205 −PTEN-Akt pathway. (±)-4-deoxyaustrocortilutein treatment induced mitochondrial ROS, reduced NF-kB signaling activity and increased up-regulation of the cell cycle inhibitors cyclindependent kinase inhibitor p21 (p21WAF1/Cip1) and the tumor suppressor protein p53 in a dose-dependent manner (Genov et al., 2016). Prisconnatanones A and I were isolated from Prismatomeris connata, showed strong anticancer activity. Prisconnatanones A (HG30) inhibits the proliferation of HEp-2, A549, and H1299 cells, inducing apoptosis through caspase-dependent apoptosis pathways and disturbing the balance between Bcl-2 and IAP families, in addition, its cytotoxicity was associated with the cell cycle arrest at G2/M phase (Feng et al., 2016;Feng et al., 2018). Prisconnatanone I showed the highest activity, with IC 50 values ranging from 2.7 µM to 3.9 µM in the suppression of lung tumor cell growth (H1229, HTB179, A549, and H520), while compounds Prisconnatanone C-H had relatively low values (IC 50 , 2.7 µM to 3.9 µM) . In conclusion, these data suggest that some natural tetrahydroanthraquinones are bioactive, and hydroxylation at C-1 significantly increases the cytotoxicity of these compounds against lung tumor cells growth.
To further explore the structure-activity relationship of bostrycin, Hong Chen et al. (2012) synthesized 18 bostrycin derivatives through structural modification at positions 2, 3, 6, and 7. And found that dioxylcarbonyl groups at C-2 and C-3 positions, tertiary amino groups at C-6 position and alkylthio groups at C-6 and C-7 positions of the bostrycin could enhance cytotoxicity of bostrycin derivatives.

Anti-Tumor Activity of Bi-Tetrahydroanthraquinones
Alterporriol L could effectively inhibit the proliferation and growth of breast cancer cell line MCF-7 (IC 50 , 13.11 mM) and MDA-MB-435 cells (IC 50 , 20.04 mM), and there was a dosedependent manner of cell death. Moreover, alterporriol L could induce cancer cell apoptosis and necrosis through triggering the generation of oxidative stress (Huang et al., 2012).
It is interesting that we have not found any report of hydroxyphenanthrenes with anti-tumor activity. This may suggest that the tetrahydroanthraquinone skeleton with carbonyl groups at C-9 and C-10 positions is important for the anti-tumor activity of tetrahydroanthraquinones.

Antimicrobial Activity
Many tetrahydroanthraquinones exhibit good antimicrobial activities. Altersolanols A-C and E inhibited the growth of all Gram-positive bacteria and Pseudomonas aeruginosa IF0 3080 with minimum inhibitory concentration (MIC) value ranging from 12.5 to 25 mg/ml. However, Altersolanol D and F, lack of hydroxy group at C-5 compared to Altersolanols A-C and E, even at concentration as high as 100 mg/ml, have not inhibited bacteria growth. This indicated that the hydroxy group at C-5 position was necessary to the antibacterial activities of tetrahydroanthraquinones (Yagi et al., 1993). Coniothranthraquinone 1 showed antibacterial activity against Staphylococcus aureus ATCC 25923 (SA) and Staphylococcus aureus SK1 (MRSA), with MIC values of 16 and 8 mg/ml, respectively (Khamthong et al., 2012;Ng et al., 2015). While trichodermaquinone showed antibacterial activity against MRSA, with a MIC value of 200 mg/ml, had no inhibition on SA (Khamthong et al., 2012). This study suggested that the hydroxyl group at C-5 position and the methyl group at C-7 position are important to the antibacterial activity of a tetrahydroanthraquinone. Deoxybostrycin and Bostrycin showed strong antimicrobial activities against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Sarcina ventriculi, Bacillus subtilis with an IC50 of 3.13 µg/ml, and inhibited Candida albicans with an IC50 of 12.5 µg/ml. Besides, Deoxybostrycin showed good anti-mycobacterial activity, it exhibited a better inhibitory effect on clinical multidrug-resistant M. tuberculosis (K2903531 and 0907961) than the first line anti-tuberculosis drug (Nigrosporin) (Yagi et al., 1993). Alterporriol G showed antibacterial activity only against Streptomyces pneumonia (Aly et al., 2008).

Antiviral Activity
Tetrahydroaltersolanol C exhibited a significant anti-PRRSV (Porcine reproductive and respiratory syndrome virus) activity with a EC 50 value of 12.11 µM, it inhibited the internalization and replication of PRRSV, but did not directly inactivate the virus or block its adsorption to cell surface (Zhang S.L. et al., 2016).
Antidiabetic Activity 4-des-hydroxyl altersolanol A significantly reduced the level of blood sugar in alloxan-induced diabetic mice (Uzor et al., 2017).

CONCLUSIONS AND PERSPECTIVES
Anthraquinone compounds and their natural derivatives, especially tetrahydroanthraquinones, showed a considerably wide range of pharmacologica1 effects, and 60 tetrahydroanthraquinones have been found since altersolanol A was originally reported in 1967 (Stoessl, 1969b). Some of them exhibited considerable cytotoxicity, antimicrobial, antiviral activity, and hypoglycemic activities. In this review, anti-tumor, anti-microbial, antiviral activity, and antidiabetic activities of tetrahydroanthraquinones are summarized in detail, and 17 active ones are involved. We try to sum up the structure and activity relationship of tetrahydroanthraquinones from previous literatures.
Anthraquinones exhibited potent antitumor effect, while they also with DNA toxicity, can be inserted into the helical structure of DNA in the form of a flat structure, affecting the transcription and DNA replication (Adhikari and Mahar, 2016). Hence, anthraquinones showed stronger toxicity than pharmacological effect. Tetrahydroanthraquinones, especially tetrahydro-9,10anthraquinones, avoided DNA toxicity caused by anthraquinone planar structure. Tetrahydroanthraquinone forms a dimensional construct of cyclohexene after hydrogenation, and forms two or more chiral centers by substitution with OH or CH 3 . This increased the potential druggability and formed multiple targeting centers, providing more possibilities for chemical modification and structure transformation. There are few reports in the available literature that the antitumor effect of tetrahydroanthraquinone is related to DNA toxicity, except for (1S,3S)-austrocortirubin . More studies suggested that the antitumor effect of tetrahydroanthraquinone is through targeting signaling pathways, including NF-kB, PI3K/Akt pathway (Xie et al., 2010;Zhu et al., 2012;Genov et al., 2016). Suggesting that the antitumor mechanisms of tetrahydroanthraquinones are different from that of anthraquinone. Tetrahydroanthraquinones deserve more attention and more research.
For anti-cancer activity, it seems that the p-quinone moiety of tetrahydroanthraquinone is fundamental, as reduction of one of the carbonyl groups of the quinone moiety nullified the cytotoxicity of the tetrahydroanthraquinone derivatives (Zhang N. et al., 2016). Adding short side chains to the benzoquinone increases cytotoxicity of tetrahydroanthraquinones, whose cyclohexyl ring is substituted with two hydroxyl groups with the appropriate stereochemistry, and elimination of both or even a single hydroxyl, or change of stereochemistry of the tertiary hydroxyl eliminates biological activity, and additive hydroxyl moiety at C-1 of a tetrahydroanthraquinone might be the active profile for inhibiting lung tumor cell growth. Linker at a 3-atom with a phenyl or para-chlorophenyl moiety also can enhance cytotoxicity (Phunlap et al., 2013;Teiten et al., 2013;Li and Jiang, 2018). For anti-microbial activity, from the few studies, the hydroxyl group on the C-5 might be crucial to the antimicrobial activity (Yagi et al., 1993).
The most pharmacological researches of tetrahydroanthraquinones focused on cytotoxicity and antitumor mechanisms, suggesting its potential for developing antitumor drugs. While we found some of them are not suitable for drug research. Bitetrahydroanthraquinones are not suitable for drug research due to large weight and large steric resistance. Tetrahydro-5,8anthraquinones are a class of rare compounds with unstable structure, with tautomerism at the 9, 10 positions of its 5,8-dione. They are not suitable for drug development due to the difficult in structural modification and pharmacological research. Hydroxyphenanthrenes is characteristic by the C9 carbonyl group undergoes a reduction reaction to form a hydroxy substitution. However, under acidic conditions, the C9 carbonyl group undergoes dehydration reaction, and becomes keto group. therefore, special attention needs to be paid to the conditions in pharmacological and synthetic research of Hydroxyphenanthrenes.
The tetrahydroanthraquinone isolated and identified are mainly from endophytes, and some of them are isolated from marine fungi and plants. Some pharmacological activities of tetrahydroanthraquinones are reported, yet are not enough. There is still a strong possibility that some tetrahydroanthraquinones with better regulatory activities remain in the shadow or have not been fully studied. Our study will serve as a valuable guideline for further research on the structural optimization, mechanism study, and development of tetrahydroanthraquinone as novel drugs.