Biphenyls in Clusiaceae: Isolation, structure diversity, synthesis and bioactivity

Clusiaceae plants contain a wide range of biologically active metabolites that have gotten a lot of interest in recent decades. The chemical compositions of these plants have been demonstrated to have positive effects on a variety of ailments. The species has been studied for over 70 years, and many bioactive compounds with antioxidant, anti-proliferative, and anti-inflammatory properties have been identified, including xanthones, polycyclic polyprenylated acylphloroglucinols (PPAPs), benzophenones, and biphenyls. Prenylated side chains have been discovered in many of these bioactive substances. To date, there have been numerous studies on PPAPs and xanthones, while no comprehensive review article on biphenyls from Clusiaceae has been published. The unique chemical architectures and growing biological importance of biphenyl compounds have triggered a flurry of research and interest in their isolation, biological evaluation, and mechanistic studies. In particular, the FDA-approved drugs such as sonidegib, tazemetostat, daclatasvir, sacubitril and trifarotene are closely related to their biphenyl-containing moiety. In this review, we summarize the progress and development in the chemistry and biological activity of biphenyls in Clusiaceae, providing an in-depth discussion of their structural diversity and medicinal potential. We also present a preliminary discussion of the biological effects with or without prenyl groups on the biphenyls.

1 Introduction

Clusiaceae family is extensively used in traditional medicine for treating a number of diseases which include cancer, inflammation, and infection (Acuna et al., 2009). There are many species belonging to the Clusiaceae family, such as Clusia L., Garcinia L., Pentadesma Sabine and so on. Among them, Garcinia is a representative species comprising of about 400 recognized plants and is extensively dispersed throughout tropical and subtropical Asia, Africa, and America (2022). The chemical compositions of these plants contain a variety of valuable natural products with associated beneficial and healing properties such as anti-tumor (Fan et al., 2015), anti-obesity (Hasegawa, 2001; Kim et al., 2004), antibacterial (Negi et al., 2008; Auranwiwat et al., 2014), antioxidant (Farombi et al., 2013), antimalarial (Elfita et al., 2009), and so on (Grossman and Yang, 2020; Spontoni do Espirito Santo et al., 2020; Kalita et al., 2021). As a result, a considerable bunch of studies have been conducted to evaluate all types of phytochemical compositions from Clusiaceae, including polycyclic polyprenylated acylphloroglucinols (PPAPs) (Tian et al., 2016; Chen et al., 2020), xanthones (Nilar and Harrison, 2002; Rukachaisirikul et al., 2003b; Elfita et al., 2009), benzophenones (Elya et al., 2006), flavonoids (Nguyen et al., 2021), biphenyls (Auranwiwat et al., 2021) and others (Ly Dieu et al., 2012; Jiang et al., 2014).

Biphenyls are odorant and white crystals typically consisting of two adjacent benzene rings connected by a C1-C1’ bond (Kwong et al., 2017) (Figure 1). The biphenyl is normally used as an advantaged and functional moiety in the field of drug design and the process of medicinal advancement (Lu et al., 2015; Anusha et al., 2016; Tarade et al., 2017; Delgado et al., 2019). They have the potentials to be developed as prospecting therapeutic agents for a range of diseases (Chen et al., 2022), such as the dual inhibitors of acetylcholinesterase and butyrylcholinesterase (Wang et al., 2017) for Alzheimer’s disease (Inuzuka et al., 2022), the transient receptor potential vanilloid type 1 (TRPV1) antagonist (Oka et al., 2018), the human immunodeficiency virus -1 (HIV-1) nonnucleoside reverse transcriptase inhibitor (Sang et al., 2019). In addition, they could also be applied as auxiliary parts to enhance the biological properties (Ding et al., 2015) or act as chiroptical probes (Santoro et al., 2020). It is noted that some FDA-approved drugs, such as sonidegib, tazemetostat, daclatasvir, sacubitril, and trifarotene (Figure 2), have been developed in recent years with biphenyl as the core structure (Bhutani et al., 2021).

FIGURE 1

FIGURE 1. Basic structure of biphenyl and five FDA-approved drugs containing biphenyl structure from 2015-June 2020.

FIGURE 2

FIGURE 2. Development of bioactive compounds based on biphenyl.

So far, Clusiaceae has yielded a variety of critical compounds with remarkable activity, such as α-mangostin (Gutierrez-Orozco and Failla, 2013), gambogic acid (Banik et al., 2018), oblongifolin C (Li et al., 2018) and so on. The majority of these key compounds belong to the structurally unique PPAPs and xanthones, which are the two principal metabolites (Chantarasriwong et al., 2010; Li et al., 2016; Xu et al., 2020). Biphenyls are secondary metabolites regularly yielded especially from individual species of the Garcinia genus (Chen et al., 2019). In addition, biphenyl can be classified as a phytoalexin that is produced in response to pathogen assault (Zhou et al., 2016) and it can be extracted from a wide range of plants with related bioactive ability (Teixeira et al., 2006; Yan et al., 2018; Ma et al., 2019; Yuan et al., 2019; Song et al., 2021). Because biphenyls have received little attention compared to PPAPs and xanthones in Clusiaceae, a comprehensive review of biphenyl chemicals in Clusiaceae is currently unavailable. Since 1974, a total of 69 new biphenyls (Tables 1–5) have been identified from Clusiaceae, all of which are structurally distinctive and possess various bioactive effects. It is obvious that a summary of the biphenyls in Clusiaceae would be beneficial for the utilization of these compounds. Therefore, we would like to sum up the development of biphenyls in the chemistry and biological activity from Clusiaceae, with the aim to provide a discussion of their structural diversity and medicinal potential.

TABLE 1

TABLE 1. Biphenyls from Clusiaceae and associated cytotoxicities.

TABLE 2

TABLE 2. Biphenyls from Clusiaceae and associated antibacterial activity.

TABLE 3

TABLE 3. Biphenyls from Clusiaceae and associated anti-tobacco mosaic virus (anti-TMV) activity at the concentration of 20 μM.

TABLE 4

TABLE 4. Biphenyls from Clusiaceae and associated anti-rotavirus activity.

TABLE 5

TABLE 5. Biphenyls from Clusiaceae and associated anti-syncytium activity.

2 Diverse biphenyls from Clusiaceae and their bioactivity

Tables 1–5 outlines the biphenyls isolated from Clusiaceae and their bioactivities. As shown in Table 1, almost two-thirds of the compounds were examined for cytotoxicity, however, only a few of them were revealed with moderate bioactivities. Nine compounds (3, 5–6, 16–18, 29, 31 and 37) showed relatively good potency against the cells tested, with IC₅₀ values below 10 μM. Tables 2, 3 list the substances that were tested for antibacterial and anti-tobacco mosaic virus (anti-TMV) activity. Compounds 3, 6, and 45 performed well in the anti-microbial test, with MIC values of roughly 20 μg/mL against corresponding bacteria. In terms of the capacity to inhibit tobacco mosaic virus, two-thirds of the compounds examined exhibited good activity, with inhibition rates greater than 20%, while the positive control ningnanmycin generally showed inhibition rates in the range of 30%–35% (Shang et al., 2014; Hu et al., 2016). Among them, compounds 18, 47 and 50 showed better inhibition rates, which were close to 30%. Tables 4, 5 present the results of a small number of compounds that were tested for anti-rotavirus and anti-HIV efficacy. It is obvious that all the substances under study have some potential when their therapeutic indices (TIs) or the selective indices (SIs) are compared to the corresponding positive controls. The TI value of the anti-rotavirus positive control Ribavirin is about 20 (Gao et al., 2016), and the SI value of the anti-syncytium positive control azidothymidine is larger than 2.73 (Chaturonrutsamee et al., 2018).

In the following section, the origins of the compounds, their structures, and an extensive description of their biological activities are presented based on the Tables. The isolated compounds are organized based on the structures and their bioactivities.

2.1 Biphenyls with associated cytotoxicities

A total of 39 compounds (Figure 3) were isolated and assayed for cytotoxicity from Clusiaceae. Three of them were from Clusia paralicola G. Mariz and the rest of the compounds were from Garcinia genus. The cytotoxicity of the substances is detailed below by categorizing them into three groups based on the number of hydroxyl groups and substitution sites on the structures.

FIGURE 3

FIGURE 3. Structures of biphenyls 1–39.

2.1.1 Biphenyls with 2,3,4-trihydroxyl group

The biphenyl structures in this section contain three hydroxyl groups at the C2, C3, and C4 positions, and their cytotoxicities have been evaluated on several cancer cell lines.

A biphenyl was isolated from the methanol extract of twigs and leaves of Garcinia bancana MIQ. from Southern Thailand, which was determined as [1.1′-biphenyl]-2-(3-methyl-2-butenyl)-3-methoxy-4.4′,5,6-tetraol (1) (Figure 3) (Rukachaisirikul et al., 2005a). The source of biphenyl 1, Garcinia bancana, is a member of the Clusiaceae family that is native to Southeast Asian countries including Thailand, Malaysia and Indonesia (Whitmore, 1973; Rukachaisirikul et al., 2005a). The n-hexane extract of the Garcinia bancana leaves showed antioxidant activity according to 1,1-diphenyl-2-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) tests (Putri et al., 2018). In the research of Auranwiwat and co-workers, cytotoxicity against KB cells of 1 was tested, but 1 was inactive to both cells with IC₅₀ > 50 µM (Table 1) (Auranwiwat et al., 2021).

Garcinia cylindrocarpa Kosterm is native to Indonesia’s Maluku Island, where it is known as “Kogbirat” and is used as a fever remedy in traditional Indonesian medicine (Sukandar et al., 2016a). Tip-pyang and others explored Garcinia cylindrocarpa for sustained research on bioactive compounds of Garcinia and attained cylindrobiphenyl B (2) (Figure 3). By utilizing the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2,3-dihydro-1H-tetrazol-3-ium bromide (MTT) colorimetric technique, biphenyl 2 showed no activity against KB, HeLa S3, MCF-7, HepG2, or HT-29 cancer cell lines. (Table 1) (Sukandar et al., 2018).

Aucuparin (3) (Figure 3), a constitutive component from the heartwood of Sorbus aucuparia (Erdtman et al., 1961), also could be extracted and separated from the Garcinia species (Chen et al., 2004; Mungmee et al., 2013; Hu et al., 2016). Although the structure of 3 is very simple, many studies have explored its biological properties such as antifungal (Cortez et al., 1998; Song et al., 2021), anti-TMV (Hu et al., 2016), anti-inflammatory, as it is a natural phytoalexin (Kokubun et al., 1995). Given that 3 has attracted a lot of attention and has been studied by many groups, some of its biological features including cytotoxicity, antibacterial activity and anti-inflammatory were summarized individually in the following sections.

A lot of groups have probed its cytotoxic effects against diverse cell lines, and 3 showed different levels of cytotoxicity against P-388 (IC₅₀ = 3.21 μg/mL (Chen et al., 2004)), HT-29 (IC₅₀ = 5.39 μg/mL (Chen et al., 2004)), XF498, A549, SK-OV-3, SK-MEL-2, HCT15 (IC₅₀ > 30 µM (Kim et al., 2009; Kim et al., 2016; Suh et al., 2017)), KB, HeLa S3, HepG2 and MCF-7 (IC₅₀ > 100 µM (Sukandar et al., 2016b)) cells (Table 1).

For the synthesis of oxygenated biphenyls, the tandem Michael addition reaction followed by aromatization reaction was developed by Chittimalla group. They successfully applied this methodology in the synthesis of 3 (Scheme 1) (Chittimalla et al., 2015). At the beginning, cyclohexa-2,4-dienone (3a) and phenylboronic acid (3b) were used as the starting materials to make 3c, which underwent quantitative methylation by reacting with MeI and K₂CO₃ in acetonitrile to give trimethoxybiphenyl 3d. After selective demethylation, biphenyl 3 was accomplished in 82% yield.

SCHEME 1

SCHEME 1. Synthesis of biphenyl 3

Garcinia linii is an endemic evergreen tree that sprang up in Langyu land along with the Green island of Taiwan and contains xanthones, biphenyls, and other compounds. Chen et al. (2019). Chen group made significant contributions to the separation of biphenyls from the root of Garcinia linii. They analyzed and identified garcibiphenyl C (4) (Figure 3), by way of spectral analyses in 2006 (Chen et al., 2006). Biphenyl 4 was tested for its cytotoxic activity against P388, KB, Col-2, BCA-1, Lu-1, ASK, NALM-6, but it was found to be ineffective against these cells (Table 1) (Ito et al., 2013; Pailee et al., 2018). With respect to the synthesis of 4, the strategy reported by Schmidt group was featured with protecting-group free strategy. (Scheme 2). At the outset, bromoarene (4b) was produced from 2,6-dimethoxyphenol (4a) via the bromination of 4a (Lee et al., 2004). Then 4b was reacted with (4-hydroxyphenyl) boronic acid (4c) in the presence of Pd/C catalyst in water to give 4 in 52% yield. In addition, this research reported that it could get access to diverse biphenyls via Suzuki−Miyaura cross coupling (Schmidt and Riemer, 2014).

SCHEME 2

SCHEME 2. Synthesis of biphenyl 4

Garcinia nigrolineata Planch. Ex T. Anderson, known as kandis in the local, is widely distributed in Malaysia (Mohd Norfaizal et al., 2014). Many xanthones have been isolated (Rukachaisirikul et al., 2003a; Rukachaisirikul et al., 2003c) from this plant. On the other hand, only two biphenyls, nigrolineabiphenyls A-B (5–6) (Figure 3) were obtained from Garcinia nigrolineata by Rukachaisirikul in 2005 (Rukachaisirikul et al., 2005b). The cytotoxicities of 5-6 on a series of tumor cell lines were studied including SW620, BT474, HepG2, CHAGO, NB4, A549, NALM-6 and so on (Table 1) (Ito et al., 2013; Mungmee et al., 2013; Zhou et al., 2015). Biphenyls 5-6 showed weak to moderate inhibitory activity towards most of the cell lines mentioned above, while 6 displayed stronger cytotoxicity against SW620 cells with the IC₅₀ values of 0.36 µM (Mungmee et al., 2013).

The first investigation to identify the phytochemical of Garcinia nuntasaenii Ngerns. and Suddee attained the isolation of garcinuntabiphenyls A-C (7–9) (Figure 3), which were evaluated for cytotoxicity (Chaturonrutsamee et al., 2018). Garcinia nuntasaenii is distributed in northeastern Thailand and commonly named “Chang-nga-ek”. It is a dioecious shrub growing with white flowers and green fruits. Its roots could be used for relieving muscle pain in Thai folk medicine (Ngernsaengsaruay and Suddee, 2016). The cytotoxic effects of biphenyls (7–9) against a panel of cultured mammalian cancer cell lines, including P-388, KB, HT-29, MCF-7, A549, ASK, were generally weak. Only the cytotoxicity of 8 to P-388 (IC₅₀ = 37.87 µM) and KB (IC₅₀ = 41.94 µM), as well as 9 to KB (IC₅₀ = 39.04 µM) were detected and quantified (Table 1).

A new biphenyl, schomburgbiphenyl (10) (Figure 3), was obtained as a white solid from the wood of Garcinia schomburgkiana Pierre and determined as [1.1′-biphenyl]-2-(3-hydroxy-3-methylbutyl)-3-methoxy-4.4′,5-triol (Mungmee et al., 2013). Its source, Garcinia schomburgkiana, is a medium-sized tree widely scattered in Vietnam, Laos, Cambodia, and Thailand and called Ma-dan in Thailand. It has previously been reported to possess the activity of DNA polymerase Inhibitory, antioxidant and anti-diabetic properties (Le et al., 2016; Gonsap and Vongsak, 2019; Thummajitsakul et al., 2020). Biphenyl 10 was analyzed for its cytotoxic activity against five human cancer cell lines, but it was not active in the test (Table 1) (Mungmee et al., 2013). Another study carried out by Hu also tested its cytotoxicities using the other five kinds of tumor cell lines (NB4, A549, SHSY5Y, PC-3, MCF-7) in 2015. And it could be known that all IC₅₀ values were above 10 µM from this research (Table 1) (Li et al., 2015).

Investigating the EtOAc extract of the stems of Garcinia schomburgkiana led to the fractionation and the elucidation of a new biphenyl derivative, schomburgbiphenyl B (11) (Figure 3), as colorless oil. The compound (11) was screened for the ability to repress the growth of several leukemia cell lines containing Jurkat, NALM-6, K562 and HPB-ALL. It was found that biphenyl 11 showed limited cytotoxicity against NALM-6 cells, with cell viability ranging from 73% to 80% at the concentration of 50 µM (Table 1) (Ito et al., 2013).

Two biphenyls, garciosines A-B (12–13) (Figure 3), were isolated, established, and confirmed from Garcinia speciose Wall by employing extensive spectroscopic methods and single crystal X-ray diffraction analysis (Pailee et al., 2018). Garcinia speciose, namely “PhaWaa” in Thailand, is an indigenous plant that can be used for the therapy of blood disorders, skin wounds, inflammation, laxative and so on (Sakunpak and Panichayupakaranant, 2012; Sangsuwon and Jiratchariyakul, 2015). Garciosines A-B (12–13) were examined with cytotoxic properties against a panel of cancer cell lines (P388, KB, Col-2, BCA-1, Lu-1, ASK, HeLa, S-3, MCF-7, HepG2, HT-29). The activity of 12–13 to restrain these tumor cells was not prominent. The IC₅₀ value of 12 against KB cells was 89.05 ± 3.11 µM, and the IC₅₀ value of 13 against P388 cells was 18.48 µM (Table 1) (Pailee et al., 2018; Sukandar et al., 2018).

The separation of doitungbiphenyls A (14) and B (15) (Figure 3) from the acetone extract of the twigs of Garcinia sp. was achieved for the first time by Laphookhieo and co-works. By virtue of 1D and 2D NMR spectroscopy as well as HR-EI-MS, they were elucidated to contain prenylated chains in the skeleton. Obviously, 15 is formed from the methylation of 14. Their bioactivities to suppress the reproduction of the tumor cells were tested by using KB and MCF-7 cell lines. However, the two compounds were inactive against the two cell lines, and 15 displayed weak inhibition against the MCF-7 cell line with an IC₅₀ value of 102.52 μM (Table 1) (Siridechakorn et al., 2014).

2.1.2 Biphenyls with 2,3-dihydroxyl group

The structural similarity of the compounds described in this section is characterized by the presence of two adjacent hydroxyl substituents at the C2, C3 positions. Their cytotoxicities against diverse tumor cell lines were summarized in the following.

Mixed forests of Garcinia bracteata C. Y. Wu ex Y. H. Li are commonly distributed on limestone hills of Yunnan and Guangxi Province of China (Li et al., 2011). To search for new bioactive metabolites, Hu et al. examined the chemical components of the twigs from Garcinia bracteata. Consequently, three biphenyls, namely bractebiphenyls A-C (16–18) (Figure 3), were extracted and separated by using 70% aqueous acetone. Their structures were elucidated by spectroscopic methods, such as UV spectrum, IR spectrum and 1D and 2D NMR techniques. As for the experimental data of cytotoxic abilities, three compounds displayed moderate cytotoxicities against five cell lines (NB4, A549, SHSY5Y, PC-3, and MCF-7), with IC₅₀ values typically below 10 µM. Among these compounds, biphenyl 18 was the most potential with high cytotoxicities against A549 and PC-3 cells (IC₅₀ = 3.6 and 2.7 µM, respectively) (Table 1) (Li et al., 2015).

For the aim of searching for undiscovered natural products of Garcinia mckeaniana Craib, the constituents belonging to the flower and twig extracts of this plant were investigated by Auranwiwat and others and a biphenyl (19) was found (Figure 3) in 2021 (Auranwiwat et al., 2021). Garcinia mckeaniana, also called Xen mu, is a common plant that is widespread in the tropical secondary forests of Sapa town and Son La province of Vietnam in particular. So far, a few studies have been conducted on the phytochemistry and biological properties of Garcinia mckeaniana (Auranwiwat et al., 2016; Ha et al., 2021; Nguyen et al., 2021; Thi Thu et al., 2021). The biphenyl (19) was denominated as mckeaninabiphenyl and had been synthesized previously (Sato and Mikawa, 1960). This was the first time that it was reported as a natural phytochemical. Its structure is symmetrically featured as 4.4′-dihydroxy-2.2′-dimethoxybiphenyl, which is like biphenyls that were isolated from fungi formerly (Li et al., 2017; Zhu et al., 2019). Its cytotoxicity was tested, but it was inactive against KB cells with IC₅₀ value > 50 µM in assays (Table 1).

Yuan group systematically discovered and structurally characterized Garmultines A-C (20–22) (Figure 3) from Garcinia multiflora Champion ex Bentham (Tian et al., 2017), which contains PPAPs with apoptosis-inducing or cytotoxic properties (Chien et al., 2008; Liu et al., 2010; Fan et al., 2015; Tian et al., 2016; Yang et al., 2020) and others (Wang et al., 2018). Compounds 21 and 22 are proved to be isomers. The cytotoxic capacities of the three novel natural biphenyls (20–22) were evaluated (Tian et al., 2017). Their cytotoxicities were tested on five human tumor cell lines (HeLa, MCF-7, A-549, MGC-803, and COLO-205), which turned out that these biphenyls (20–22) were moderate against the five cells with the IC₅₀ values ranging from 12.4 to > 40 μg/mL (Table 1). It concluded that an additional prenyl chain at C9 (20) could make compound 20 more active in inhibiting tumor cells.

Two biphenyls, multiflorabiphenyls B1 (23) and multiflorabiphenyl D (24) (Figure 3) were obtained from the acetone-extracted leaves of Garcinia multifora through bioassay-directed fractionation. The cytotoxic abilities of compounds 23–24 against five human cancer cell lines (HeLa, SGC7901, TE1, HCT116, and Capan 2) were evaluated with IC₅₀ values > 10 µM (Table 1) (Fu et al., 2015).

Garcinia oblongifolia Champ. ex Benth. is a medium-sized shrub mainly distributed in tropical areas of southern China and northern Vietnam and has been used to reduce the pains of burns and diminish inflammation (Liu et al., 2016). Xanthones, PPAPs and other bioactive components have been found in this plant (Hamed et al., 2006; Zhang et al., 2016). Four new biphenyls, oblongifoliagarcinines A–D (25–28) (Figure 3), were acquired from samples of Garcinia oblongifolia collected in Guangxi province of China and structurally determined on the basis of spectroscopic analysis. The cytotoxic effects of 25–28 were assessed against the tumor cell lines A549 and HL-60 (Table 1). It turned out that biphenyls 25–28 were inactive toward these two cancer cells in vitro (Wu et al., 2008). Whereas, compounds 25 and 26 showed weak influence on the growth of HeLa, MCF-7, A-549, MGC-803, and COLO-205 cells with IC₅₀ values ranging from 18.4 to > 40 μg/mL (Tian et al., 2017).

The new biphenyl (29) (Figure 3) was obtained and confirmed as 3-methoxy-5-methoxycarbonyl-4-hydroxy-biphenyl after the extraction, separation and purification from the stems of Garcinia oligantha Merrill (Liu et al., 2015). Garcinia oligantha is a tall shrub mainly growing in the Guangdong and Hainan provinces of China and northern Vietnam (Li et al., 2011). The plant was usually explored for the bioactive xanthones possessing diverse activity such as cytotoxic property and suppressing convulsant behavior (Tang et al., 2016; Tang et al., 2019; Gong et al., 2020; Yang et al., 2021). The biphenyl (29) was measured for its cytotoxic effects against NB4, A549, SHSY5Y, PC-3 and MCF-7 tumor cells. The results showed 29 could modestly exert the repression toward tumor proliferation with IC₅₀ values of 7.1, 6.2 and 4.8 µM against SHSY5Y, A549 and MCF-7 cells, respectively (Table 1) (Liu et al., 2015).

Schomburgbiphenyl A (30) (Figure 3) was also extracted as colorless oil from the stems of Garcinia schomburgkiana at the same time with Schomburgbiphenyl B (11). Like compound 11, 30 was accessed for the cytotoxicity against a series of leukemia cell lines containing Jurkat, NALM-6, K562 and HPB-ALL cells. It (30) was not very effective to repress the proliferation of these tumor cells in study (Table 1) (Ito et al., 2013).

2.1.3 Biphenyls with 2, 4-dihydroxyl group

Biphenyls with bis-hydroxyl substituted at the C2 and C4 positions and their cytotoxic testing results are outlined in this section.

Three novel biphenyls clusiparalicolines A-C (31–33) (Figure 3) were obtained by the bioassay-guided fractionation from the roots of Clusia paralicola G. Mariz (Seo et al., 1999), which is a native species distributed in Brazil (POWO, 2022). These three biphenyls were tested for cytotoxicity against KB cells. The results showed that biphenyls 31–33 could inhibit the proliferation of KB cells modestly (Table 1). The report also assessed the DNA strand scission ability to evaluate their antineoplastic potential. Compounds 31 and 32 demonstrated considerable DNA strand scission action. The DNA relaxation rates were 77% and 65%, respectively, at the concentration of 2.5 g/mL (the rate of bleomycin at 0.025 g/mL was about 50%). Compound 33 was observed to be inactive. Looking into their structures, the ring generated by cyclization involving the prenyl and hydroxyl groups distinguishes compounds 31 and 32. And compound 33 lacks the catechol and geranyl moiety in comparison to compounds 31 and 32. As a result, it is possible that the 3,3-dimethylallyl group and the hydroxyl group of compound 31 have no effect on DNA strand scission activity, because there was no significant difference in DNA strand scission activity between compounds 31 and 32. Furthermore, based on previous work by Wall and Wani’s group (Huang et al., 1996), it is confirmed that the presence of the catechol and geranyl moiety in 31 and 32 may be connected with DNA strand-scission activity.

The first synthesis of biphenyl 31 was successfully finished in 2002 by Fukuyama’s team (Scheme 3). The design of two geranylated and prenylated phenols is needed for the synthesis of clusiparalicoline A (31) since it is not entirely symmetrical. Beginning with O-dimethylphloroglusinol 31a, the preparation of left part was undertaken. After the protection, bromination, C-alkylation, removal of the TBDMS and subsequent triflation, the left part of 31g with a triflate group was provided quantitatively. Starting with the commercially available 3,4-dihydroxybenzaldehyde 31h, the protection of the catechol group, Baeyer–Villiger oxidation of the aldehyde, and reduction were performed to afford compound 31i. Then, the generated phenolic group was protected as an allyl ether, and subsequent bromination, deallylation, palladium-catalyzed Stille reaction yielded compound 31l. Next, it was successful to convert the bromide 31l into a pinacol boronic ester 31m using the Suzuki-Miyaura protocol. Following that, Suzuki coupling between 31g and 31m was carried out smoothly, yielding the coupling product 31n in 90% yield. At last, following the deprotection of all MOM groups and separation by HPLC, the desired biphenyl 31 was synthesized (Takaoka et al., 2002).

SCHEME 3

SCHEME 3. Synthesis of biphenyl 31.

Cylindrobiphenyl A (34) was found by Tip-pyang and others during the investigation of exploring Garcinia cylindrocarpa (Figure 3). Its (34) cytotoxicity against KB, HeLa S3, MCF-7, Hep G2, or HT-29 cancer cell lines was assayed by MTT in vitro. But it was inactive to all tested cells (Table 1) (Sukandar et al., 2018).

Garcibiphenyls A-B (35–36) (Figure 3) were separated and determined from Garcinia linii by Chen group in 2004 (Chen et al., 2004). Compounds 35 and 36 were assessed to figure out their cytotoxicities against two tumor cells. Their ED₅₀ value against P-388 were 10.2 μg/mL, 6.63 μg/mL, respectively. And the ED₅₀ values of 35–36 against HT-29 were 13.5 μg/mL, 12.7 μg/mL, respectively (Table 1) (Chen et al., 2004).

Garcibenzopyran (37) (Figure 3) was found and identified with 35–36 from Garcinia linii during the same investigation conducted by Chen group (Chen et al., 2004). The ED₅₀ values against P-388 and HT-29 cell lines of 37 were 3.98 μg/mL and 6.90 μg/mL, respectively, which supported that 37 could be slightly beneficial for anti-cancer and anti-proliferation therapy (Table 1) (Chen et al., 2004).

Multiflorabiphenyl C (38) (Figure 3), an isomer of multiflorabiphenyl D (24), was obtained from the leaves of Garcinia multifora. The cytotoxic activity of compound 38 against five human cancer cell lines (HeLa, SGC7901, TE1, HCT116, and Capan 2) was evaluated, and the results showed that its IC₅₀ values were all above 10 µM (Table 1) (Fu et al., 2015).

Garciosine C (39) (Figure 3) was another biphenyl isolated and established from Garcinia speciose by extensive spectroscopic methods in 2018 (Pailee et al., 2018). The cytotoxic ability of garciosine C (39) was examined on a panel of cancer cell lines (P388, KB, Col-2, BCA-1, Lu-1, ASK, HeLa, S-3, MCF-7, HepG2, HT-29). In fact, biphenyl 39 cannot inhibit tumor cells effectively. The IC₅₀ value of 39 against P388 cell was 32.36 µM. In addition, it was inactive against the other cell lines (Table 1) (Pailee et al., 2018; Sukandar et al., 2018).

2.1.4 Structure-activity relationship of biphenyls with associated cytotoxicity

A brief analysis of the structure-activity relationship for the cytotoxic activity of these functionalized biphenyls was discussed in this section based on the reference data that is currently available. In addition to the analyses mentioned above, the following discussion could be useful for the research of the biphenyls according to Table 1 and Figure 3.

Compounds 5 and 6 (Figure 3) were both derived from the Garcinia nigrolineata (Rukachaisirikul et al., 2005b). And it could be known from the research of Hu group and Suttisri group that compound 6 had a higher inhibitory effect on tested PC-3, MCF-7 and SW620 cells than that of compound 5 (Table 1) (Mungmee et al., 2013; Zhou et al., 2015). It could be inferred that the methoxyl substitution on R⁵ (C9) had a better influence on the bioactivity compared to the hydroxyl substitution. From the structures and their cytotoxicity of compounds 7 and 8, 7 and 9 (Figure 3 and Table 1), it indicated that methoxylation on the R⁶ (C10) or the R⁴ (C5) positions may improve the cytotoxic effect. Although the cytotoxic effects of compounds 14 and 15 were not greatly outstanding, it suggested that compound 14 was slightly superior to compound 15 (Table 1) (Siridechakorn et al., 2014). Thus, it is obvious that a meta-hydroxyl substitution at the 3,3-dimethylallyl chain in their structures may be more advantageous for activity. The comparison of biphenyls 16 and 17 suggested that hydroxylation of the terminal carbon of the 3,3-dimethylallyl group did not have much effect on their activity (Li et al., 2015). Similarly, the experimental data for compounds 25 and 26 showed that the 3,3-dimethylallyl substitution at the C9 position did not significantly influence activity (Tian et al., 2017).

2.2 Biphenyls with associated antibacterial activity

A total of 11 biphenyls (Figure 3 and Figure 4) isolated from Clusiaceae were evaluated for antibacterial activity, four of which (1, 3, 6, 15) were listed in the cytotoxicity section above. Except for compound 43 (Figure 4), which was produced from Clusia burlemarxii Bittrich, another 10 compounds were isolated and extracted from Garcinia. They were also described below according to their structures.

FIGURE 4

FIGURE 4. Structures of biphenyls 40–46.

2.2.1 Biphenyls with 2,3,4-trihydroxyl or 2,3,5-trihydroxyl group

In addition to the cytotoxicity, several 2,3,4-trihydroxy-substituted biphenyls were also subjected to antimicrobial evaluation. The antimicrobial activity of these biphenyls and another undescribed 2,3,5-trihydroxybiphenyl are summarized in this section.

The biphenyl (1) (Figure 3) exhibited weak antibacterial activity to Methicillin-resistant Staphylococcus aureus (MRSA) with MIC values of 64 μg/mL (Rukachaisirikul et al., 2005a) (Table 2). In terms of antibacterial activity (Table 2), a study indicated that biphenyl 3 (Figure 3) could suppress Gram-positive bacteria, which showed antimicrobial activity against Bacillus subtilis with MIC values of 3.12 μg/mL and against S. aureus with a MIC value of 12.5 μg/mL, respectively. It has no effect on Gram-negative bacteria including Pseudomonas aeruginosa and Escherichia coli (MIC ≥100 μg/ml). Meanwhile, penicillin-resistant S. aureus (PRSA) strains (MIC = 6.25 μg/mL) seemed to be more sensitive to 3 than penicillin-susceptible S. aureus (PSSA) strains (MIC = 12.5 μg/mL), which was advantageous for clinical drug development. The observation that anti-bactericidal activity of 3 functionalized in a dose-dependent manner was proved by investigating the kinetics of bactericidal activity against S. aureus at six concentrations of 3 (0.25 ×, 0.5 ×, 1 ×, 2 ×, 4 × and 8 × the MIC). It was surprising that there was no regrowth of bacteria after monitoring for up to 24 h (Cortez et al., 2002). The suppressive degree of 3 against Mycobacterium tuberculosis 90 ± 221387 was also tested to evaluate its antitubercular activity and it turned out that 3 played a weak role in antitubercular effect (Chen et al., 2006). With respect to biphenyl 6 (Figure 3), a study tested the antibacterial activity of 6 against three different strains of Helicobacter pylori (H. pylori) (Table 2). The results indicated 6 could restrain H. pylori in a gentle manner with MIC values of 226.3 µM, 56.5 µM, 226.3 µM against H. pylori ATCC 43504, H. pylori DMST 20165 and H. pylori HP40, respectively (Nontakham et al., 2014). On the other hand, compound 15 (Figure 3) was indicated to show anti-staphylococcal activity with MIC values at 50 μg/mL towards series of S. aureus strains (Table 2) (Zheng et al., 2021).

Two previously unknown biphenyls, garciesculenbiphenyls A-B (40–41) (Figure 4) were recently isolated and identified from Garcinia esculenta Y. H. Li, an endemic tree mainly distributed in Yunnan province of China (Zhu et al., 2014). Compounds 40 and 41 are two chemicals that are structurally related. Compound 41 could be converted to 40 after oxo-cyclization. These two compounds were tested for antibacterial activity against MSSA-Newman, two MRSA strains USA300 LAC and USA400 MW2, and VISA-Mu50 (Table 2). As it revealed, compound 40 presented weak anti-staphylococcal activity with MIC values at 50 μg/mL, whereas compound 41 did not show obvious anti-staphylococcal activity (Zheng et al., 2021).

2.2.2 Biphenyls with 2, 3-dihydroxyl group

The compound 42 (Figure 4) was isolated from Garcinia cowa Roxb. Garcinia cowa, also known as Cha muang in Thailand. It is a plant that can produce a variety of bioactive substances and is used as an antipyretic folk medicine (na Pattalung et al., 1994; Likhitwitayawuid et al., 1998; Mahabusarakam et al., 2005; Panthong et al., 2006) (+)-Garciniacowol (42), a dimeric dihydrobenzopyran with highly symmetrical structure, was found and identified from the stembarks of Garcinia cowa (Siridechakorn et al., 2012). The antibacterial property of 42 was analyzed (Table 2) and the results showed that 42 was inert against Gram-positive bacteria such as S. aureus-TISTR 1466 and MRSA-SK1. On the other hand, 42 had a mild effect on Gram-negative bacteria such as Escherichia coli TISTR 780 and Salmonella typhimurium TISTR 292 with MIC values at 128 g/mL for both.

2.2.3 Biphenyls with 2, 4-dihydroxyl group

2,2-dimethyl-3,5-dihydroxy-7-(4-hydroxyphenyl)chromane (43) (Figure 4) was extracted and determined from the trunk of Clusia burlemarxii Bittrich, a shrub distributed in Brazil. The research carried out the preliminary tests in vitro to determine the inhibitory effect of biphenyl 43 against a series of bacteria. The results of the initial analysis revealed that biphenyl 43 significantly inhibited all tested Gram-positive bacteria which was stronger against Micrococcus luteus (MIC = 25 μg/mL⁻¹) and S. aureus (MIC = 50 μg/mL⁻¹). However, it was weaker against Bacillus subtilis and Streptococcus mutans with MIC values at 100 μg/mL⁻¹. Additionally, it had no effect on Gram-negative bacteria (Table 2) (Ribeiro et al., 2011).

Garcibiphenyls D-E (44–45) (Figure 4) were discovered at the same time as garcibiphenyl C (4) from Garcinia linii by Chen group in 2006 (Chen et al., 2006). Regarding to biphenyls 44 and 45, their anti-tubercular effects in vitro were evaluated against Mycobacterium tuberculosis 90 ± 221387. Both of them showed moderate activity with MIC values at 50.3 ± 4.2 μg/mL, 25.4 ± 3.1 μg/mL, respectively (Table 2) (Chen et al., 2006).

(S)-3-hydroxygarcibenzopyran (46) (Figure 4) was found and identified simultaneously with biphenyls 4, 44–45 from Garcinia linii (Chen et al., 2006). It is apparent that 46 is the derivative of 37 with an additional hydroxyl on the pyran ring. Although the antibacterial effect of biphenyl 46 was investigated, the testing result displayed that biphenyl 46 could not inhibit Mycobacterium tuberculosis 90 ± 221387 effectively (MIC >100 μg/mL) (Table 2) (Chen et al., 2006).

2.2.4 Structure-activity relationship of biphenyls with antibacterial activity

According to the study of Xu group in 2021, it could be known that biphenyls 15 (Figure 3), 40 (Figure 4) had comparable antibacterial capacities. Furthermore, both biphenyl 15 and 40 were more active than compound 41 (Figure 4) (Zheng et al., 2021). Hence, it could assume that the antibacterial activity may be stronger when the 3,3-dimethylallyl chain was positioned at para-position of the hydroxyl group (C1) or cyclized with the hydroxyl group rather than at the ortho-position of hydroxyl group (C5). Conclusions could also be obtained by comparing the activity of compounds 44 and 45, 44 and 46 (Figure 4; Table 2): 1) 3-hydroxymethyl-3-methyl-but-2-enyl substitution might be more beneficial for antibacterial activity than 2-hydroxy-3-methyl-but-3-enyl substitution; 2) the cyclization of 2-hydroxy-3-methyl-but-3-enyl may impair the antibacterial abilities of the compounds.

2.3 Biphenyls with associated anti-TMV activity

The ability of 15 different substances (Figure 3 and Figure 5) to inhibit the tobacco mosaic virus was examined. And Garcinia genus was the source of all compounds. They can be separated into the following two major groups based on their structural features.

FIGURE 5

FIGURE 5. Structures of biphenyls 47–59.

2.3.1 Biphenyls with 2,3,4-trihydroxyl group

Despite with a simple structure, biphenyl 3 (Figure 3) has a wide range of activities. It could moderately suppress the tobacco mosaic virus with the inhibition rates of 24.5 ± 2.8% (Table 3) (Hu et al., 2016). Additionally, biphenyl 5 and 6 (Figure 3) derived from compound 3 presented modest anti-TMV properties. Their inhibition rates were 23.5 ± 2.7% and 18.9 ± 2.9% at the concentration of 20 μM, respectively (Table 3) (Hu et al., 2016). The anti-TMV ability of 10 (Figure 3) was also assessed at the concentration of 20 μM, which showed weak inhibitory capacity that its inhibition rate was 16.7 ± 2.6% (Table 3) (Li et al., 2015). With respect to the anti-TMV activity of biphenyls (14–15) (Figure 3), they were found to be modest against the tobacco mosaic virus with the inhibition rates ranging from 15.8 ± 2.0% to 24.8 ± 2.6% (Table 3) (Shang et al., 2014; Li et al., 2015).

One new biphenyl, multiflorabiphenyl B2 (47) (Figure 5), found in the twigs of Garcinia multiflora was analyzed and elucidated via spectral techniques. Assays were managed to evaluate its anti-TMV activity, which demonstrated that 47 was potential in anti-TMV with inhibition rates of 28.3%, which was similar to the inhibition rates of the positive control, ningnanmycin (a commercial product for plant disease in China, 33.5%) (Table 3) (Xu et al., 2016).

Three biphenyl derivatives, tetralatabiphenyls A–C (48–50) (Figure 5), were isolated and elucidated structurally for the first time from the ethanol extract of the twigs of Garcinia tetralata C. Y. Wu ex Y. H. Li. Garcinia tetralata is a plant peculiarly distributed in the south and southwest Yunnan province in China. Up to now, the phytochemical investigation of this plant was not paid much attention (Wang et al., 2008; Guo et al., 2011). To evaluate the bioactive characterizations of biphenyls 48–50, the activity to resist the tobacco mosaic virus was assayed. Tetralatabiphenyl C (50) showed the strongest activity among these biphenyls (48–50) with an inhibition rate of 31.1 ± 3.5% at the concentration of 20 μM, while the inhibition rates of 48 and 49 were 21.5 ± 2.6%, 22.8 ± 2.8% respectively (Table 3) (Hu et al., 2016).

2.3.2 Biphenyls with 2,3-dihydroxyl group

The anti-TMV inhibition rates of 16–18 (Figure 3) at the concentration of 20 µM were 15.5 ± 2.3%, 18.2 ± 2.7%, 28.4 ± 2.5% (Table 3), respectively, while 18 showed similar inhibition rates compared with ningnanmycin (30.2%). In addition, this study also tested the anti-TMV activity of biphenyl 25 (Figure 3) and it showed that 25 could inhibit tobacco mosaic virus moderately with the inhibition rate of 21.0 ± 2.5% at the concentration of 20 µM (Table 3) (Li et al., 2015). Multiflorabiphenyl A2 (51) (Figure 5) was another biphenyl isolated from the twigs of Garcinia multiflora. Like biphenyl 47 (Figure 5), it was subject to the tests for evaluating its anti-TMV activity. The results exhibited that it was a mild inhibitor for tobacco mosaic virus with inhibition rates of 25.4% (Table 3) (Xu et al., 2016).

2.3.3 Structure-activity relationship of biphenyls with anti-TMV activity

Contrary to the cytotoxicity, compound 5 had higher anti-tobacco mosaic virus activity than compound 6 (Figure 3; Table 3). It could be considered that the hydroxyl group at the R⁵ (C9) position may be helpful to increase the anti-TMV activity. Since compound 3 and compound 5 exhibited similar activity, it presumed that the adjacent double hydroxyl group at C9 and C10 had no impact on the compounds’ potential to inhibit the tobacco mosaic virus. The results of the anti-TMV activity tests for compounds 14 and 15 were also in conflict with the results of the cytotoxic activity tests. Since biphenyl 15 was shown to have a higher rate of inhibition than biphenyl 14 in both studies (Shang et al., 2014; Li et al., 2015), it can be deduced that methoxylation of the hydroxyl group at the meta-isopentenyl position in the structures was advantageous for enhancing the resistance to tobacco mosaic virus (Figure 3; Table 3). However, the tobacco mosaic virus inhibition rates of compounds 16 and 17 were also similar, in agreement with their cytotoxic test results. This suggested that the shift from 3,3-dimethylallyl group to 3-hydroxymethyl-3-methyl-but-2-enyl chain in their structures does not affect their activity levels (Figure 3; Table 3).

2.4 Biphenyls with associated anti-rotavirus activity

The biphenyls in the Clusiaceae family that have anti-rotavirus effect are all from the genus Garcinia. They all feature a basic structural backbone of 2,3,4-trihydroxyl substitution.

Garcinia lancilimba C. Y. Wu ex Y. H. Li is a small tree mainly distributed in humid dense forests of southern Yunnan province. A number of prenylated xanthones and biphenyls were isolated from this plant (Yang et al., 2007; Han et al., 2008; Gao et al., 2018). Garcilancibiphenyls A-C (52–54) (Figure 5), which are structurally characterized by the acetoxyprenyl group on a benzene ring, were identified via spectroscopic evidence from the extract of the air-dried and powdered stems of Garcinia lancilimba at room temperature. In the report, the anti-rotavirus activity (Table 4) of 52–54 was tested on MA104 cells in terms of CC₅₀, EC₅₀ and the TI (CC₅₀/EC₅₀). It was evident that 52 and 53 were potential for medicinal development against rotavirus with TI values above 10 (17.65, 14.56, 19.8 for 52, 53, Ribavirin, respectively) (Gao et al., 2018).

Multibiphenyls A-C (55–57) were three new biphenyls isolated from Garcinia multiflora Champion ex Bentham (Figure 5) (Gao et al., 2016). The distinct structures of these biphenyls are interestingly correlated. Apparently, 57 could be obtained from the deacetylation of 56, while 56 might be the product derived from the cyclization of 55. The potential of 55–57 to prevent the cytopathic effects caused by rotavirus was quantified in MA104 cells for the sake of assessing their bioactive significance and competence. The determination of antiviral activity was displayed as the values of CC₅₀, EC₅₀ and TI, together with ribavirin serving as a positive control. The results showed that all TI values were greater than 10, demonstrating the good anti-rotavirus potential of these biphenyls (55–57) (Table 4).

Two new biphenyls (58–59) (Figure 5) were yielded in a continuous search for more chemical components from Garcinia tetralata. Biphenyl 58 was determined as 2-isopropenyl-6-methoxy-7-hydroxy-(4-hydroxyphenyl)-dihydrobenzofuran, which can be known as the first biphenyl substituted with 2-isopropenyl dihydrobenzofuran. Another one (59) was recorded as [1.1′-biphenyl]-3-methoxy-4.4′,5-triol following the extensive analysis of spectroscopy techniques. The compounds (58–59) were screened to figure out their anti-rotavirus activity in MA104 cells. Both of them exhibited good anti-rotavirus potential with SI values were above 10 (Table 4) (Ji et al., 2017).

Except for compound 54, the other compounds tested for anti-rotavirus activity had TI or SI values greater than 10 (Table 4). Comparing the structures of biphenyls 54 and 55, it can be inferred that a double hydroxyl substitution next to the prenylated chain would favour the safety and efficacy of the compounds against rotavirus. While compound 55 can be converted to compound 56 via chain cyclization, this change has no influence on the activity (Figure 5).

2.5 Biphenyls with associated anti-HIV activity

A total of 7 biphenyls (Figure 3) were tested for their anti-HIV ability. They have been all mentioned above. Among them, six compounds had 2,3,4-trihydroxyl substituted structures.

2.5.1 Biphenyls with 2,3,4-trihydroxyl group

Probing the anti-HIV ability of 4 (Figure 3) was practiced by methods of syncytium inhibition assay and reverse transcriptase (RT) assay. Biphenyl 4 exhibited moderate activity in the syncytium inhibition assay. It could reduce 50% of syncytium formation at the concentration of 40.17 µM and its SI (IC₅₀/EC₅₀) was 1.88 in the model of 1A2 cells infected by ^ΔTat/RevMC99 virus (Table 5). However, its repressive effect on HIV-1 reverse transcriptase was not very good. Its inhibition rate was only 8.57% at the concentration of 200 μg/mL. Therefore, its IC₅₀ was not determined in the anti-HIV-1 RT assay (Pailee et al., 2018).

As for the anti-HIV activity of the biphenyls (7–9) (Figure 3), they presented various efficacy in the anti-HIV-1 RT assay and the syncytium inhibition assay with the system of ^ΔTat/RevMC99 virus and 1A2 cell line. For anti-HIV-1 RT assay of 7-9, both 7 and 8 were mild to repress the HIV-1 reverse transcriptase with the inhibition rates of 39.54% and 49.36% at the concentration of 200 μg/mL respectively. On the other hand, 9 was very active with the inhibition rate reaching up to 91.15% at the concentration of 200 μg/mL and its IC₅₀ value was 202.50 µM by contrast. In the respect of syncytium inhibition assay, all the three compounds were active to suppress the syncytium formation by ^ΔTat/RevMC99 virus in 1A2 cells, and similar SI scores were obtained at 1.68, 2.98, 3.48 for 7, 8, 9, respectively (Table 5).

The remaining two compounds with 2,3,4-trihydroxyl substitution that were measured for anti-HIV activity were biphenyls 12 and 13 (Figure 3). With respect to their (12–13) anti-HIV effects, the tests were also performed by utilizing syncytium inhibition assay and the RT assay. They all demonstrated activity in the syncytium inhibition assay proceeding with the ^ΔTat/RevMC99 virus and 1A2 cell line system, with SI values all above one and were 1.91, >4.76 respectively (Table 5). Biphenyl 13 displayed moderate activity, whilst biphenyls 12 was inactive in the HIV-1 RT assay on the contrary. The prescreened inhibition rates of 12–13 at the concentration of 200 μg/mL were −2.53% and 53.83% respectively, but their IC₅₀ values were not determined (Pailee et al., 2018).

2.5.2 Biphenyls with 2,4-dihydroxyl group

Biphenyl 39 (Figure 3) was isolated and analyzed in the same study as compounds 12 and 13. Along with biphenyls 12 and 13, it was also subjected to both the syncytium inhibition assay and the HIV-1 RT assay. In fact, the result of the syncytium inhibition test for compound 39 was better than compound 12. Its (39) SI value was above one and was 7.51 in the anti-syncytium test (Table 5). However, it (39) was inactive in the HIV-1 RT assay as the inhibition rate at the concentration of 200 μg/ml was 7.84%. The IC₅₀ value was not determined. (Pailee et al., 2018).

2.5.3 Structure-activity relationship of biphenyls with anti-HIV activity

It was clear from the aforementioned and Table 5 that the anti-HIV effects of the investigated biphenyls were generally similar. Compound 9 (Figure 3) demonstrated the best performance in the anti-HIV-1 RT assay. It was suspected that, in comparison to compound 7 (Figure 3), the methylation of hydroxyl at the R⁴(C5) site of biphenyl 9 favored to enhance inhibition ability.

2.6 Biphenyls with other bioactive abilities

2.6.1 Biphenyls with antioxidant activity

Through 2.2′-azinobis-(3-ethylbenzthiazoline-6-sulphonate) (ABTS) radical cation decolorization assay, the anti-oxidant property of biphenyls 20–22 (Figure 3) and biphenyls 25–26 (Figure 3) was evaluated. They all turned out to have good or moderate anti-oxidant possibilities, with IC₅₀ values of 7.78 µM, 38.3 µM, 8.78 µM, 7.84 µM and 29.57 µM for 20–22, 25–26, respectively. Ascorbic acid was employed as a positive control, with an IC₅₀ value of 7.70 µM. The compound 22 appears to be stronger than 21 in terms of anti-oxidant effect, which indicated the influence of the position of the methoxy group on the phenyl. Meanwhile, although the cytotoxicities of 25 and 26 were similar, it can be seen that the bioactive properties along with the anti-oxidant ability of 26 were certainly better than 25, which might be owing to the additional prenylated group on the phenyl of 26. (Tian et al., 2017).

2.6.2 Biphenyls with anti-inflammatory activity

Superoxide anion radical (O₂⁻) is a predecessor of other reactive oxygen species (ROS) and could be generated by activated neutrophils in response to stimuli (Reichl et al., 2001; Selloum et al., 2001). The over-production of O₂⁻ is a major cause for the development of inflammation and the scavenging of excess O₂⁻ is helpful for anti-inflammatory (Kroes et al., 1992; Salvemini et al., 2001). Experiments were performed to evaluate the efficacy of 3 (Figure 3) to suppress O₂⁻ generation induced by chemotactic peptide N-Formyl-L-methionyl (Met)-L-leucyl (Leu)-l-phenylalanine (Phe) (fMLP). The results shown that 3 presented effective inhibitory activity (IC₅₀ = 17.0 ± 2.8 μM) on O₂⁻ generation compared with positive control Ibuprofen (IC₅₀ = 27.5 ± 3.5 μM) (Chen et al., 2009). Furthermore, the anti-neuroinflammatory activity and neuroprotective effect of 3 were probed through measuring nitric oxide (NO) inhibition in lipopolysaccharide (LPS)-stimulated murine microglia BV2 cell and determining the secretion of nerve growth factor (NGF) in C6 glial cells, respectively (Kim et al., 2016; Suh et al., 2017). It indicated that the inhibitory activity of 3 to reduce the production of NO was potent with IC₅₀ values of 20.04 μM (IC₅₀ values of positive control L-NMMA = 21.82 μM), and the potency of 3 in offering more NGF for neuroprotection was moderate with NGF secretion levels of 125.76 ± 4.52% (the values of positive control 6-Shogaol = 158.18 ± 6.56%). In 2021, Kim and Yoon group presented a plausible mechanism of how 3 inhibited idiopathic pulmonary fibrosis (IPF), a lung disease generating lung scarring, in a bleomycin (BLM)-induced lung fibrosis mouse model. The research found out that 3 could depress the genes of inflammation and decrease macrophage activation marker genes, along with raising the expression level of anti-fibrotic markers in vivo. More significantly, it revealed that 3 could hamper the production of inflammatory cytokine-induced by transforming growth factor-β (TGF-β) from macrophages and the collagen synthesis from fibroblasts. These results demonstrated that 3 could play a protective role in lung fibrosis via its anti-inflammatory ability and it might be a promising therapy for IPF (Lee et al., 2021). Meanwhile, biphenyl 15 (Figure 3) could slightly exert anti-inflammatory activity against cyclooxygenase-2 (COX-2), an enzyme increased may due to inflammatory events, with the IC₅₀ value of 108.54 ± 0.42 μM (IC₅₀ values of positive control celecoxib = 18.08 ± 0.12 μM) (Ma et al., 2019).

2.6.3 Biphenyls with antimalarial activity, anti-diabetic activity, neurotrophic activity, or anti-virulence activity

Except for cytotoxicity and antibacterial, biphenyl 1 (Figure 3) showed weak antimalarial activity against Plasmodium falciparum with the IC₅₀ values of 39.4 µM against TM4/8.2, and 43.1 µM against K1CB1, respectively (Auranwiwat et al., 2021).

Furthermore, the anti-diabetic activity of biphenyl 4 (Figure 3) was assessed by testing the inhibition against α-glucosidase in parallel with the inducibility of glucose consumption by 3T3-L1 cells. It could be known that the α-glucosidase inhibitory activity of 4 was not determined. However, it can induce glucose consumption without causing toxic effects with IC₅₀ values of 34.7 µM. Metformin was used as positive control with an IC₅₀ value of 45.4 µM (Phukhatmuen et al., 2020).

A study examined the impact of biphenyl 31 (Figure 3) on neurite outgrowth in rat cortical neurons in a primary culture. It discovered that 1 μM of biphenyl 31 could stimulate neurite outgrowth. At this concentration, its activity could be comparable to the basic fibroblast growth factor (bFGF, 40 ng/mL). However, when 10 μM of 31 was administered to neural cells, all neurons were killed during 6 days culture period. The morphology and viability of cortical neurons at a lower dosage of 0.1 μM were not affected by 31. It was suggested that biphenyl 31 with a biaryl moiety containing alkenyl groups, would have some beneficial effects on the growth and survival of neurons (Takaoka et al., 2002).

5,6,6′-trihydroxy-[1.1′-biphenyl]-3.3’dicarboxylic acid (60) (Figure 6) is a new natural product from the ethyl acetate extract of Mesua ferrea L. flower. The purpose of the research was to identify chemical inhibitors for the protein secretion system of Salmonella enterica, which could be thought to be responsible for the pathogenicity of the bacteria. However, biphenyl 60 lacked sufficient activity to exert inhibitory effects (Zhang et al., 2019).

FIGURE 6

FIGURE 6. Structures of biphenyls 60–70.

2.7 Biphenyls with biological activity not investigated

2.7.1 Biphenyls with 2,3,4-trihydroxyl group

Garcinia kola Heckel, a plant that is native throughout West and West Central Africa, has been intensively studied for many years due to its edible seeds, usually known as bitter kola or male kola, and medicinal potential in the treatment of a variety of infectious disorders (Hussain et al., 1982; Iwu et al., 2002; Emmanuel et al., 2022). In 1994, Niwa group isolated and identified a 6-aryl-1,2-benzopyran derivative named garcipyran (61) from Garcinia Kola. (Figure 6) (Niwa et al., 1994a).

Two distinct biphenyls, in terms of garcifurans A-B (62–63) (Figure 6), from the methanol extract of Garcinia Kola roots collected in Nigeria were obtained by Niwa in 1994 (Niwa et al., 1994b). 62 and 63 were found to be the natural biphenyls claimed to possess a 5-arylbenzofuran nucleus for the first time. In order to validate the structure assignment of 63, the total synthesis of 63 was accomplished by Kelly group in 1997 (Scheme 4). The benzofuran 63d was prepared through condensation between 5-bromo-2-hydroxybenzaldehyde (63a) and bromo-malonic ester, followed by hydrolysis, and subsequent decarboxylation according to the literature (Kurdukar and Subba Rao, 1963). Next, arylstannanes 63g-63h were gained by lithiation and quenching with Bu₃SnCl or Me₃SnCl after the protection of 63e with CCl₂Ph₂. Afterward, the palladium-catalyzed coupling reaction between 63 g/h and 63d smoothly led to the precursors 63i in 18% yield and 44% yield respectively. Heating 63i under reflux in AcOH/H₂O to deprotect the protecting group achieved 63 in 73% yield (Kelly et al., 1997).

SCHEME 4

SCHEME 4. Synthesis of biphenyl 63.

2.7.2 Biphenyls with 2,4-dihydroxyl group

Calophymembranside A (64) (Figure 6), a novel biphenyl C-glycoside, was identified via chemical analysis of the traditional Chinese medicine Calophyllum membranaceum Gardn. et Champ. The structure of 64 has been determined to be 3,5-dihydroxybiphenyl-4-C-β-glucopyranoside. It is the only biphenyl C-glycoside described in this article (Zou et al., 2005). Furthermore, in 2006, chromatographic treatment of the dichloromethane extract of Clusia melchiorii Gleason trunk resulted in the discovery of a novel biphenyl, 2,2-dimethyl-5-hydroxi-7-phenylchromene (65) (Figure 6) (Teixeira et al., 2006). To the best of our knowledge, Garcinia mangostana L (mangosteen) is a tropical tree used as medicine in Southeast Asia over the past decades and has been well-known because of its fruit, which contains a great deal of polyphenolic xanthones exhibiting various biological effects in vitro (Obolskiy et al., 2009). The novel geranylated biphenyl derivative 3-hydroxy-4-geranyl-5-methoxybiphenyl (66) (Figure 6) was separated and elucidated from extracts of root bark, stem bark and the latex collected from the green fruits of Garcinia mangostana by Dharmaratne and co-workers (Dharmaratne et al., 2005). Meanwhile, multiflorabiphenyl A1 (67) (Figure 6) was found in the stem barks of Garcinia multiflora in 2013 (Jing et al., 2013). And 3.4′,5-trihydroxy-4-(3-hydroxy-3-methylbutyl) biphenyl (68) (Figure 6) and 3,5-dihydroxy-4-(3-hydroxy-3-methylbutyl) biphenyl (69) (Figure 6) were extracted and analyzed from Pentaphafangium Sofomonse Warb (Cotterill et al., 1974).

2.7.3 Others

After the separation of clusiaparalycolines A-C (30–31) (Figure 3), clusiaparalycoline D (70) (Figure 6) was isolated and elucidated during a re-examination of Clusia paralycola roots in 2002 (Delle Monache et al., 2002).

3 Conclusion and remarks

This review summarized the research progress of the biphenyls from Clusiaceae. The chemical structure and biological activity of 70 biphenyls were discussed in this review. Among these biphenyls, 52 compounds are found to present prenylated segment or mutative structures. Since the discovery of biphenyl 68–69 in Pentaphafangium Sofomonse, a total of 24 other Garcinia plants have been identified as sources of various biphenyls, in which Garcinia multiflora and Garcinia linii are the top two plants with the most biphenyls ascertained. The discovery of compounds 68–69 can be traced back to 1974 (Niwa et al., 1994a). And compound 3, which was obtained from other species (Erdtman et al., 1961), could be extracted and generated from different plants of Garcinia.

Biphenyls 1–70 have been subjected to extensive bioactive studies, primarily involving cytotoxicity, antibacterial and antivirus activity. Compound 6, a derivative of chemical 3 with one additional hydroxyl and methoxyl substitution, showed especially potential in repressing the proliferation of P388 cell line with IC₅₀ values of 0.36 μM (Mungmee et al., 2013). Therefore, its mechanism of action deserves to be further studied. The biphenyls 5, 16–18, 29, 31 and 37 also displayed promising cytotoxic effects, with IC₅₀ values below 10 μM (Table 1). With regard to the bioactive qualities of other biphenyls, compound 3 is effective at inhibiting Bacillus subtilis with MIC values of 3.12 μg/mL (Cortez et al., 2002). Both compounds 44 and 45 were tested for antimicrobial activity. The MIC values for 45 were nearly half of those for 44 (Table 2). The results implied that the structural change from a 2-hydroxy-3-methyl-but-3-enyl side chain to a 3-hydroxymethyl-3-methyl-but-2-enyl side chain in 44 would have a positive influence on their antibacterial activity. Furthermore, the structure-activity relationship of compounds 16–18 based on the anti-tobacco mosaic virus activities (Table 3) indicated that the cyclization of the prenylated chain to form a six-membered heterocyclic ring might enhance the anti-TMV abilities. And biphenyl 50 is the most promising compound to resist tobacco mosaic virus with the inhibition rates of 31.1 ± 3.5% (Hu et al., 2016). Moreover, the compounds also performed well in antiviral test, with compound 52 exhibiting great potential against rotavirus with TI values of 17.65 (Gao et al., 2018).

Most of the biphenyls collected in this review have free hydroxyl groups, which may undergo metabolic deactivation by forming sulfates or glucuronides. This could be one of the reasons that some of the biphenyls in this review have moderate or no bioactivity. For example, compound 12 had no cytotoxicity against the P-388 cell line, whereas compound 13 with a protected C2 hydroxyl group had moderate cytotoxicity. Similarly, compound 37 with a tetrahydropyran ring had better cytotoxicity against P-388 and HT-29 compared to compound 36 with same core structure. To avoid the metabolic deactivation, the free hydroxyl group on the phenyl may be replaced by its bio-isosterism in the drug design. In addition, biphenyls are known for atropisomerism and have been exploited in drug discovery. It should be noted that compounds 42 and 60 with bulky groups next to C6 and C7 may have this structural feature.

Although biphenyl is a kind of compound with simple structure, it is worth to be studied because of its easy modification and diverse bioactivity. Several biphenyls from Clusiaceae do possess outstanding activity in multiple fields, such as compounds 6, 50 and 52. Evaluation of the action mechanism of these promising biphenyls should be noted and endeavored in the future.

Author contributions

All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

Funding

We are grateful to the National Natural Science Foundation of China (81973438, 82174025), the NSFC-Joint Foundation of Yunnan Province (U1902213), Fok Ying-Tong Education Foundation (161039), the Guangdong Province Key Area R&D Program of China (2020B1111110003) for financial support.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The reviewer DZ declared a past co-authorship with the author HX to the handling editor.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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