Skip to main content
NCBI home page
Marine Life Science & Technology logoLink to Marine Life Science & Technology
. 2021 Sep 27;4(1):62–73. doi: 10.1007/s42995-021-00117-8

Structural diversity and biological activity of natural p-terphenyls

Guoliang Zhou 1, Tianjiao Zhu 1, Qian Che 1, Guojian Zhang 1,2,✉, Dehai Li 1,2,✉
PMCID: PMC10077223  PMID: 37073357

Abstract

p-Terphenyls are aromatic compounds consisting of a central benzene ring substituted with two phenyl groups, and they are mainly isolated from terrestrial and marine organisms. The central ring of p-Terphenyls is usually modified into more oxidized forms, e.g., para quinone and phenols. In some cases, additional ring systems were observed on the terphenyl-type core structure or between two benzene moieties. p-Terphenyls have been reported to have cytotoxic, antimicrobial, antioxidant and α-glucosidase inhibitory effects. In this review, we will mainly summarize the structural diversity and biological activity of naturally occurring p-Terphenyls referring to the research works published before.

Supplementary Information

The online version contains supplementary material available at 10.1007/s42995-021-00117-8.

Keywords: p-Terphenyl, Marine organism, Structure, Biological activity, Cytotoxic

Introduction

Terphenyls are a large class of aromatic compounds consisting of a chain of three benzene rings and most of them belong to p-terphenyls. These compounds are mainly produced by fungi and a small number of Actinomycetes. Chemical research on p-terphenyls could be traced back to 1877 (Liu 2006). Since then, over 230 p-terphenyls have been isolated and the number is still increasing (Li et al. 2018). Most of the natural p-terphenyls were isolated from terrestrial organisms. However, the sources and production of the terrestrial organisms are limited, and marine organisms are considered the most recent source of bioactive natural products in relation to terrestrial plants and nonmarine microorganisms (Jiménez 2018). An increasing number of p-terphenyls have also been found from the marine-derived microorganisms (Li et al. 2018; Liu 2006). p-Terphenyls usually possess an aromatic or a para quinone function in the central ring modified by different oxygen functions. Lateral benzene rings were usually modified by hydroxy groups, methoxy groups, and isoprenyl or O-isoprenyl groups at C-3, C-4, C-3″ or/and C-4″ (Fig. 1). In rare cases, p-terphenyls with additional ring systems, nitrogenous p-terphenyls, p-terphenyl glycosides and other types of p-terphenyls have also been reported. Consistent with the structural diversity, these compounds usually exhibit cytotoxic, antimicrobial, antioxidant and α-glucosidase inhibitory effects (Li et al. 2018).

Fig. 1.

Fig. 1

Open in a new tab

Structure of p-terphenyl

By referring to the literature published over the past 60 years, this review mainly summarizes the structural varieties of naturally occurring p-terphenyls, the biological activities of certain p-terphenyls and biogenetic origins, with intent to inspire the forthcoming natural product work within the scope of discovering polyphenyl containing bioactive structures. Differing from the reviews published before (Calì et al. 2003; Li et al. 2018; Liu 2006), the structures of p-terphenyls were divided into seven major categories based on the modification and substitutions types on the p-terphenyl core structure. Each category has been systematically discussed. In addition, the biosynthesis and chemical synthesis of p-terphenyls have also been discussed.

Chemical structures of p-terphenyl derivatives

p-Terphenyls are mainly divided into seven major categories based on the modification and substitution types on the p-terphenyl core structure. These types include p-terphenyls with a 1,2,4-trisubstituted ring B, p-terphenyls bearing four oxygenated functions at the central ring, benzofuranoid p-terphenyls, p-terphenyls with a para quinone function at the central ring, nitrogenous p-terphenyls, p-terphenyl glycosides and p-terphenyls of other groups.

p-Terphenyls with a 1,2,4-trisubstituted ring B

Based on the chemical nomenclature system, the central ring (ring B) of p-terphenyls which bears three oxygenated functions are formally named as a 1,2,4-trisubstituted ring. p-Terphenyls structures with a 1,2,4-trisubstituted ring B are widely distributed throughout various organisms including fungi, actinomycetes, and even lichen. In addition to the three substitutions on ring B, more oxidative modifications are possible with the results of hydroxy and methoxy substitutions, and further derivative processes like O-isoprenyl groups and isoprenyl groups could also take place on rings A and C at C-3, C-4, C-3″ or/and C-4″ (Fig. 1).

Compound 1 was isolated from Aspergillus candidus LINK strain CMI 16046, a fungus obtained from the Commonwealth Mycological Institute, Kew Gardens, England (Kurobane and Vining 1979). Compounds 2–4 were obtained from Aspergillus candidus, a toxic strain isolated from wheat flour collected at Saku-shi, Nagano Prefecture (Takahashi et al. 1976). Compounds 5–7 were also obtained from Aspergillus candidus RF-5672, which was isolated from a soil sample collected on Shodo Island, Kagawa Prefecture, Japan (Kamigauchi et al. 1998). Among these compounds, terphenyllin (2), 4″-deoxyterphenyllin (3) and 4″-deoxyterprenin (7) exhibited cytotoxicity against several cell lines. Compared with other p-terphenyls, 4″-deoxyterprenin (7) exhibited higher potency of cytotoxicity. Further studies showed that 4″-deoxyterprenin (7) selectively inhibited pyrimidine biosynthesis which accounted for its potent cytotoxic property (Fig. 2) (Stead et al. 1999).

Fig. 2.

Fig. 2

Open in a new tab

Structures of compounds 1–27

Compounds 8–10 were isolated from a cultured marine-derived fungus of Aspergillus candidus and showed cytotoxic activity against human epidermoid carcinoma KB cells with IC50 values of 8.5, 3.0 and 2.5 μg/ml, respectively. Their structures were elucidated on the basis of 2D NMR analysis (Fig. 2) (Wei et al. 2007).

Another four prenylated polyhydroxy-p-terphenyl metabolites (11–14) were obtained from Aspergillus taichungensis ZHN-7-07, a root soil fungus isolated from the mangrove plant Acrostichum aureum. They were tested for cytotoxicity against HL-60, A-549, and P-388 cell lines. Prenylterphenyllin A (12) exhibited moderate activities against all three cell lines (IC50 1.53–10.90 μmol/L), while 4″-dehydro-3-hydroxyterphenyllin (14) displayed moderate activities only against the P-388 cell line (IC50 2.70 μmol/L) (Fig. 2) (Cai et al. 2011).

Compounds 15–19 were isolated from an endophytic fungus Aspergillus sp. YXf3, isolated from the leaves of Ginkgo biloba. Compounds 18 and 19 represented a rare type of p-terphenyl structure characterized by the presence of a pyran ring with only these two cases reported. Compounds 18 and 19 showed antibacterial activities against X. oryzae pv. oryzicola Swings and E. amylovora with the same MIC values of 20 μg/ml (Fig. 2) (Yan et al. 2017).

Terferol (20) was isolated from the cultures of Streptomyces showdoensis. It was found to possess inhibitory activity against cAMP-PDE and cGMP-PDE from various rat tissues. The terferol (20) concentration required for 50% inhibition of cAMP-PDE was 0.82 μmol/L (Nakagawa et al. 1984). Butlerins A, B and C (21–23) were obtained from the lichen Relicina connivens and their structures were established by X-ray analysis as well as spectroscopic comparisons (Elix et al. 1995). 3,3″-Dihydroxy-6'-desmethylterphenyllin (24) was isolated from the sclerotia of Penicillium raistrickii and exhibited mild antiinsectan and antibacterial activity (Fig. 2) (Belofsky et al. 1998).

6′-Hydroxy-4,2′,3′,4″-tetramethoxy-p-terphenyl (25) was isolated from Nocardiopsis gilva YIM 90087, a halophilic actinomycete isolated from saline soil samples. Compound 25 showed antifungal activity against Candida albicans with a MIC of 32 μg/ml and antibacterial activity against Bacillus subtilis with a MIC value of 64 μg/ml. In addition, compound 25 also showed free radical scavenging capacity at 2 mg/ml (Tian et al. 2013). 2′-O-Methylprenylterphenyllin (26) and 3′-O-methylterphenyllin (27) were obtained from an endophytic fungus Aspergillus sp. YXf3 isolated from the leaves of Ginkgo biloba. Among them, compound 26 showed antibacterial activity against X. oryzae pv. oryzicola Swings and E. amylovora with the same MIC values of 20 μg/ml (Fig. 2) (Yan et al. 2017).

p-Terphenyls bearing four oxygenated functions at the central ring

Mushrooms have been regarded as a significant source of bioactive secondary metabolites. Some basidiomycetes in the genus of Paxillus, Thelephora, Hydnellum and Sarcodon and cultures of mushrooms are discovered to be fruitful producers of p-terphenyls. Compounds 28–80 were all isolated from mushrooms. These compounds possess four substitutions on ring B, among which, at least one was esterified.

Leucomentins-2-4 (28–30) were isolated from Paxillus atrotomentosus and these compounds constitute esters of leucoatromentin with (2Z,4S,5S)-4,5-epoxy-2-hexenoic acid in the central ring. Another two similar p-terphenyls (31 and 32) as well as leucomentin-2 (28) and leucomentin-4 (30) were found from Paxillus panuoides in the search for neuroprotective compounds from mushrooms against glutamate-induced injury in primary mouse cortical cell cultures. Leucomentins showed potent inhibition of lipid peroxidation and H2O2 neurotoxicity. Further studies suggested iron-mediated oxidative damage in these processes. Leucomentins can chelate iron when DNA is presented with iron and H2O2 and inhibit DNA single strand breakage (Fig. 3) (Holzapfel et al. 1989; Lee et al. 2003).

Fig. 3.

Fig. 3

Open in a new tab

Structures of compounds 28–60

Curtisians A–D (33–36) were obtained from the methanolic extract of the fruit body of Paxillus curtisii, collected at Keryoung mountain in Chungnam Province, Korea (Yun et al. 2000). Curtisians E–Q (37–49) were all isolated from the methanolic extract of fruit bodies of the basidiomycete Paxillus curtisii, collected in Kyoto City, Japan (Quang et al. 2003a, b, c). Curtisians R–V (50–54) were isolated from the fruiting bodies of Paxillus curtisii, collected at Odae National Parks in Korea (Fig. 3) (Lee et al. 2009).

These compounds (33–54) possessing acetyl, benzoyl, butyryl, phenylbutyryl, 3-hydroxybutyryl and 3-acetoxybutyryl substituents at the central ring were all obtained from the fruiting bodies of Paxillus curtisii. The absolute configurations of the 3-acetoxybutyryl and 3-hydroxybutyryl were determined to be S through chemical reactions and gas chromatography-mass spectroscopy (GC–MS) analysis (Quang et al. 2003b). Curtisians A, B, C and D (33–36) exhibited inhibitory activity against lipid peroxidation with IC50 values of 0.15, 0.17, 0.24 and 0.14 μg/ml, respectively. Curtisians I-V (41–54) were reported to exhibit antioxidant activity (Fig. 3) (Lee et al. 2009; Quang et al. 2003a, c; Yun et al. 2000).

Ganbajunins C–G (55–59) were first isolated from the fruiting bodies of the basidiomycetes Thelephora ganbajun, obtained at Wudin county in Yunnan province, P. R. China. Ganbajunin C (55) and ganbajunin E (57) were also detected in the inedible mushroom Thelephora aurantiotincta (Hu et al. 2001; Hu and Liu. 2001, 2003; Quang et al. 2003d, e). Ganbajunins C–E (55–57) were isomers with two phenylacetyloxy groups located on the p-terphenyl core structure (Hu et al. 2001). Thelephorin A (60) was first obtained from the fruiting bodies of the mushroom Thelephora vialis, collected in Yamagata Prefecture, Japan and also detected from the inedible mushroom Thelephora aurantiotincta (Quang et al. 2003d; Tsukamoto et al. 2002). Thelephorin A (60) exhibited antioxidative activity with an EC50 value of 0.028 mol/L, which was 10 times as active as ascorbic acid (Fig. 3) (Tsukamoto et al. 2002).

Aurantiotinin A (61) was isolated from the fruiting bodies of the basidiomycete Thelephora aurantiotincta, collected at Simao in Yunnan Province China (Hu and Liu 2003). The structure of aurantiotinin A contained a phenylacetyloxyl group, four hydroxyl groups and an unusual group as shown in Fig. 4. Its structure was established by spectral method and further confirmed by treating with phenylboronic acid. Thelephantins A–C (62–64) were three benzoyl p-terphenyl derivatives from the inedible mushroom Thelephora aurantiotincta, collected in Shizenhogo-center, Saeki-cho, Wake-gun, Okayama, Japan. Thelephantins D–G (65–68) were isolated from the methanolic extract of fruit bodies of the thelephoraceous basidiomycete Thelephora aurantiotincta, collected in the Forest Park in Okayama Prefecture, Japan. These compounds possess groups including butyroxyl group, benzoyl group, n-hexanoxyl group, p-hydroxylbenzoyl group, 3,4-dimethyl-pentanoxyl group or/and phenylacetyloxy group at C-2′ and C-5′ on the central ring (Fig. 4) (Quang et al. 2003d, e).

Fig. 4.

Fig. 4

Open in a new tab

Structures of compounds 61–80

Thelephantins J–L and thelephantin N (69–72) were isolated from the fruiting bodies of the inedible mushroom Hydnellum caeruleum, collected in Yatugatake mountain, Shinshou, Nagano Prefecture, Japan (Fig. 4). They shared the same ring A and ring C as shown in Fig. 4. Among them, Compounds 69–71 possess two or three benzoyl groups at the central aromatic ring while compound 72 possesses one rare 3-pyridinecarboxyl group at the central aromatic ring. Their structures were determined by high-resolution MS, 2D NMR and chemical reactions (Fig. 4) (Quang et al. 2004).

Compounds 73 and 74 were isolated from the mushroom Thelephora aurantiotincta, collected in Yunnan province of China. They were reported to have cancer-selective cytotoxicity. A preliminary structure–activity relationship revealed that the O-dihydroxy substitution of the central benzene ring was necessary for the cytotoxicity. The cytotoxicity of compound 73 was attributed to cell cycle arrest at the G1 phase via cell cycle-mediated genes (Fig. 4) (Norikura et al. 2013).

Compounds 75–77 were isolated from the fruiting bodies of Hydnellum concrescens, collected in the Jiuzhai Valley in the Sichuan Province of China. These compounds exhibited inhibitory activity against α-glucosidase with the IC50 values of 0.99, 3.11 and 5.16 μmol/L, respectively (Wang et al. 2014). Kinetic analysis of α-glucosidase indicated that concrescenin A (75) and concrescenin B (76) inhibited the activity of α-glucosidase in a noncompetitive fashion with the Ki values of 0.02 and 0.21 μmol/L. A preliminary structure–activity relationship revealed that the substitution of the benzoyl moiety at the central ring had a great influence on the activity. In the same year, compounds 78–80 were obtained from the edible mushroom Sarcodon leucopus collected in Tibet. They were found to have antioxidant effects by protecting DNA strands from free radical-induced cleavage at 200 μmol/L (Fig. 4) (Ma et al. 2014).

Benzofuranoid p-terphenyls

p-Terphenyls possessing an ether bond which bridged C-2 (Ring A) and C-2′ (Ring B) and possessing two or three oxygen functions at the middle ring were named as benzofuranoid p-terphenyls.

Compounds 81–88 were mainly isolated from Aspergillus sp. These compounds possess two methoxy groups assigned at C-3′ and C-6′. Candidusins A and B (81, 82) were first isolated from the culture of Aspergillus candidus and exhibited inhibitory activity against the development of sea urchin embryos. Further study revealed that candidusins A and B could inhibit DNA and RNA synthesis, but not protein synthesis which probably accounted for cytotoxicity. Candidusins A and B also exhibited antibacterial activity against Bacillus subtilis (Fig. 5) (Kobayashi et al. 1982).

Fig. 5.

Fig. 5

Open in a new tab

Structures of compounds 81–97

Candidusin C (83) was isolated from the fungus Aspergillus campestris (Rahbak et al. 2000). Prenylcandidusins A–C (84–86) belonging to prenylated polyhydroxy-p-terphenyls were obtained from Aspergillus taichungensis ZHN-7-07, a root soil fungus isolated from the mangrove plant Acrostichum aureum (Fig. 5). Prenylcandidusin B (85) displayed moderate activities against the P-388 cell line with an IC50 value of 1.57 μmol/L (Fig. 5) (Cai et al. 2011).

4″-Deoxycandidusin A (87) and 4,5-dimethoxycandidusin A (88) were isolated from Aspergillus sp. YXf3, an endophytic fungus obtained from a healthy leaf of Ginkgo biloba collected in the campus of Nanjing University (Nanjing, P. R. China). 4″-Deoxycandidusin A displayed moderate neuraminidase inhibitory activity with an IC50 value of 9.05 μmol/L (Fig. 5) (Guo et al. 2012).

Compounds 89–97 were also benzofuranoid p-terphenyls with two or three oxygen functions including phenylacetoxy, acetoxy and p-hydroxy-benzoyl groups assigned at the middle ring.

Arenarin A (89) was a cytotoxic metabolite from the sclerotia of Aspergillus arenarius and exhibited cytotoxicity against human tumor cell lines. Arenarin A also showed mild activity in feeding assays against the dried-fruit beetle Carpophilus hemipterus (Oh et al. 1998). Compounds 90 and 91 were obtained from the sclerotia of Penicillium raistrickii which was originally isolated from moldy cotton yarn in Great Yarmouth, Great Britain (Fig. 5) (Belofsky et al. 1998).

Ganbajunin B (92) was first isolated from the fruiting bodies of the basidiomycete Thelephora ganbajun, collected in Yunnan Province, China (Hu et al. 2001) and was also detected in the fruiting bodies of the mushroom Thelephora terrestris (Rudulovic et al. 2005). Thelephantin H (93) possessing a phenylacetoxyl group and a p-hydroxylbenzoyl group at the central ring was isolated from the inedible mushroom Thelephora aurantiotincta, collected in the Forest Park in Okayama Prefecture, Japan (Quang et al. 2003e). Thelephantin M (94) possessing two benzoyl groups at the central ring was obtained from the methanolic extract of the fruiting bodies of the inedible mushroom Hydnellum caeruleum, collected in Yatugatake mountain, Shinshou, Nagano Prefecture, Japan (Fig. 5) (Quang et al. 2004).

Terrestrins E–G (95–97) were isolated from the methanol extract of fruiting bodies of the Japanese inedible mushroom Thelephora terrestris, collected in Aichi Prefecture, Japan. These compounds also possess ester groups including a phenylacetoxy group, an acetoxy group and/or a p-hydroxy-benzoyl group at the central ring (Fig. 5) (Rudulovic et al. 2005).

p-Terphenyls with a para quinone function at the central ring

Compounds 98–123 were all isolated from fungi, mainly mushrooms. The central ring of these p-terphenyls is usually oxidized into quinone and substituted with additional oxygen functions as well.

Aurantiacin (98) was isolated from the fungus Hydnum aurantiacum (Gripenberg 1958) and ascocorynin (99) was isolated from the fungus Ascocoryne sarcoides which was obtained from a spore print of its conidial state (Quack et al. 1982). Flavomentins A–C (100–102) possessing mono- or diesters which formed from (2Z,4E)-2,4-hexadienoic acid or (2Z,4S,5S)-4,5-epoxy-2-hexenoic acid were isolated from the mushroom Paxillus atrotomentosus and Paxillus panuoides (Fig. 6) (Bsel et al. 1989).

Fig. 6.

Fig. 6

Open in a new tab

Structures of compounds 98–123

2-O-Methylatrometin (103) and ganbajunin A (104) were isolated from fruiting bodies of the basidiomycete Thelephora ganbajun, collected at Wudin country in Yunnan Province, China. 2-O-Methylatrometin (103) was also detected in the inedible mushroom Thelephora aurantiotincta, collected in Shizenhogo-center, Saeki-cho, Wake-gun, Okayama, Japan (Fig. 6) (Hu et al. 2001; Quang et al. 2003d).

Atromentin (105) was isolated from fruiting bodies of the basidiomycete Thelephora aurantiotincta and also discovered in the fungus Boletopsis leucomelaena and other fungus (Hu and Liu 2003; Jägers et al. 1987a; Liu 2006). Thelephantin I (106) was obtained from the methanolic extract of the fruiting bodies of the inedible mushroom Hydnellum caeruleum, collected in Yatugatake mountain, Shinshou, Nagano Prefecture, Japan (Fig. 6) (Quang et al. 2004).

Leucomelone (107) was isolated from the edible mushroom Sarcodon leucopus collected in Tibet and was found to have antioxidant effects. Leucomelone (107) also showed strong α-glucosidase inhibitory activity with an IC50 value of 3.53 μmol/L (Ma et al. 2014). Rickenyl E (108) was obtained from the fungus Hypoxylon rickii MJF10324, collected from the Caribbean island Martinique and exhibited antioxidative activity as well as moderate cytotoxicity (Fig. 6) (Kuhnert et al. 2015).

Compounds 109–113 were obtained from Floricola striata, an endolichenic fungus isolated from the lichen Umbilicaria sp., collected from Mount Jiaozi of Yunnan Province in China. Among them, floricolins B–D (109–111) exerted fungicidal activity against Candida albicans. Further antifungal investigations with floricolin C (110) revealed the mode of action of inducing high fluidity and permeabilization of the plasma membrane (Fig. 6) (Li et al. 2016).

In compounds 114–123, the central ring was oxidized into a para quinone and rings B and C were bridged by an ether bond through C-2 to C-2′. Cyclovariegatin (114) was identified as the cap skin pigment of Suillus grevillei var. badius (Edwards and Gill 1973). Cycloleucomelone (115) was isolated from fruit bodies of the basidiomycete Boletopsis leucomelaena (Jägers et al. 1987b). Compounds 116–120 were obtained from Anthracophyllum discolor and A. archeri (Jägers et al. 1987a). Floricolins E–G (121–123) were isolated from the extract of the endolichenic fungus Floricola striata (Fig. 6) (Li et al. 2016).

Nitrogenous p-terphenyls

Compounds (124–135) belonging to unusual nitrogenous p-terphenyl derivatives were all isolated from fruiting bodies of the basidiomycete Sarcodon leucopus and Sarcodon scabrosus. They possess an N-oxide moiety and a hydroxamic acid function in a 1,4-diazine ring, which were bonded to positions 3 and 4 of the external dihydroxylated ring of the p-terphenyl core.

Sarcodonin (124) was isolated from fruiting bodies of the basidiomycete Sarcodon leucopus, collected on the slopes of Mount Etna near Catania. Its structure was determined by use of an array of spectroscopic techniques, chemical degradation, ROESY data and molecular mechanics (MM +) calculations. Sarcodonin (124) exhibited moderate cytotoxicity against KB and P-388 tumor cells with ED50 values of 10.0 and 27.0 μg/ml, respectively (Fig. 7) (Geraci et al. 2000).

Fig. 7.

Fig. 7

Open in a new tab

Structures of compounds 124–135

Compounds 125–132 were isolated from fruiting bodies of the basidiomycete Sarcodon leucopus (Cali et al. 2004). Their structures were established by spectral analysis and chemical conversions. Sarcoviolin α (131) and episarcoviolin α (132) were obtained as a mixture. Sarcodonin (124), sarcodonins α (125), sarcodonin γ (127), episarcodonin (128) and the mixture of sarcoviolin α (131) and episarcoviolin α (132) were found to be active in assays against tumor cells (Cali et al. 2004). Sarcodonin δ (133) was isolated from fruiting bodies of the basidiomycete Sarcodon scabrosus, collected at Ailao Mountain of Yunnan Province, China (Ma and Liu 2005). Its structure was elucidated by spectral and chemical methods (Fig. 7).

Sarcoviolin β (134) and episarcoviolin β (135) as well as sarcodonins α (125), episarcodonin (128) and episarcodonin α (129) were obtained from the edible mushroom Sarcodon leucopus collected in Tibet. These compounds exerted antioxidant effects, and further study indicated that they could protect DNA strands from free radical-induced cleavage at 200 μmol/L. Sarcoviolin β and episarcoviolin β were also found to have strong α-glucosidase inhibitory activity with IC50 values of 0.58 and 1.07 μmol/L, respectively (Fig. 7) (Ma et al. 2014).

p-Terphenyl glycosides

Compounds 136–142 belong to p-terphenyl glycosides. These compounds possess a common terphenyl-type core structure with a glycoside unit attached via a β-linkage. To date, only 7 p-terphenyl glycosides were isolated.

Terfestatin A (136) was the first p-terphenyl glycoside isolated from Streptomyces sp. F40. This terfestatin A-producing organism was isolated from soil collected at Okayama city, Japan. Terfestatin A was also obtained from solid cultures of an isolate of Gliocladium sp., a fungus collected from a sample of C. sinensis that was collected in Linzhi, Tibet. It possesses a common terphenyl-type core structure, but with a glucose unit attached via a β-linkage. Its structure was determined by spectroscopic analyses, chemical degradation, and total synthesis (Guo et al. 2007; Hayashi et al. 2008; Yamazoe et al. 2004). Terfestatin A was an auxin-signaling inhibitor and its binding model was also proposed based on a structure–activity study (Hayashi et al. 2008; Yamazoe et al. 2004).

Gliocladinin B (137) was also isolated from Gliocladium sp. Differing from terfestatin A, gliocladinin B has methoxy substituents at C-4 and C-4″ and showed modest antimicrobial activity against Staphylococcus aureus. In addition, it also displayed inhibitory effects on the growth of human tumor cell lines, HeLa and HCT116, with IC50 values of 40 and 80–100 μmol/L, respectively (Fig. 8) (Guo et al. 2007).

Fig. 8.

Fig. 8

Open in a new tab

Structures of compounds 136–142

Echosides A–E (138–142) were obtained with the aid of chromophore-guided fractionation from Streptomyces sp. LZ35ΔgdmAI, isolated from the intertidal soil collected at Jimei, Xiamen, China. Echoside D (141) and echoside E (142) bear a rare benzothiazole moiety in the terphenyl-type core structure. Compounds 138–140 showed different degrees of inhibitory activity against topoisomerases. Compounds 138 and 140 also exhibited modest activity against Bacillus subtilis strain ACCC 11060 and Mycobacterium smegmatis strain MC2 155 at 30 μg/disc (Fig. 8) (Deng et al. 2014).

p-Terphenyls of other groups

Compounds 143–195 are p-terphenyls with diversified substructures including 4,5-methylenedioxy ring B, a spiro structure in which a 4,5-dihydroxy-1,2-benzoquinone is linked to a lactone acetal unit, benzobisbenzofuranoid moieties, ring open products, a benzothiazole moiety, and p-terphenyl structures with a highly oxidized B ring and dimerized p-terphenyls.

Compounds 143–146 were isolated from Punctularia atropurpurascens. Compound 143 possesses a 3,6-diphenyl-4,5-methylenedioxy-1,2-benzoquinone structure. The structure of compound 145 was confirmed by synthesis from atromentin (105). Compounds 143, 144 and 146 were reported to show weak antibacterial and cytotoxic activity (Supplementary Fig. S1) (Anke et al. 1984; McMorris and Anchel 1963, 1967).

Spiromentins A–D (147–150) were obtained from the cultures of Paxillus atrotomentosus (Supplementary Fig. S1). They possess a unique spiro structure in which a 4,5-dihydroxy-1,2-benzoquinone is linked to a lactone acetal unit (Bsel et al. 1989). Spiromentins E–J (151–156) are derivatives of benzene-1,2,4,5-tetraol isolated from the fungus Paxillus atrotomentosus (Supplementary Fig. S1) (Buchanan et al. 1995). Compounds 157–163 were all obtained from the fungus Peniophora sanguinea. Their structures were confirmed by X-ray analysis (Supplementary Fig. S2) (Gripenberg and Martikkala 1969; Gripenberg 1971; Gripenberg et al. 1979a, b; 1980).

Corticins A–C (164–166) belonging to benzobisbenzofuranoid metabolites were obtained from the fungus Corticium caeruleum (Briggs et al. 1976). Hexamethyl ether of leuco-thelephoric acid (167) was isolated from the basidiomycete Corticium caeruleum. Its structure was determined by direct method using counter-measured X-ray data (Silverton 1973; Weisgraber et al. 1972). Leuco-peracetates of thelephoric acid (168) possesses six acetyl groups and was isolated from the fruiting bodies of the basidiomycete Boletopsis leucomelaena (Jägers et al. 1987b). Polyozellin (169) was obtained from Polyozellus multiplex, collected in mountain Odae, Korea. It was an inhibitor of prolyl endopeptidase. This compound also significantly promoted differentiation of HL-60 human promyelocytic emia cells. Further in vivo study is needed to evaluate its potential as a cancer preventive agent (Hwang et al. 1997; Kim et al. 2004). Polyozellic acid (170) and thelephoric acid (171) were isolated from the mushroom Polyozellus multiplex, collected in Yamanashi Prefecture, Japan. These two compounds showed inhibitory effects on proliferation, tubule formation, and invasion of human umbilical vein endothelial cells. The quinone moiety within these molecules possibly contributes to their antiangiogenesis activity (Supplementary Fig. S2) (Kim et al. 2004; Nagasawa et al. 2014).

Compounds 172 and 173 were isolated from Hydnellum ferrugineum and H. concrescens. The structure of 172 was confirmed by single-crystal X-ray analysis (Gripenberg 1981, 1974). Arenarins B and C (174, 175) were isolated from the sclerotia of Aspergillus arenarius (NRRL 5012), obtained from soil collected in Mysore, India. Arenarins B and C were the first examples possessing an additional carbocyclic ring attached to the terphenylquinone core structure. These two compounds showed mild activity in feeding assays against the fungivorous beetle Carpophilus hemipterus. In addition, arenarin B showed cytotoxicity against human tumor cells in the NCI’s 60-cell line panels, displaying a GI50 value of 3.8 μg/ml (Supplementary Fig. S2) (Oh et al. 1998).

Compounds 176–182 were obtained from Floricola striata, an endolichenic fungus isolated from the lichen Umbilicaria sp., collected from Mount Jiaozi of Yunnan Province in China (Li et al. 2016). Betulinan B (177) was also found from the endolichenic fungus Lenzites betulina and inhibited lipid peroxidation with an IC50 value of 2.88 μg/ml (Lee et al. 1996). Compounds 179–182 were enantiomeric mixtures, and their configurations were established by single-crystal X-ray diffraction analysis (Supplementary Fig. S2) (Li et al. 2016).

Gliocladinin A (183) was collected from solid cultures of Gliocladium sp. (XZC04-CC-302), isolated from a sample of Cordyceps sinensis that was collected in Linzhi, Tibet. Gliocladinin A showed modest antimicrobial activity against Staphylococcus aureus as well as inhibitory effects on the growth of two human tumor cell lines, HeLa and HCT116 (Supplementary Fig. S2) (Guo et al. 2007).

Rings A and C of compounds 184–186 were all or partly replaced by an α, β-unsaturated-γ-lactone ring instead of the aromatic ring (Guo et al. 2012; Liu et al. 2012). Terphenolide (184) was produced from Aspergillus sp. YXf3, an endophytic fungus isolated from a healthy leaf of Ginkgo biloba collected in the campus of Nanjing University (Nanjing, P. R. China). Terphenolide (184) displayed moderate neuraminidase inhibitory activity with an IC50 value of 5.79 μmol/L (Guo et al. 2012). Compounds 185 and 186 were isolated from Aspergillus sp. (Supplementary Fig. S2) (Liu et al. 2012).

Compound 187 was collected from halophilic actinomycete Nocardiopsis gilva YIM 90087, isolated from saline soil samples using the modified International Streptomyces Project (ISP) 5 medium supplemented with 15% NaCl (w/v). It was a novel p-terphenyl derivative bearing a benzothiazole moiety (Supplementary Fig. S2) (Tian et al. 2013).

Allantonaphthofurans A–C (188–190) were isolated from submerged cultures of the ascomycete Allantophomopsis lycopodina. The NMR-based structure elucidation was challenging due to the low H/C ratio. Structures were verified by comparison of recorded and computed NMR chemical shifts from quantum chemical calculations of several constitutional isomers and were further analyzed with the aid of DP4 and DP4 + probabilities (Supplementary Fig. S2) (Andernach et al. 2016).

Hawaiienols A–D (191–194) were obtained from cultures of Paraconiothyrium hawaiiense, a fungus isolated from a Septobasidium sp.-infected Diaspidiotus sp. collected from Cang Mountain, Dali, Yunnan Province, China. Their absolute configurations were assigned by single-crystal X-ray diffraction analysis and electronic circular dichroism calculations. Hawaiienol A (191) possesses a unique 4,7-dioxatricyclo [3.2.1.03,6]octane moiety in its p-terphenyl skeleton and showed significant activity against SH-SY5Y cells, with an IC50 value of 9.3 μmol/L while hawaiienols B-D (192–194) did not show detectable activity at 50 μmol/L (Supplementary Fig. S2) (Ren et al. 2018).

Biosynthesis and chemical synthesis of p-terphenyls

The basic skeletons of p-terphenyls are reported to be derived from arylpiruvic acids (shikimate-chorismate pathway) (Calì et al. 2003; Dewick 1994; Liu 2006). The mechanism of biosynthetic pathway has been established by feeding 13C- and 14C-labeled precursors to cultures that p-terphenyls were accomplished by initial condensation between two molecules of either phenylpyruvic acid or phenylalanine (Dewick 1994; Li et al. 2018). Atromentin represents the key intermediate of a large family of homobasidiomycete secondary metabolites, whose structural diversity is generated by numerous modifications. It is also considered to be an important intermediate of many p-terphenyl derivatives, including cycloleucomelone, thelephoric acid and some leucomentins (Schneider et al. 2008). The atromentin biosynthesis genes and enzymes in the homobasidiomycete Tapinella panuoides has been illuminated by Schneider in 2008. In this fungus, the tri-domain enzyme atromentin synthetase AtrA adenylated and dimerized 4-hydroxyphenylpyruvic acid into atromentin while 2-oxoglutarate aminotransferase AtrD provided the substrate for the dimerization step (Schneider et al. 2008). The echosides (138–142) biosynthetic gene cluster has also been identified from Streptomyces sp. LZ35. By analyzing the genome draft of strain LZ35, the ech gene cluster was identified to be responsible for the biosynthesis of echosides, which was further confirmed by gene disruption and HPLC analysis. Meanwhile, the echA-gene was identified as a polyporic acid synthetase and biochemically characterized in vitro (Zhu et al. 2014).

The chemical synthesis of p-terphenyls has also been extensively studied. Among them, coupled reactions and cyclization reactions are more commonly used, and the reaction mechanisms of these two methods are relatively mature (Ho et al. 2013; Kawada et al. 1998; Qiu et al. 2013b; Shi et al. 2015; Tsuji et al. 2008; Zhang et al. 2009). The Suzuki reaction is a typical coupling reaction. This reaction uses a Pd complex to catalyze the reaction of arylboronic acid and aryl halide to obtain the basic skeleton of p-terphenyls (Supplementary Fig. S3) (Kawada et al. 1998). For example, to analyze the in vitro anticancer activities of p-terphenyls, Qiu and co-workers reported the chemical synthesis of a series of p-terphenyl derivatives based on the palladium (O)-catalyzed aryl–aryl coupling reactions. These compounds were all prepared from 4-hydroxyphenyl boronic acid or 4-methoxyphenylboronic acid via Suzuki cross-coupling reactions. Taking 4-hydroxyphenyl boronic acid as an example, a cross-coupling Suzuki reaction between 4-hydroxyphenyl boronic acid and 1,4-dibromobenzene or 1,4-dibromo-2,3-dimethoxybenzene led to the production of the corresponding biphenyl derivatives, which underwent another Suzuki cross-coupling reaction with the (3,4-dimethoxyphenyl)boronic acid to give the key p-terphenyl skeleton intermediates. The p-terphenyls derivatives could then be formed from the intermediates by a series of demethylation reactions (Supplementary Fig. S3) (Qiu et al. 2013b). The Diels–Alder reaction is also a useful cyclization reaction to construct the middle ring of p-terphenyls by [4 + 2] annulations. Inspired by the one-pot benzannulation of Diels–Alder reaction between the trans-1,2-dichloroethene and 1,3-butadiene, Ho and co-workers reported a very convenient one-pot benzannulation of Diels–Alder reaction to produce a series of p-terphenyls. In this method, heating a mixture of 1,4-diphenyl-1,3-butadiene and trans-1,2-dichloroethene in a high-pressure sealed glass tube at a certain temperature finally afforded the p-terphenyl structure (Supplementary Fig. S4) (Ho et al. 2013). Other methods including Ullmann reactions (Hassan et al. 2001), Stille reactions (Qiu et al. 2013a), [2 + 2 + 2] cycloadditions (Tsuji et al. 2008) and Cs2CO3-promoted synthesis (Xie et al. 2019) can be also used to obtain p-terphenyls.

Conclusions

This review summarized 194 p-terphenyls, and most of them were obtained from the fruiting bodies and cultures of mushrooms. Compounds 1–19 with 1,4-dimethoxy-2-hydroxy ring B or compounds 81–88 possessing an ether bond which bridged C-2 and C-2′ and two methoxy groups assigned at C-3′ and C-6' were mainly obtained from the genus Aspergillus, while p-terphenyls with ester groups were mainly found from mushrooms. Compounds (124–135) possessing a complex nitrogenous system were all isolated from fruiting bodies of the basidiomycete Sarcodon leucopus and Sarcodon scabrosus (Deng et al. 2014). Recently, an increasing number of p-terphenyl with novel structures were also isolated from marine-derived microbes associated with marine sediment, mangrove and intertidal soil (Cai et al. 2011; Deng et al. 2014; Wei et al. 2007). For example, among the reported seven p-terphenyl glycosides, five (138–142) were obtained from marine-derived fungus bearing a rare benzothiazole moiety. With the development of science and technology, people now have the ability to obtain marine organisms living in deep areas. We think more marine-derived p-terphenyls with novel structures will be found in the future. p-Terphenyls showed a variety of biological activities, including cytotoxic, antimicrobial, antioxidant and α-glucosidase inhibitory effects. In addition, a few p-terphenyls were reported to have anti-insectan activity, neuraminidase inhibitory activity, neuroprotective activity and inhibitory activity on auxin signaling. Among these activities, cytotoxicity is the most widely studied and the mechanisms of certain p-terphenyls have also been elucidated including inhibiting pyrimidine biosynthesis, cell cycle arrest at the G1 phase via cell cycle-mediated genes and inhibiting DNA and RNA synthesis. Based on the above analysis, we can also find some structure and activity relationships. For example, p-terphenyls with a 1,2,4-trisubstituted ring B, especially for compounds 1–19, tend to exhibit cytotoxic activities. Compounds 73 and 74 showed cancer-selective cytotoxicity and a preliminary structure–activity relationship revealed that the O-dihydroxy substitution of the central benzene ring was necessary for the cytotoxicity. Compounds 75–77 exhibited inhibitory activity against α-glucosidase and a preliminary structure–activity relationship revealed that the substitution of the benzoyl moiety at the central ring had a great influence on the activity. It has been reported that some p-terphenyls exhibit significant biological activities, especially the cytotoxic activities, and they are also easily synthesized since they contain few chiral centers. However, to our knowledge, few in vivo studies have been performed with p-terphenyls. We think the in vivo studies are also important for us to better understand pharmacological activity and to design relevant lead compounds.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 733 KB) (732.9KB, docx)

Acknowledgements

This work was financially supported by the NSFC-Shandong Joint Fund (U1906212, U1606403), the Pilot National Laboratory for Marine Science and Technology (2018SDKJ0401-2, 2016ASKJ08-02), the National Natural Science Foundation of China Major Project for Discovery of New Leading Compounds (81991522), the National Science and Technology Major Project for Significant New Drugs Development (2018ZX09735004), the Major National Science and Technology Projects of the Ministry of Science and Technology (81991522), the Fundamental Research Funds for the Central Universities (201941001), Project funded by China Postdoctoral Science Foundation (2017M622286), and the Taishan Scholar Youth Expert Program in Shandong Province (tsqn201812021).

Author contributions

DL, GZ, QC and TZ designed this review. GZ wrote the article. All authors read and approved the final manuscript.

Declarations

Conflict of interest

The authors declare no conflicts of interest.

Animal and human rights statement

This article does not contain any studies with human participants or animals performed by any of the authors.

Contributor Information

Guojian Zhang, Email: zhangguojian@ouc.edu.cn.

Dehai Li, Email: dehaili@ouc.edu.cn.

References

  1. Andernach L, Sandjo LP, Liermann JC, Schlämann R, Richter C, Ferner JP, Schwalbe H, Schüffler A, Thines E, Opatz T. Terphenyl derivatives from Allantophomopsis lycopodina. J Nat Prod. 2016;79:2718–2725. doi: 10.1021/acs.jnatprod.6b00690. [DOI] [PubMed] [Google Scholar]
  2. Anke H, Casser I, Herrmann R, Steglich W. New terphenylquinones from mycelial cultures of Punctularia atropurpurascens (basidiomycetes) Z Naturforsch. 1984;39:695–698. doi: 10.1515/znc-1984-7-801. [DOI] [Google Scholar]
  3. Belofsky GN, Gloer KB, Gloer JB, Wicklow DT, Dowd PF. New p-terphenyl and polyketide metabolites from the sclerotia of Penicillium raistrickii. J Nat Prod. 1998;61:1115–1119. doi: 10.1021/np980188o. [DOI] [PubMed] [Google Scholar]
  4. Briggs LH, Cambie RC, Dean IC, Hodges R, Ingram WB, Rutledge PS. Chemistry of fungi. XI corticins A, B, and C, benzobisbenzofurans from Corticium caeruleum. Aust J Chem. 1976;29:179–190. doi: 10.1071/CH9760179. [DOI] [Google Scholar]
  5. Bsel H, Bresinsky A, Geigenmüller G, Herrmann R, Kilpert C, Steglich W. Flavomentine und spiromentine, neue terphenylchinon-derivate aus PaxiZZus atrotomentosus und P. panuoides (Boletales) Liebigs Ann Chem. 1989;8:803–810. doi: 10.1002/jlac.198919890228. [DOI] [Google Scholar]
  6. Buchanan MS, Hashimoto T, Takaoka S, Asakawa Y. (+) -Osmundalactone, γ-lactones and spiromentins from the fungus Paxillus atrotomentosus. Phytochemistry. 1995;40:1251–1257. doi: 10.1016/0031-9422(95)00467-L. [DOI] [Google Scholar]
  7. Cai SX, Sun SW, Zhou HN, Kong XL, Zhu TJ, Li DH, Gu QQ. Prenylated polyhydroxy-p-terphenyls from Aspergillus taichungensis ZHN-7-07. J Nat Prod. 2011;74:1106–1110. doi: 10.1021/np2000478. [DOI] [PubMed] [Google Scholar]
  8. Calì V, Spatafora C, Corrado T. Polyhydroxy-p-terphenyls and related p-terphenylquinones from fungi: overview and biological properties. Stud Nat Prod Chem. 2003;29:263–307. doi: 10.1016/S1572-5995(03)80009-1. [DOI] [Google Scholar]
  9. Cali V, Spatafora C, Tringali C. Sarcodonins and sarcoviolins, bioactive polyhydroxy-p-terphenyl pyrazinediol dioxide conjugates from fruiting bodies of the basidiomycete Sarcodon leucopus. Eur J Org Chem. 2004;3:592–599. doi: 10.1002/ejoc.200300407. [DOI] [Google Scholar]
  10. Deng JJ, Lu CH, Li SR, Hao HL, Li ZY, Zhu J, Li YY, Shen YM. p-Terphenyl O-β-glucuronides, DNA topoisomerase inhibitors from Streptomyces sp. LZ35ΔgdmAI. Bioorg Med Chem Lett. 2014;24:1362–1365. doi: 10.1016/j.bmcl.2014.01.037. [DOI] [PubMed] [Google Scholar]
  11. Dewick PM. The biosynthesis of shikimate metabolites. Nat Prod Rep. 1994;11:173. doi: 10.1039/np9941100173. [DOI] [PubMed] [Google Scholar]
  12. Edwards RL, Gill M. Constituents of the higher fungi. Part X1V. 3',4',4-trihydroxypulvinone, thelephoric acid, and novel pyrandione and furanone pigments from Suillus grevillei (Klotsch) Sing. [Boletus elegans (Schum. per Fries)] J Chem Soc Perkin Trans I. 1973;4:1921–1929. doi: 10.1039/P19730001921. [DOI] [Google Scholar]
  13. Elix JA, Gaul KL, Hockless DCR, Wardlaw JH. Structure determination of butlerins A, B and C-three new lichen p-terphenyls. Aust J Chem. 1995;48:1049–1053. doi: 10.1071/CH9951049. [DOI] [Google Scholar]
  14. Geraci C, Ner P, Paterno C, Tringali C. An unusual nitrogenous terphenyl derivative from fruiting bodies of the basidiomycete Sarcodon leucopus. J Nat Prod. 2000;63:347–351. doi: 10.1021/np990293d. [DOI] [PubMed] [Google Scholar]
  15. Gripenberg J. Fungus pigments. Acta Chem Scand. 1958;12:1411–1414. doi: 10.3891/acta.chem.scand.12-1411. [DOI] [PubMed] [Google Scholar]
  16. Gripenberg J. Fungus pigments. XXII. Peniosanguin and its methyl ether. Acta Chem Scand. 1971;B25:2999–3005. doi: 10.3891/acta.chem.scand.25-2999. [DOI] [Google Scholar]
  17. Gripenberg J. Fungus pigments. XXIII. hydnuferrugin: a novel type of a 2,5-diphenylbenzoquinone-derived pigment. Tetrahedron Lett. 1974;5:619–622. doi: 10.1016/S0040-4039(01)82287-5. [DOI] [Google Scholar]
  18. Gripenberg J. Fungus pigments. XXIX. the pigments of Hydnellum ferrugineum (Fr.) Karstein and H. zonatum (Batsch) Karsten. Acta Chem Scand. 1981;B35:513–519. doi: 10.3891/acta.chem.scand.35b-0513. [DOI] [Google Scholar]
  19. Gripenberg J, Martikkala J. Fungus pigments. XIX. xylerythrin and its 5-O-methyl-derivative. Acta Chem Scand. 1969;B23:2583–2588. doi: 10.3891/acta.chem.scand.23-2583. [DOI] [Google Scholar]
  20. Gripenberg J, Hiltunen L, Pakkanen T. Fungus pigments. XXVI. A revised structure of peniophorinin. Acta Chem Scand. 1979;B33:1–5. doi: 10.3891/acta.chem.scand.33b-0001. [DOI] [Google Scholar]
  21. Gripenberg J, Hiltunen L, Pakkanen T. Fungus pigments XXVII xylerythrin. Acta Chem Scand. 1979;B33:6–10. doi: 10.3891/acta.chem.scand.33b-0006. [DOI] [Google Scholar]
  22. Gripenberg J, Hiltunen L, Pakkanen T. Fungus pigments. XXVIII. The structure of peniophorin. Acta Chem Scand. 1980;B34:575–578. doi: 10.3891/acta.chem.scand.34b-0575. [DOI] [Google Scholar]
  23. Guo HJ, Hu HJ, Liu SC, Liu XZ, Zhou YG, Che YS. Bioactive p-terphenyl derivatives from a Cordyceps-colonizing isolate of Gliocladium sp. J Nat Prod. 2007;70:1519–1521. doi: 10.1021/np070231k. [DOI] [PubMed] [Google Scholar]
  24. Guo ZK, Yan T, Guo Y, Song YC, Jiao RH, Tan RX, Ge HM. p-Terphenyl and diterpenoid metabolites from endophytic Aspergillus sp. YXf3. J Nat Prod. 2012;75:15–21. doi: 10.1021/np200321s. [DOI] [PubMed] [Google Scholar]
  25. Hassan J, Hathroubi C, Gozzi C, Lemaire M. Preparation of unsymmetrical biaryls via palladium-catalyzed coupling reaction of aryl halides. Tetrahedron. 2001;57:7845–7855. doi: 10.1016/S0040-4020(01)00752-9. [DOI] [Google Scholar]
  26. Hayashi K, Yamazoe A, Ishibashi Y, Kusaka N, Oono Y, Nozaki H. Active core structure of terfestatin A, a new specific inhibitor of auxin signaling. Bioorg Med Chem. 2008;16:5331–5344. doi: 10.1016/j.bmc.2008.02.085. [DOI] [PubMed] [Google Scholar]
  27. Ho JH, Lin YC, Chou LT, Chen YZ, Liu WQ, Chuang CL. Syntheses of p-terphenyls and 11,12-dihydroindeno[2,1-a]fluorene by one-pot benzannulation of Diels-Alder reactions of trans-1,2-dichloroethene and dienes. Tetrahedron Lett. 2013;54:1991–1993. doi: 10.1016/j.tetlet.2013.02.002. [DOI] [Google Scholar]
  28. Holzapfel M, Kilpert C, Steglich W. Über Leucomentine, farblose Vorstufen des Atromentins aus dem Samtfuβkrempling (Paxillus atrotomentosus) Liebigs Ann Chem. 1989;8:797–801. doi: 10.1002/jlac.198919890227. [DOI] [Google Scholar]
  29. Hu L, Liu JK. Two novel phenylacetoxylated p-terphenyls from Thelephora ganbajun Zang. Z Naturforsch. 2001;56:983–987. doi: 10.1515/znc-2001-11-1213. [DOI] [PubMed] [Google Scholar]
  30. Hu L, Liu JK. p-Terphenyls from the basidiomycete Thelephora aurantiotincta. Z Naturforsch. 2003;58:452–454. doi: 10.1515/znc-2003-5-627. [DOI] [PubMed] [Google Scholar]
  31. Hu L, Gao JM, Liu JK. Unusual poly (phenylacetyloxy) -substituted 1,1':4',1″-terphenyl derivatives from fruiting bodies of the basidiomycete Thelephora ganbajun. Helv Chim Acta. 2001;84:3342–3349. doi: 10.1002/1522-2675(20011114)84:11<3342::AID-HLCA3342>3.0.CO;2-K. [DOI] [Google Scholar]
  32. Hwang JS, Song KS, Kim WG, Lee TH, Koshino H, Yoo ID. Polyozellin, a new inhibitor of prolyl endopeptidase from Polyozellus multiplex. J Antibiot. 1997;50:773–777. doi: 10.7164/antibiotics.50.773. [DOI] [PubMed] [Google Scholar]
  33. Jägers E, Hillen-Maske E, Schmidt H, Steglich W, Horak E. Acetylierte terphenylchinon-derivate aus Anthracophyllum-Arten (Agaricales) Z Naturforsch. 1987;42:1354–1360. doi: 10.1515/znb-1987-1022. [DOI] [Google Scholar]
  34. Jägers E, Hillen-Maske E, Steglich W. Inhaltsstoffe von Boletopsis leucomelaena (Basidiomycetes): Klärung der chemischen Natur von “Leucomelon” und “Protoleucomelon”. Z Naturforsch. 1987;42:1349–1353. doi: 10.1515/znb-1987-1021. [DOI] [Google Scholar]
  35. Jiménez C. Marine natural products in medicinal chemistry. ACS Med Chem Lett. 2018;9:959–961. doi: 10.1021/acsmedchemlett.8b00368. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Kamigauchi T, Sakazaki R, Nagashima K, Kawamura Y, Yasuda Y, Matsushima K, Tani H, Takahashi Y, Ishii K, Suzuki R, Koizumi K, Nakai H, Ikenishi Y, Terui Y. Terprenins, novel immunosuppressants produced by Aspergillus candidus. J Antibiot. 1998;51:445–450. doi: 10.7164/antibiotics.51.445. [DOI] [PubMed] [Google Scholar]
  37. Kawada K, Arimura A, Tsuri T, Fuji M, Komurasaki T, Yonezawa S, Kugimiya A, Haga N, Mitsumori S, Inagaki M, Nakatani T, Tamura Y, Takechi S, Taishi T, Kishino J, Ohtani M. Total synthesis of terprenin, a highly potent and novel immunoglobulin E antibody suppressant. Angew Chem Int Ed. 1998;37:973–975. doi: 10.1002/(SICI)1521-3773(19980420)37:7<973::AID-ANIE973>3.0.CO;2-T. [DOI] [PubMed] [Google Scholar]
  38. Kim JH, Lee JS, Song KS, Kwon CS, Kim YK, Kim JS. Polyozellin isolated from polyozellus multiplex induces phase 2 enzymes in mouse hepatoma cells and differentiation in human myeloid leukaemic cell lines. J Agric Food Chem. 2004;52:451–455. doi: 10.1021/jf034748n. [DOI] [PubMed] [Google Scholar]
  39. Kobayashi A, Takemura K, Koshimizu K, Nagano H, Kawazu K. Candidusin A and B: new p-terphenyls with cytotoxic effects on sea urchin embryos. Agric Biol Chem. 1982;46:585–589. [Google Scholar]
  40. Kuhnert E, Surup F, Herrmann J, Huch V, Müller R, Stadler M. Rickenyls A-E, antioxidative terphenyls from the fungus Hypoxylon rickii (Xylariaceae, Ascomycota) Phytochemistry. 2015;118:68–73. doi: 10.1016/j.phytochem.2015.08.004. [DOI] [PubMed] [Google Scholar]
  41. Kurobane I, Vining LC. 3-Hydroxyterphenyllin, a new metabolite of Aspergillus candidus. structure elucidation by 1H and 13C nuclear magnetic resonance spectroscopy. J Antibiot. 1979;32:559–564. doi: 10.7164/antibiotics.32.559. [DOI] [PubMed] [Google Scholar]
  42. Lee IK, Yun BS, Cho SM, Kim WG, Kim JP, Ryoo IJ, Koshino H, Yoo ID. Betulinans A and B, two benzoquinone compounds from Lenzites betulina. J Nat Prod. 1996;59:1090–1092. doi: 10.1021/np960253z. [DOI] [PubMed] [Google Scholar]
  43. Lee IK, Yun BS, Kim JP, Ryoo IJ, Kim YH, Yoo ID. Neuroprotective activity of p-terphenyl leucomentins from the mushroom Paxutus panuoicles. Biosci Biotechnol Biochem. 2003;67:1813–1816. doi: 10.1271/bbb.67.1813. [DOI] [PubMed] [Google Scholar]
  44. Lee IK, Jung JY, Kim YS, Rhee MH, Yun BS. p-Terphenyls from the fruiting bodies of Paxillus curtisii and their antioxidant properties. Bioorg Med Chem. 2009;17:4674–4680. doi: 10.1016/j.bmc.2009.04.064. [DOI] [PubMed] [Google Scholar]
  45. Li W, Gao W, Zhang M, Li YL, Li L, Li XB, Chang WQ, Zhao ZT, Lou HX. p-Terphenyl derivatives from the endolichenic fungus Floricola striata. J Nat Prod. 2016;79:2188–2194. doi: 10.1021/acs.jnatprod.6b00197. [DOI] [PubMed] [Google Scholar]
  46. Li W, Li XB, Lou HX. Structural and biological diversity of natural p-terphenyls. J Asian Nat Prod Res. 2018;20:1–13. doi: 10.1080/10286020.2017.1381089. [DOI] [PubMed] [Google Scholar]
  47. Liu JK. Natural terphenyls: developments since 1877. Chem Rev. 2006;106:2209–2223. doi: 10.1021/cr050248c. [DOI] [PubMed] [Google Scholar]
  48. Liu SS, Zhao BB, Lu CH, Huang JJ, Shen YM. Two new p-terphenyl derivatives from the marine fungal strain Aspergillus sp. AF119. Nat Prod Commun. 2012;7:1057–1062. [PubMed] [Google Scholar]
  49. Ma BJ, Liu JK. An unusual nitrogenous terphenyl derivative from fruiting bodies of the basidiomycete Sarcodon scabrosus. Z Naturforsch. 2005;60:565–568. doi: 10.1515/znb-2005-0515. [DOI] [Google Scholar]
  50. Ma K, Han JJ, Bao L, Wei TZ, Liu HW. Two sarcoviolins with antioxidative and α-glucosidase inhibitory activity from the edible mushroom Sarcodon leucopus collected in Tibet. J Nat Prod. 2014;77:942–947. doi: 10.1021/np401026b. [DOI] [PubMed] [Google Scholar]
  51. McMorris TC, Anchel M. Phlebiarubrone, a basidiomycete pigment related to polyporic acid. Tetrahedron Lett. 1963;4:335–337. doi: 10.1016/S0040-4039(01)90632-X. [DOI] [Google Scholar]
  52. McMorris TC, Anchel M. The structure of the basidiomycete ortho quinone, phlebiarubrone, and of its novel acetylation product. Tetrahedron. 1967;23:3985–3991. doi: 10.1016/S0040-4020(01)97907-4. [DOI] [Google Scholar]
  53. Nagasawa I, Kaneko A, Suzuki T, Nishio K, Kinoshita K, Shiro M, Koyama K. Potential anti-angiogenesis effects of p-terphenyl compounds from Polyozellus multiplex. J Nat Prod. 2014;77:963–968. doi: 10.1021/np401046z. [DOI] [PubMed] [Google Scholar]
  54. Nakagawa F, Takahashi S, Naito A, Sato S, Iwabuchi S, Tamura C. Terferol, an inhibitor of cyclic adenosine 3',5'-monophosphate phosphodiesterase II structural elucidation. J Antibiot. 1984;37:10–12. doi: 10.7164/antibiotics.37.10. [DOI] [PubMed] [Google Scholar]
  55. Norikura T, Fujiwara K, Yanai T, Sano Y, Sato T, Tsunoda T, Kushibe K, Todate A, Morinaga Y, Iwai K, Matsue H. p-Terphenyl derivatives from the mushroom Thelephora aurantiotincta suppress the proliferation of human hepatocellular carcinoma cells via iron chelation. J Agric Food Chem. 2013;61:1258–1264. doi: 10.1021/jf3041098. [DOI] [PubMed] [Google Scholar]
  56. Oh H, Gloer JB, Wicklow DT, Dowd PF. Arenarins A-C: new cytotoxic fungal metabolites from the sclerotia of Aspergillus arenarius. J Nat Prod. 1998;61:702–705. doi: 10.1021/np980001t. [DOI] [PubMed] [Google Scholar]
  57. Qiu D, Meng H, Jin L, Wang S, Tang SB, Wang X, Mo FY, Zhang Y, Wang JB. Synthesis of aryl trimethylstannanes from aryl amines: a sandmeyer-type stannylation reaction. Angew Chem Int Ed. 2013;52:11581–11584. doi: 10.1002/anie.201304579. [DOI] [PubMed] [Google Scholar]
  58. Qiu J, Zhao BB, Shen Y, Chen W, Ma YD, Shen YM. A novel p-terphenyl derivative inducing cell-cycle arrest and apoptosis in MDA-MB-435 cells through topoisomerase inhibition. Eur J Med Chem. 2013;68:192–202. doi: 10.1016/j.ejmech.2013.07.020. [DOI] [PubMed] [Google Scholar]
  59. Quack W, Scholl H, Budzikiewicz H. Ascocorynin, a terphenylquinone from Ascocoryne sarcoides. Phytochemistry. 1982;21:2921–2923. doi: 10.1016/0031-9422(80)85069-2. [DOI] [Google Scholar]
  60. Quang DN, Hashimoto T, Nukada M, Yamamoto I, Tanaka M, Asakawa Y. Antioxidant activity of curtisians I-L from the inedible mushroom Paxillus curtisii. Planta Med. 2003;69:1063–1066. doi: 10.1055/s-2003-45159. [DOI] [PubMed] [Google Scholar]
  61. Quang DN, Hashimoto T, Nukada M, Yamamoto I, Tanaka M, Asakawa Y. Curtisians E-H: four p-terphenyl derivatives from the inedible mushroom Paxillus curtisii. Phytochemistry. 2003;64:649–654. doi: 10.1016/S0031-9422(03)00263-2. [DOI] [PubMed] [Google Scholar]
  62. Quang DN, Hashimoto T, Nukada M, Yamamoto I, Tanaka M, Asakawa Y. Curtisians M-Q: five novel p-terphenyl derivatives from the mushroom Paxillus curtisii. Chem Pharm Bull. 2003;51:1064–1067. doi: 10.1248/cpb.51.1064. [DOI] [PubMed] [Google Scholar]
  63. Quang DN, Hashimoto T, Nukada M, Yamamoto I, Tanaka M, Asakawa Y. Thelephantins A, B and C: three benzoyl p-terphenyl derivatives from the inedible mushroom Thelephora aurantiotincta. Phytochemistry. 2003;62:109–113. doi: 10.1016/S0031-9422(02)00403-X. [DOI] [PubMed] [Google Scholar]
  64. Quang DN, Hashimoto T, Nukada M, Yamamoto I, Tanaka M, Asakawa Y. Thelephantins D-H: five p-terphenyl derivatives from the inedible mushroom Thelephora aurantiotincta. Phytochemistry. 2003;63:919–924. doi: 10.1016/S0031-9422(03)00220-6. [DOI] [PubMed] [Google Scholar]
  65. Quang DN, Hashimoto T, Hitaka Y, Tanaka M, Nukada M, Yamamoto I, Asakawa Y. Thelephantins I-N: p-terphenyl derivatives from the inedible mushroom Hydnellum caeruleum. Phytochemistry. 2004;65:1179–1184. doi: 10.1016/j.phytochem.2004.02.018. [DOI] [PubMed] [Google Scholar]
  66. Rahbak L, Frisvad JC, Christophersen C. An amendment of Aspergillus section Candidi based on chemotaxonomical evidence. Phytochemistry. 2000;53:581–586. doi: 10.1016/S0031-9422(99)00596-8. [DOI] [PubMed] [Google Scholar]
  67. Ren FX, Chen SX, Zhang Y, Zhu SM, Xiao JH, Liu XZ, Su RB, Che YS. Hawaiienols A-D, highly oxygenated p-terphenyls from an insect-associated fungus, Paraconiothyrium hawaiiense. J Nat Prod. 2018;81:1752–1759. doi: 10.1021/acs.jnatprod.8b00106. [DOI] [PubMed] [Google Scholar]
  68. Rudulovic N, Quang DN, Hashimoto T, Nukada M, Asakawa Y. Terrestrins A-G: p-terphenyl derivatives from the inedible mushroom Thelephora terrestris. Phytochemistry. 2005;66:1052–1059. doi: 10.1016/j.phytochem.2005.03.008. [DOI] [PubMed] [Google Scholar]
  69. Schneider P, Bouhired S, Hoffmeister D. Characterization of the atromentin biosynthesis genes and enzymes in the homobasidiomycete Tapinella panuoides. Fungal Genet Biol. 2008;45:1487–1496. doi: 10.1016/j.fgb.2008.08.009. [DOI] [PubMed] [Google Scholar]
  70. Shi W, Yu TT, Cui DM. Advances in the synthetic methods of terphenyls. Chin J Org Chem. 2015;35:362–372. doi: 10.6023/cjoc201409007. [DOI] [Google Scholar]
  71. Silverton JV. The crystal and molecular structure of leuco-thelephoric acid hexamethyl ether. Acta Crystallogr B. 1973;29:293–298. doi: 10.1107/S0567740873002372. [DOI] [Google Scholar]
  72. Stead P, Affleck K, Sidebottom PJ, Taylor NL, Drake CS, Todd M, Jowett A, Webb G. Isolation and characterisation of a prenylated p-terphenyl metabolite of Aspergillus candidus possessing potent and selective cytotoxic activity; studies on mechanism of action. J Antibiot. 1999;52:89–95. doi: 10.7164/antibiotics.52.89. [DOI] [PubMed] [Google Scholar]
  73. Takahashi C, Yoshihira K, Natori S, Umeda M. The structures of toxic metabolites of Aspergillus candidus. I. The compounds A and E, cytotoxic p-terphenyls. Chem Pharm Bull. 1976;24:613–620. doi: 10.1248/cpb.24.613. [DOI] [PubMed] [Google Scholar]
  74. Tian SZ, Pu X, Luo GY, Zhao LX, Xu LH, Li WJ, Luo YG. Isolation and characterization of new p-terphenyls with antifungal, antibacterial, and antioxidant activities from halophilic actinomycete Nocardiopsis gilva YIM 90087. J Agric Food Chem. 2013;61:3006–3012. doi: 10.1021/jf400718w. [DOI] [PubMed] [Google Scholar]
  75. Tsuji H, Yamagata KI, Fujimoto T, Nakamura E. Manganese-catalyzed benzene synthesis by [2+2+2] coupling of 1,3-dicarbonyl compound and terminal acetylene. J Am Chem Soc. 2008;130:7792–7793. doi: 10.1021/ja8015186. [DOI] [PubMed] [Google Scholar]
  76. Tsukamoto S, Macabalang AD, Abe T, Hirota H, Ohta T. Thelephorin A: a new radical scavenger from the mushroom Thelephora vialis. Tetrahedron. 2002;58:1103–1105. doi: 10.1016/S0040-4020(01)01214-5. [DOI] [Google Scholar]
  77. Wang SM, Han JJ, Ma K, Jin T, Bao L, Pei YF, Liu HW. New α-glucosidase inhibitors with p-terphenyl skeleton from the mushroom Hydnellum concrescens. Fitoterapia. 2014;98:149–155. doi: 10.1016/j.fitote.2014.07.019. [DOI] [PubMed] [Google Scholar]
  78. Wei H, Inada H, Hayashi A, Higashimoto K, Pruksakorn P, Kamada S, Arai M, Ishida S, Kobayashi M. Prenylterphenyllin and its dehydroxyl analogs, new cytotoxic substances from a marine-derived fungus Aspergillus candidus IF10. J Antibiot. 2007;60:586–590. doi: 10.1038/ja.2007.75. [DOI] [PubMed] [Google Scholar]
  79. Weisgraber K, Weiss U, Milne GWA, Silverton JV. Hexamethyl ether of leuco-thelephoric acid from Corticium caeruleum. Phytochemistry. 1972;11:2585–2587. doi: 10.1016/S0031-9422(00)88543-X. [DOI] [Google Scholar]
  80. Xie ZP, Zeng M, Shi W, Cui DM, Zhang C. Cs2CO3-Promoted synthesis of p-terphenyls from allyl ketones. J Saudi Chem Soc. 2019;23:215–221. doi: 10.1016/j.jscs.2018.06.009. [DOI] [Google Scholar]
  81. Yamazoe A, Hayashi K, Kuboki A, Ohira S, Nozaki H. The isolation, structural determination, and total synthesis of terfestatin A, a novel auxin signaling inhibitor from Streptomyces sp. Tetrahedron Lett. 2004;45:8359–8362. doi: 10.1016/j.tetlet.2004.09.055. [DOI] [Google Scholar]
  82. Yan W, Wuringege LSJ, Guo ZK, Zhang WJ, Wei W, Tan RX, Jiao RH. New p-terphenyls from the endophytic fungus Aspergillus sp. YXf3. Bioorg Med Chem Lett. 2017;27:51–54. doi: 10.1016/j.bmcl.2016.11.033. [DOI] [PubMed] [Google Scholar]
  83. Yun BS, Lee IK, Kim JP, Yoo ID. Curtisians A-D, new free radical scavengers from the mushroom Paxillus curtisii. J Antibiot. 2000;53:114–122. doi: 10.7164/antibiotics.53.114. [DOI] [PubMed] [Google Scholar]
  84. Zhang L, Liang FS, Cheng X, Liu Q. A new route to multifunctionalized p-terphenyls and heteroaryl analogues via [5C+1C (N)] annulation strategy. J Org Chem. 2009;74:899–902. doi: 10.1021/jo802318p. [DOI] [PubMed] [Google Scholar]
  85. Zhu J, Chen W, Li YY, Deng JJ, Zhu DY, Duan J, Liu Y, Shi GY, Xie C, Wang HX, Shen YM. Identification and catalytic characterization of a nonribosomal peptide synthetase-like (NRPS-like) enzyme involved in the biosynthesis of echosides from Streptomyces sp. LZ35. Gene. 2014;549:352–358. doi: 10.1016/j.gene.2014.05.053. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary file1 (DOCX 733 KB) (732.9KB, docx)

Articles from Marine Life Science & Technology are provided here courtesy of Springer

RESOURCES