Current Topics: Review
Spiromeroterpenoids from the Higher Plants
2025 Volume 73 Issue 3 Pages 138-155
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2025 Volume 73 Issue 3 Pages 138-155
Meroterpenoids are a distinctive class of natural products found in various organisms, including animals, plants, bacteria, algae, and particularly fungi. Among them, spiromeroterpenoids, which have a spiro-ring connecting a terpenoid and a non-terpenoid moiety, are markedly unique. Currently, only a limited number of plants from the families Myrtaceae, Hypericaceae, Annonaceae, Asteraceae, and Lauraceae are known to biosynthesize spiromeroterpenoids. The non-terpene moiety of plant-derived spiromeroterpenoids is generally a polyketide, mainly a functionalized phloroglucinol derivative such as syncarpic acid and tasmanone. However, a flavanone, as found in the syzygioblanes isolated from Syzygium oblanceolatum (Myrtaceae), is another rare non-terpene component. The terpene moieties are restricted to monoterpenes or sesquiterpenes. The spiro-ring is generally formed by [m + n] cyclization or, in some cases, by radical or ionic cyclization.
Secondary metabolites, also known as natural products, are generally classified by their biosynthetic pathways, including the following 4 examples: (1) acetate-producing fatty acids/polyketides, (2) shikimate-yielding aromatic amino acids/phenylpropanoids, (3) acetate–shikimate hybrid giving flavonoids/stilbenes/styrylpyrones, and (4) mevalonate/deoxyxylulose phosphate (MEP) generating isoprenoids (terpenoids/steroids).1) The terpenoids are a large family of structurally diverse natural products with skeletons constructed from C5 isoprene units and are further classified by the number of C5 units, such as monoterpenoids with 2 units, sesquiterpenoids with 3 units, diterpenoids with 4 units, sesterterpenoids with 5 units, triterpenoids with 6 units, and tetraterpenoids with 8 units. Meroterpenoids, an exceptional class of terpenoids, are biosynthesized via hybridization of the mevalonate/MEP pathway with other pathways to incorporate terpenoids and non-terpenoids into the natural product molecule.2) Since this original definition makes it difficult to classify meroterpenoids clearly, Goyer et al.3) provided a thorough discussion of compounds that contain terpenes but are not classified as meroterpenoids.
The hybridization of biosynthetic pathways leads to structurally diverse compounds that exhibit various bioactivities, including antibacterial, antiviral, and anticancer activities.4,5) The main sources of meroterpenoids are fungi, microorganisms, algae, and plants. The meroterpenoids can be roughly split into 2 categories based on whether the terpenoid is combined with a polyketide or a non-polyketide non-terpenoid (Fig. 1). The latter skeleton can be further classified as phloroglucinol, coumarin, flavonoid, alkaloid, and others. Although numerous reviews have been published on meroterpenoids, most of them have focused on fungal meroterpenoids or specific plant genera. To date, no comprehensive review focused on phyto-meroterpenoids has been published. Among the diverse structures of meroterpenoids, compounds containing a spiro-ring constructed between the terpenoid and non-terpenoid are rare and especially unique. In many cases, the spiro-ring could be formed by an [m + n] cyclization or, in some cases, by a radical or ionic cyclization (Fig. 1). Only a few plant families produce spiromeroterpenoids. The family Myrtaceae is the most abundant source, followed by the family Hypericaceae. A few species of the families Annonaceae, Asteraceae, and Lauraceae also produce spiromeroterpenoids. The terpenoid moieties in plant-derived spiromeroterpenoids are mainly monoterpenes and cyclic sesquiterpenes, while the non-terpenoid portions are predominantly polyketides, including various phloroglucinol derivatives and simple alkyl chains produced by the acetate pathway. Other non-terpenoid components include homogentisic acid produced by the shikimate pathway and flavanones generated by mixed acetate and shikimate pathways. Thus, meroterpenoids containing flavonoids are generated through 3 biosynthetic pathways: acetate, shikimate, and isoprenoid. Interestingly, the terpenoid moiety is usually attached to the acetate side of the flavonoid. Here, we focus specifically on unique plant-derived meroterpenoids that contain a spiro-ring formed between a terpene and a non-terpene. This review describes the structures, biosynthetic pathways, and biological activities of plant-derived spiromeroterpenoids, categorizing them based on their original plant families and the types of non-terpenoid moieties present.
In the family Myrtaceae, many species, including Rhodomyrtus tomentosa, Callistemon viminalis, Myrtus communis, Callistemon salignus, Corymbia intermedia, Baeckea frutescens, Psidium guajava, Eucalyptus robusta, Eucalyptus tereticornis, Melaleuca leucadendron, and Syzygium oblanceolatum, biosynthesize meroterpenoids. Commonly, the non-terpenoid moiety is a phloroglucinol derivative with 1 of 4 basic skeletons: (1) syncarpic acid, (2) tasmanone, (3) diformylphloroglucinol, or (4) benzophenone (Fig. 1). Recently, exceptional spiromeroterpenoids with an unusual flavanone rather than phloroglucinol as a non-terpenoid moiety have been reported from S. oblanceolatum.
2.1. Syncarpic Acid-Based SpiromeroterpenoidsMore than 40 kinds of spiromeroterpenoids containing a syncarpic acid derivative have been reported. Half of them were isolated from R. tomentosa, native to tropical and subtropical regions of Southeast Asia.6) The spiromeroterpenoids found in R. tomentosa are thought to be biosynthesized by the cyclization of leptospermone or isoleptospermone with sesquiterpenoids or monoterpenoids via a hetero-Diels–Alder (DA) reaction. Sesquiterpene-derived tomentodiones E–G (1–3)7) and rhodotomentodione E (4)8) are biosynthesized from β-calacorene (Fig. 2), rtomentones A and B (5 and 6)9) from β-cubebene, rtomentone C (7)9) from (+)-aromadendrene, and rhodomentones A and B (8 and 9),10) as well as rhodomytrials A and B (10 and 11),11) from β-caryophyllene. The 2 latter compounds, 10 and 11, are structurally unique; 2 molecules of leptospermone are cyclized with β-caryophyllene. Monoterpene-derived tomentodiones J–M (12–15)7) and rtomentone E (16)9) originate from (+)-sabinene, while rtomentones G and H (17 and 18),9) 4S-focifolidione (19),12) and 4R-focifolidione (20)12) derive from β-pinene.
Similarly, spiromeroterpenoids 21–30 were isolated from C. viminalis13) (Fig. 3). Their structures are marked by flavesone or leptospermone as the syncarpic acid derivative. Callistiviminenes A and B (21 and 22)13) contain the sesquiterpene (–)-bicyclosequiphellandrene. Callistiviminenes F–H (23–25)13) and myrtucommulone L (26), originally isolated from M. communis,14) derive from the monoterpenoid (+)-sabinene. Other monoterpene-derived spiromeroterpenoids include (±)-callistiviminene I [(±)-27]13) and callistiviminene J (28),13) based on β-pinene, as well as callistiviminene K and L (29 and 30),13) based on β-phellandrene.
Among flavesone-based spiromeroterpenoids, sesquiterpene-derived myrtucomvalones A and B (31 and 32)15) and compound 3316) were isolated from M. communis, and monoterpene-derived callisalignenes E and F (34 and 35)17) were isolated from C. salignus. The myrtucomvalones, compound 33, and callisalignenes are biosynthesized from β-cubebene, β-caryophyllene, and β-phellandrene, respectively. Isoleptospermone-based callisalignenes I (36)18) with the monoterpene β-pinene were also isolated from C. salignus.
Similar to the above compounds (17–20, 27, 28, and 36), intermediones A–C (37–39)19) isolated from C. intermedia are also syncarpic acid- and β-pinene-based spiromeroterpenoids. However, a pendant phenyl group instead of an alkyl chain is present on the non-terpenoid moiety.
The syncarpic acid-based spiromeroterpenoids have been investigated for various biological activities, including cytotoxic activities against cancer cell lines,7,9,10,12,16,18) hAChE inhibitory effects,8) antimicrobial activities,10,12,14,17) inhibitory effects on tumor metastasis,11) inhibitory effects on lipopolysaccharide (LPS)-induced nitric oxide (NO) production,13) antiviral effects,15) and antimalarial activities.19) Compound 33 showed growth inhibitory effects against HepG2 and MDA-MB-231 cells with IC50 values of 4.39 ± 0.84 and 19.9 ± 4.64 µM.16) Callisalignene I (36) displayed cytotoxic effects against HCT116 and A549 cells with IC50 values of 16.3 and 10.0 µM, respectively.18) Intermediones A and B (37 and 38) exhibited antimalarial activities with IC50 values of 12.5 and approximately 9.9 µM, respectively.19)
2.2. Tasmanone-Based SpiromeroterpenoidsTasmanone-based spiromerpenoids have been isolated only from B. frutescens, native to eastern Southeast Asia and Australia.20) This species has also been used as a traditional herbal medicine in these regions. Most isolated spiromeroterpenoids from B. frutescens are commonly biosynthesized via a hetero-DA reaction between tasmanone as the hetero-diene for 40–5021–23) and 52–6924,25), or its 2-methylbutanoyl derivative, isolateriticone, for 5123) and a sesquiterpenoid or monoterpenoid as the dienophile (Fig. 4). Exceptionally, the unique spirocyclic structures of (±)-frutescones Q and R [(±)-70 and (±)-71]22) are assembled through a conventional DA reaction between tasmanone as the dienophile and myrcene, an acyclic monoterpene, as the diene.
Regarding the terpene component, the sesquiterpene-derived meroterpenoids include frutescones A and D (40 and 41)23) from β-caryophyllene, frutescones H–J (42–44)22) and T (45)23) from (–)-bicyclosequiphellandrene, and frutescones L, M, and U (46, 47,22) and 4823)) from β-cubebene. In the monoterpene-derived (±)-frutescone N [(±)-49],22) frutescones O and S (5022 and 5123)), and baeckfrutones B–D, F, G, I–K, and N–R (52–64),24,25) the spiro-ring is formed with sabinene. Frutescone P (65)22) and baeckfrutones E, H, and L (66–68)24) contain β-pinene, while baeckfrutone A (69)24) contains β-phellandrene.
The tasmanone-based spiromeroterpenoids were evaluated for several biological activities, including cytotoxic activities against cancer cell lines,21,24,25) inhibitory effects on LPS-induced NO production,22–25) inhibitory effects against LPS-induced upregulation of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6),22) and AChE inhibitory effects.24) Frutescones A and D (40 and 41) showed moderate cytotoxic activities against Caco-2 with IC50 values of 8.1 and 10.2 µM, respectively.21) Frutescones N–R (49, 50, 65, 70, and 71) exhibited significant anti-inflammatory activities with IC50 values ranging from 0.36 to 6.50 µM.22) Frutescone O (50) also exhibited inhibitory effects against LPS-induced upregulation of TNF-α in a dose-dependent manner, which was partially attributed to the suppression of nuclear factor-kappaB (NF-κB) p65 nuclear translocation.22) Frutescone S (51) displayed potent NO inhibitory activity with an IC50 value of 0.8 µM.23) Baeckfrutones B, D, and J (52, 54, and 58) showed significant cytotoxic effects against DU145 with IC50 values of 1.3, 6.5, and 4.0 µM, respectively.24)
2.3. Diformylphloroglucinol-Based SpiromeroterpenoidsSpiromeroterpenoids 72–8926–32) containing diformylphloroglucinol have been found in P. guajava L. (Fig. 5), native to Central and South America,33) where it has been used as a traditional medicine. They are thought to be biosynthesized by a hetero-DA reaction between benzophenone or isoamyl phenyl ketone and sesquiterpenoids or monoterpenoids. Sesquiterpene-derived psiguadiols A–C (72–74)26) and guajamer I (75)27) originate from β-caryophyllene, guajamer B (76)27) and psiguajadials H and I (77 and 78)28) from bicyclosequiphellandrene, psiguajadial A (79)28) from β-cubebene, and psidial F (80)29) from sesquisabinene B. Monoterpene-derived guajamers C and G (81 and 82),27) psiguajadial K (83),28) guadial A (84),30) and psiguajavadial A (85)31) are derived from sabinene and (±)-guajamer D [(±)-86],27) guajamers E and F (87 and 88),27) and guadial C (89)32) from β-pinene.
Protein tyrosine phosphatase 1B (PTP1B) inhibitory activities,26) antibacterial effects,27) inhibitory activities against phosphodiesterase-4 (PDE4),28) inhibitory effects on LPS-induced NO production,29) cytotoxic activities against cancer cell lines,30–32) and inhibitory activities against DNA topoisomerase I (Topo I)31) have been tested using the diformylphloroglucinol-based spiromeroterpenoids (72–89). Psiguadiols A–C (72–74) displayed PTP1B inhibitory activities with IC50 values of 4.7, 11.0, and 11.9 µM, respectively.26) Guajamers B–G (76, 81, 82, and 86–88) exhibited antibacterial effects against Staphylococcus epidermidis with minimum inhibitory concentrations (MICs) from 8 to 32 µmol/L.27) Psiguajadial A, H, I, and K (77–79 and 83) showed moderate inhibitory activities against PDE4 with IC50 values in the range of 1.8–3.7 µM.28) Psiguajavadial A (85) displayed cytotoxic activities against HCT116 and A549 with IC50 values of 7.6 and 3.0 µM, respectively, and also showed a dose-dependent inhibition of Topo I activity.31)
Eucalyptus globulus is another source of sabinene- or phellandrene-derived spiromeroterpenoids, including euglobal-Ib, -Ic, -IIa, and -IIb (90–93)34) (Fig. 6). A similar compound, euglobal-B1-1 (94), was also found in Eucalyptus blakelyi.35) Euglobal-Ib and -B1-1 (90 and 94) displayed antitumor promoter activity with 70–80% inhibition of 12-O-tetradecanoylphorbol 13-acetate (TPA)-activated EBA-EA activation at a 1000 mol ratio of compound/TPA.35)
Eucalyptus robusta contains both mono- and sesquiterpene-derived spiromeroterpenoids. The pinene-derived robustadiols A and B (95 and 96) were originally isolated by Xu et al.,36) and their structures were revised later.37,38) Eucalrobusones G–I (97–99),39) eucalrobusone T (100),40) and 7R-eucalrobusone T (101)40) are derived from β-cubebene. Eucalrobusone Q (102),40) eucalrobusone J (103),41) and eucalrobusone L (104)41) have a cadinene derivative, aromadendrane, and (+)-calarene, respectively, as the sesquiterpene component. Compound 104 has a unique coumarin structure constructed by a cyclization associated with a cation transfer generated from (+)-calarene.
Antileishmanial, antimalarial, antimicrobial, and cytotoxic activities of robustadiols A and B (95 and 96) have been evaluated. Both compounds showed moderate antileishmanial activity with IC50 values of 20 and 16 µg/mL, respectively, and weak antimalarial activity with IC50 values of 2.7–4.8 µg/mL.42) Selected eucalrobusones were evaluated for antifungal activity, and 100 and 103 exhibited potent activities against Candida glabrata with MIC50 values of 7.4 and 2.6 µg/mL, respectively.40,41)
Eucalyptus tereticornis reportedly produces formylphloroglucinol-based spiromeroterpenoids, including eucalteretial D (105),43) which contains the sesquiterpene aromadendrane and (±)-eucateretin A [(±)-106],44) which contains the monoterpene sabinene, together with euglobal-Ic and -B1-1 (9134) and 9435)) and euglobal-G3 (107), which was originally isolated from Eucalyptus grandis.45) Eucalteretial D (105) displayed no cytotoxic activity,43) while (–)-eucateretin A [(–)-106] showed inhibitory effects on ATP-citrate lyase with an IC50 value of 10.2 µM.44)
2.4. Benzophenone-Based SpiromeroterpenoidsSpiromeroterpenoids containing methoxymethylbenzophenone were isolated from M. leucadendron, which is widespread in northern Australia, Southeast Asia, and New Guinea.46) A hetero-DA reaction of benzophenone with sesquiterpenoids or monoterpenoids has been proposed as the biosynthetic pathway for all spiromeroterpenoids isolated from this plant species. Leumelaleucol L (108) was isolated as a bicyclosequiphellandrene-derived spiromeroterpenoid (Fig. 7), while the monoterpene portions of (±)-leumelaleucol A [(±)-109] and leumelaleucol B (110) are derived from β-pinene, those of leumelaleucols D and E (111 and 112) from β-phellandrene, and those of leumelaleucols F–H (113–115) from (–)-sabinene.47) This study also evaluated the neuroprotective effects of benzophenone-based spiromeroterpenoids. When PC-12 cells were treated with neurotoxins, leumelaleucols E and G (112 and 114) showed potent effects, with > 65% cell viability at a concentration of 25 µM.47)
Cyclic sesquiterpene-derived spiromeroterpenoids, named syzygioblanes,48,49) have been isolated from the Indonesian medicinal plant, S. oblanceolatum, native to Borneo, the Philippines, and Sulawesi48) in Southeast Asia. The unique structures of syzygioblanes A–H (116–123) differ from those of most spiromeroterpenoids. The spiro-ring is formed between unusual combinations of terpenes (various cyclic sesquiterpenes, including eudesmane/cadinane types) and non-terpenes (the flavanone desmethoxymatteucinol) (Fig. 8). The proposed biosynthetic pathway involves the enzymatic dearomative hydroxylation of desmethoxymatteucinol, followed by a DA cyclization with a cyclic sesquiterpene containing exocyclic methylene to form a unique spiro-ring. The evaluation of antiproliferative activity revealed that all compounds displayed more potent inhibitory effects against multidrug-resistant (MDR) tumor cell lines than chemosensitive tumor cell lines; thus, they demonstrated collateral sensitivity (CS).50) Especially, syzygioblane A clearly exhibited CS with a selective index (SI: IC50 against chemosensitive tumor cell divided by IC50 against the MDR cell line) of 15. Its IC50 values were 0.4 µM against an MDR cell line, KB-VIN, and 5.8 µM against a non-MDR cell line, KB.
Phloroglucinol-based spiromeroterpenoids have been isolated from the genus Hypericum in the family Hypericaceae. They were structurally classified as (1) hybridized derivatives of terpenes with phloroglucinols and (2) cyclized derivatives of a geranyl or prenyl side chain on phloroglucinols.
3.1. Hybridized Derivatives of Terpenes with PhloroglucinolsTwo unique spiromeroterpenoids, hypulatones A (124) and B (125),51) composed of the sesquiterpene humulene and geranyl- and prenyl-substituted phloroglucinols, were isolated from Hypericum patulum. Similar humulene-derived spiromeroterpenoids, (±)-hyperkouytins A–F (126–131),52) were also isolated from Hypericum kouytchense. Chiral HPLC was used to separate each enantiomer from the racemates (Fig. 9). Although the biosynthetic pathway to these meroterpenoids is unclear, radical cyclization51) or nucleophilic cyclization of epoxidized humulene52) was proposed. Tasmanone-based hyjapone A (132)53) conjugated with the sesquiterpene β-caryophyllene was isolated from Hypericum japonicum. This compound is unique in that 2 molecules of norflavesone are coupled with 1 molecule of β-caryophyllene via a hetero-DA reaction. The monoterpene-derived hyperjapones F–H (133–135)54) were also isolated from H. japonicum. The terpene moiety in hyperjapones F (133) and G (134) is sabinene, while that of hyperjapone H (135) is β-pinene. Their biosynthetic pathway likely involves a hetero-DA reaction similar to that of other phloroglucinol-based spiromeroterpenoids described above.
Hypulatones A and B (124 and 125) showed selective inhibition for late sodium current (INa); the IC50 value of 125 was 0.2 µM.51) The late INa inhibitory effects of both compounds were more than 100-fold greater than the effects on the Cav3.1, Kv1.5, and hERG ion channels. (±)-Hyperkouytin A [(+)-126] and (–)-hyperkouytin C [(–)-128] were evaluated for antiproliferative activity against MV-4-11 (leukemia); their IC50 values were 9.7 and 7.0 µM, respectively.52) Hyjapone A (132) exhibited no cytotoxic activity against RAW264.7 and 36% inhibition of NO production at 10 µM.53) Compounds 133–135 showed no antiproliferative activity against 5 human tumor cell lines: AGS, HeLa, HepG2, HCT116, and MDA-MB-468.54)
3.2. Cyclized Derivatives of Geranyl or Prenyl Side Chains on PhloroglucinolsThe spiromeroterpenoids isolated from Hypericum ascyron have a unique 6/6/5 tricyclic spiro structure derived from a geranyl side chain on an acylphloroglucinol. Thus, these meroterpenoids are commonly categorized as polycyclic polyprenylated acylphloroglucinols (PPAPs). Tomoeones A–H (136–143)55) were first isolated in 2008. The structures of tomoeones C (138), D (139), G (142), and H (143) were later revised56,57) (Fig. 10). The postulated biosynthetic pathway involves the formation of the 5-membered ring via an epoxidation of C-8 and C-9 on the geranyl group, followed by the formation of the 6-membered ring via an epoxidation of C-13 and C-14. Hyperascyrones A–F (144–149)56) and hyperiforin C (150)57) are similar PPAPs isolated from H. ascyron and Hypericum forrestii, respectively.
Two other PPAPs, hyperispirones A (151) and B (152)58) with more complex heptacyclic and tetracyclic ring systems, respectively, were isolated from Hypericum beanii. A rearranged PPAP, norprzewalsone A (153)59) with a unique 5/6/5/6/6 pentacyclic ring system, was isolated from Hypericum przewalskii; its biosynthesis would involve ring opening of the phloroglucinol moiety. Hyperireflexolides A (154) and B (155),60) in which the phloroglucinol moiety is oxidatively cleaved, were isolated from Hypericum reflexum. The structure of hyperireflexolide B (155) was recently revised as 156 based on a proposed biosynthetic pathway61); however, further investigation, such as total synthesis, is needed to define the precise structure.
Tomoeones A–H (136–143) were tested for antiproliferative activities against MCF-7, CPLP205, KB, and K562, as well as MDR tumor cell lines, KB-C2 and K562/Adr.55) Compounds 137 and 138 displayed potent activity: the former compound was selectively active against KB with an IC50 value of 6.2 µM, while the latter compound had an IC50 value of 17.1 µM against KB and K562/Adr. Hyperascyrones A–F (144–149) were evaluated for antiproliferative activity against HL-60, SMMC-7721, A-549, MCF-7, SW480, and BEAS-2B, as well as for anti-human immunodeficiency virus (HIV) activities.56) Among them, compound 146 significantly inhibited HL-60 cell growth with an IC50 value of 4.2 µM, and 149 exerted moderate anti-HIV activity with an EC50 value of 2.4 µM and a selectivity index of 5.6. Hyperispirones A (151) and B (152) were examined for antiangiogenesis efficacy and showed potent inhibitory activity at 10 and 20 µM concentrations against the tube formation of human umbilical vein epithelial cells.58) Norprzewalsone A (153) moderately inhibited NO production in LPS-stimulated RAW264.7 cells.59)
Unique spiromeroterpenoids have also been isolated from specific genera in the following 3 families: Annonaceae, Asteraceae, and Lauraceae.
Geranylated homogentisic acid derivatives, named miliusanes, were isolated from the genus Miliusa (Annonaceae). They contain a spirolactone produced by the cyclization of a hydroxy moiety in the terpene portion with a carboxyl group in the non-terpene portion. After the isolation of miliusate (157) and miliusol (158) from Miliusa balansae in 2004,62) other miliusane analogs containing spiro structures were also reported including miliusanes I–XVII (159–175)63) and XXXII–XXXVII (176–181)64) isolated from M. sinensis, as well as miliusanes XXI–XXVII (182–188)65) and miliusane-dimer A (189)66) isolated from M. balansae (Fig. 11). Although the absolute configuration of C-1″ in 189 is different from that of C-1′ in miliusane XXXIX, the former dimeric compound could be biosynthesized similarly to a Rauhut–Currier reaction of miliusol (158) and miliusane XXXIX.
The laboratory of H.H.S. Fong studied the cytotoxic effects of 157–175 against 7 human tumor cell lines and found that 157–159, 161, 164, and 165 inhibited all tested cell growth with IC50 values of < 10 µM.63) The antiproliferative activities of 155–162, 167, 172, 173, and 175–188 against several human tumor cell lines, including HCT116 (colorectal), A375 (melanoma), and others, were also examined later by the research group of H.J. Zhang.64,65) Compounds 159, 161, 177, and 180 displayed potent activity with IC50 values of < 10 µM against all tested cell lines. The in vivo efficacy of 158 was also evaluated.65) The inhibition of HCT116 migration and the induction of HCT116 senescence by 159 and 177 were also reported.64) While the CC50 value of 158 was 38 µM against Huh-7, compounds 180 and 189 exhibited no significant cytotoxic activity. Compound 158 also showed potent activity against HCoV-229E and ZIKV with high SIs (CC50 of cytotoxicity/IC50 of antivirus activity) of 33 and 61, respectively.66)
Spiromeroterpenoids derived from geranylated coumarins have been isolated from 2 species in the family Asteraceae (Fig. 12). (+)-Spiroethuliacoumarin (190) was isolated from Erhulia conywides67) and more recently from Centralus pauciflorus.68) Pauciflorins N and O (191 and 192) were also isolated from the latter plant.68) Compounds 190 and 192 were evaluated for antiproliferative activity and showed 20–35% growth inhibition at 30 µM against MFC-7, MDA-MB-231, HeLa, SiHa, and A2780.
Twelve polyketide chain-derived spiromeroterpenoids, cryptolaevilactones A–L (193–204),69,70) were isolated from Cryptocarya laevigata (Lauraceae) (Fig. 13). These compounds feature a distinctive spiro[3.5] nonane moiety, presumably formed by [2 + 2] cycloaddition of the monoterpene β-phellandrene with a δ-lactone-containing polyketide. This biosynthetic pathway was supported by the simultaneous isolation of the lactone-polyketide chain, cryptolaevilactone M. Cryptolaevilactones A–C (193–195) and L (204) are diastereomers with different configurations at 3 chiral centers: C-11, C-12, and C-4′. Cryptolaevilactones D–F (196–198), G–J (199–202), and K (203) would be biosynthesized from the related 193–195 through intramolecular Michael addition, dehydration, and acetylation, respectively.
Natural products have contributed significantly to various areas of human life, including not only medicine but also food, agriculture, nutrition, cosmetics, and biotechnology. A key feature of natural products is the diversity of their chemical structures, which leads to a wide range of biological activities. Bioactive natural products have played crucial roles in drug discovery and the elucidation of phenomena in human life.
The total number of natural products potentially existing in the world is hard to estimate, especially given the many undiscovered compounds. However, it is estimated that over 300000 natural products have been isolated and their structures elucidated.71,72) Notably, approximately 70% of them are derived from plants, with terpenoids being one of the most abundant compound families. Meroterpenoids are a unique class of terpenoids produced by hybrid biosynthetic pathways. Among them, meroterpenoids featuring a spiro-ring formed between a terpenoid and a non-terpenoid are particularly exceptional. This review summarizes the sources, structures, biosynthetic pathways, and biological activities of plant-derived spiromeroterpenoids. The plants producing spiromeroterpenoids are found in only 5 plant families, Myrtaceae, Hypericaceae, Annonaceae, Asteraceae, and Lauraceae, comprising 16 genera and 26 species (Table 1). Among them, the genera Eucalyptus (Myrtaceae) and Hypericum (Hypericaceae) contain multiple species that produce spiromeroterpenoids. The non-terpene moieties are mainly phloroglucinol derivatives, including syncarpic acid and tasmanone, along with formylated, prenylated, acylated, and other functionalized natural products. Flavanone is an extremely rare non-terpene component. The terpene portion is limited to monoterpenes or sesquiterpenes. The spiro-ring is likely generally formed by a DA reaction and, in some cases, by [2 + 2], radical, or ionic cyclization.
| Family | Genus | Species | Non-terpene | |
|---|---|---|---|---|
| Myrtaceae | Rhodomyrtus | tomentosa | Syncarpic acid | Fig. 2 |
| Callistemon | viminalis | |||
| Myrtus | communis | Fig. 3 | ||
| Callistemon | salianus | |||
| Corymbia | intermedia | |||
| Baeckea | frutescens | Tasmanone | Fig. 4 | |
| Psidium | guajava L. | Diformylphloroglucinol | Fig. 5 | |
| Eucalyptus | globulus | Fig. 6 | ||
| robusta | ||||
| blakelyi | ||||
| tereticormis | Formylphloroglucinol | |||
| grandis | ||||
| Melaleuca | leucadendron | Benzophenone | Fig. 7 | |
| Syzygium | oblanceolatum | Flavanone | Fig. 8 | |
| Hypericaceae | Hypericum | patulum | Prenylphloroglucinol | Fig. 9 |
| kouytchense | ||||
| japonicum | Tasmanone | |||
| ascyron | Polycyclic polyprenylated acylphloroglucinol (PPAP) | Fig. 10 | ||
| forrestii | ||||
| beanii | ||||
| przewalskii | ||||
| reflexum | ||||
| Annonaceae | Miliusa | sinensis | Homogentisic acid | Fig. 11 |
| balansae | ||||
| Asteraceae | Erhulia | conywides | Coumarin | Fig. 12 |
| Centralus | pauciflorus | |||
| Lauraceae | Cryptocarya | laevigata | Polyketide chain | Fig. 13 |
Undoubtedly, many undiscovered natural products are present worldwide. While only a limited number of plants have currently been shown to produce spiromeroterpenoids, recent advances in purification and structural analysis techniques have the potential to continually identify natural products with unique structures and biological activities, including plant-derived spiromeroterpenoids.
We appreciate the critical comments, suggestions, and editing of the manuscript by Dr. S. L. Morris-Natschke (UNC-CH). This work was supported by JSPS KAKENHI Grant Number: 16H05811, the Mitani Foundation for Research and Development, the Shibuya Science Culture and Sport Foundation, and the Yamazaki Spice Promotion Foundation, awarded to K.N.-G. This work was also partially supported by JSPS KAKENHI Grant Number: 20K05726, awarded to Y.S.
The authors declare no conflict of interest.
