2025 Volume 73 Issue 7 Pages 581-594
This review summarizes the structures, names, and bioactivities of 207 briarane-type diterpenoids, including 113 newly identified metabolites, isolated between 2020 and 2024. All the briaranes discussed were derived from octocorals belonging to the genera Briareum, Dichotella, Ellisella, Junceella, and Erythropodium. Some of these compounds have demonstrated potential biomedical activities.
Building on previous review articles on briarane-type natural products,1–7) this review covers literature published from 2020 to 2024. It examines 207 naturally occurring briarane diterpenoids, including 113 newly identified metabolites, all characterized by a γ-lactone moiety fused to a trans-fused bicyclo[8.4.0]tetradecane ring system (Chart 1). These compounds were isolated from various octocorals, particularly those belonging to the genera Briareum, Dichotella, Ellisella, Erythropodium, and Junceella. Notably, many of these substances exhibit bioactivity, suggesting potential biomedical applications. The review categorizes briarane-related compounds taxonomically by genus and species.
As the sole natural source of briarane-type diterpenoids, the taxonomy of Octocorallia was revised in 2022.8) The first briarane metabolite, briarein A, was isolated in 1977 from the Caribbean octocoral Briareum asbestinum.9) Since then, the genus Briareum has remained the most significant producer of briarane-type natural products. In 2020, a previously reported metabolite, briarane B-3 (1)10,11) (Fig. 1), was isolated from B. asbestinum collected off the Yucatán Peninsula, Mexico.10) The structure of 1 was originally proposed by Harvell et al. in 1993, though no spectroscopic evidence was provided.11) Notably, Nath et al. used only 35 µg of 1 and employed 1H-NMR residual chemical shift anisotropy (RCSA) measurements to determine its structure, further confirmed through DP4+ analysis.10) The absolute configuration of 1 was established using circular dichroism (CD), vibrational circular dichroism (VCD), and electronic circular dichroism (ECD) spectroscopic data, with additional confirmation from single-crystal X-ray diffraction (SC-XRD).10,12)
Further studies led to the isolation of four previously undescribed derivatives, 2-butyryloxybriarane B-3 (2), 9-acetylbriarenolide S (3), briarenolide W (4),13) and 12-isobriarenolide P (5), along with four known analogs: briantheins X–Z (6–8)14–17) and lactone 14 (9)18) (Fig. 1). The structures of briaranes 2–9 were elucidated by comparing their spectroscopic data with previously reported compounds and were further confirmed via SC-XRD analysis (for brianthein Y (7)).12,14)
Regarding bioactivity, brianthein X (6) significantly reduced nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation at a concentration of 100 µM and exhibited inhibitory effects on cyclooxygenase-2 (COX-2) and interleukin-6 (IL-6) release in lipopolysaccharide (LPS)-stimulated THP-1 macrophages (human acute monocytic leukemia cells).12) Additionally, the antiviral activity of three chlorinated briaranes, briantheins Y (7), Z (8), and V (10) (Fig. 1), originally isolated from B. asbestinum,14,17,19) was evaluated. These compounds exhibited anti-coronavirus (CoV) activity against the CoV-A59 strain, with EC50 values of 702.98, 147.87, and 83.75 µM, respectively.20) Furthermore, briarane 8 also demonstrated antiviral activity against the herpes simplex virus-1 (HSV-1) strain, with an EC50 value of 147.87 µM.20)
2.2. Briareum stechei (Kükenthal, 1908) (Family Briareidae)Over the past 48 years, the octocoral Briareum stechei (synonyms: Briareum excavatum, Solenopodium stechei, and Solenopodium excavatum)21) has been recognized as one of the most significant sources of briarane-type natural products. Distributed throughout the Indo-Pacific Ocean, continued research on the chemical constituents of B. stechei has led to the identification of 40 newly discovered compounds, including briarenols F–Z (11–31),22–29) briastecholides A–P (32–47),30–37) 12-epi-briacavatolide B (48),38) 11-dehydroxybriavioid B (49),39) and 12-epi-briastecholide L (50).39) Additionally, 27 known briaranes have been isolated, including excavatolides A (51),25,40) C (52),22,40) E (53),32,40) and M (54)34,41); briacavatolides B (55)38,42) and C (56)22,42); briaexcavatolides E (57),28,43) F (58),25,29,43) and P (59)23,31,44); briaexcavatins G (60),37,45) P (61),23,46) and X (62)37,47); solenolides A–C (63–65)28–30,48) and E (66)25,28,48); briarenolides M (67),29,49) R (68),25,49) and S (69)30,49); brianolide (70)28,29,50); brianodins A (71)33,51) and B (72)35,51); briarlides G (73)33,52) and P (74)33,53,54); and violides G (75),33,55,56) O (76),33,57) and P (77).33,57) These compounds were isolated from B. stechei specimens collected from the waters near Taiwan and Okinawa, where the convergence of the Kuroshio Current (Black Current or Japan Current) and the South China Sea Surface Current fosters high biodiversity.
The structures of briaranes 11–77 (Fig. 2) were elucidated through spectroscopic methods, while the absolute configurations of several compounds, including briarenol G (12)24); briastecholides N (45)36) and P (47)37); excavatolides A (51),25) C (52),22) E (53),32) and M (54)34); briaexcavatolide F (58)25); briaexcavatins G (60) and X (62)37); solenolide C (65)30); brianolide (70)28,29); and brianodin A (71),33) were further confirmed via SC-XRD. Among these, briastecholide G (38) was identified as the first briarane featuring a 3/14-ether linkage, forming a 10/6/5/5-fused tetracyclic system in its scaffold.33) Additionally, briarenol O (20) represents the second known 2-ketobriarane analogue.26,58)
In anti-inflammatory activity assays, several compounds demonstrated inhibition of inducible nitric oxide synthase (iNOS) expression at a concentration of 10 µM. These include briarenol H (13) (43.34%),22) briastecholide H (39) (17.01%),33) excavatolide C (52) (47.26%),22) briacavatolide C (56) (48.90%),22) briaexcavatolide P (59) (35.37 and 46.53%),23,31) brianodin A (71) (37.95%), briarlides G (73) (28.76%) and P (74) (1.21%), and violide G (75) (26.66%)33) (the values in parentheses indicate the expression levels of iNOS; lower values reflect a stronger inhibitory effect of the compound on iNOS production). However, some compounds significantly increased COX-2 expression at 10 µM, including briarenol U (26) (149.29%),28) excavatolide C (52) (167.06%),22) briarenol X (29) (159.21%), and solenolide A (63) (196.03%).29) These findings suggest that excavatolide C (52), despite its cytotoxicity,20) selectively suppresses iNOS expression.22) The interaction between iNOS and COX-2 plays a critical role in various pathological conditions. These two enzymes are frequently co-expressed in diseased tissues and serve as key contributors to inflammatory processes. The crosstalk between iNOS and COX-2 signaling pathways during inflammation is complex. Notably, nitric oxide (NO) produced by iNOS has been shown to negatively regulate COX-2 induction in response to inflammatory stimuli.59) Interestingly, COX-2 expression can also be upregulated by peroxisome proliferator-activated receptors (PPARs) and the Wnt/β-catenin pathway through specific response elements within its promoter regions.60,61) Although excavatolide C (52) effectively suppresses iNOS expression, we speculate that it may simultaneously activate signaling pathways-such as those involving PPARs-that enhance COX-2 expression.
Furthermore, with respect to the inhibition of iNOS expression, briarenol I (14) demonstrated comparatively weaker activity (60.27%) than briaexcavatolide P (59), which exhibited more potent inhibitory effects (35.37 and 46.53%).23,31) These findings imply that the presence of a hydroxy group at C-16 in briarenol I (14) may attenuate its inhibitory potency.23) Briarenol U (26) was observed to promote inflammation by increasing COX-2 expression, while solenolide E (66) was inactive, indicating that the inflammatory activity of these compounds is largely influenced by the functional groups at C-12.28) Interestingly, these preliminary findings contrast with previous claims that most briarane-type natural products derived from octocorals exhibit anti-inflammatory properties.62)
2.3. Briareum violaceum (Quoy & Gaimard, 1833) (Family Briareidae)In continued studies on the chemical constituents of the cultured octocoral Briareum violaceum (synonyms: Briareum violacea, Clavularia violacea, and Pachyclavularia violacea),21) seven new briaranes, briavioids A–G (78–84),63–65) as well as seven known briaranes, briaexcavatin M (85),46,63) excavatolide F (86),41,63) briacavatolides B (55) and C (56),42,65) briaexcavatin L (87),65,66) briaexcavatolide U (88),65,67) and briarenol K (16)23,65) (Figs. 2, 3), were isolated. The structures of briaranes 16, 55, 56, and 78–88 were elucidated using spectroscopic methods. SC-XRD analysis was performed to determine the absolute configurations of briavioids A (78)63,65) and D (81).64) Notably, briavioid D (81) represents the first known briarane featuring a 7,8-epoxy group within the γ-lactone moiety, along with a rare 11,14-ether bridge.64)
A pro-inflammatory assay revealed that at a concentration of 10 µM, excavatolide F (86) significantly reduced iNOS release to 28.60%. In contrast, briaranes 80 (briavioid C) and 85 (briaexcavatin M) were found to be inactive. These findings suggest that the anti-inflammatory activity of these compounds is largely influenced by the functional groups present at C-12.63)
2.4. Briareum sp. (Family Briareidae)Continuing chemical studies on the constituents of an octocoral identified as Briareum sp., collected from the waters of Taiwan, led to the isolation of a known briarane, excavatolide B (89),40,68) along with two new briaranes, briaviolides Y (90) and Z (91)68) (Fig. 4). The absolute configuration of excavatolide B (89) was further determined by SC-XRD analysis, while the structures of briaranes 90 and 91 were elucidated using spectroscopic methods.68)
Two structurally distinct probes of excavatolide B (89) were prepared based on structure–activity relationship (SAR) studies and successfully utilized to identify Stimulator of Interferon Genes (STING) as a direct target of 89 in living mammalian cells.69) The epoxy-γ-lactone moiety in 89 is essential for specific interaction with STING and its ability to inhibit STING signaling by directly competing with STING palmitoylation at Cys91. This discovery introduces a new class of covalent STING inhibitors and provides initial mechanistic insights into the anti-inflammatory activity of excavatolide B (89).69)
2.5. Dichotella gemmacea (Milne Edwards & Haime, 1857) (Family Ellisellidae)In 2021, a total of 28 new briaranes, gemmolides A–Z (92–117), along with gemmolides Z1 (118) and Z2 (119)70) were isolated, as well as 11 known analogs, including gemmacolides AZ (120) and BA (121)70,71); junceellolide D (122)72); (−)-4-deacetyljunceellolide D (123)73); juncin Z (124)74); gemmacolide ZXXVIII (125)75,76); frajunolide N (126)77); juncenolide H (127)78); gemmacolides A (128)79) and V (129)80); and fragilisinin H (130).81) These compounds were obtained from the octocoral Dichotella gemmacea (synonyms: Verrucella gemmacea, Ellisella gemmacea, and Junceella gemmacea), collected from the waters of Weizhou Island, China70) (Fig. 5).
The structures of all briaranes 92–130 were elucidated through spectroscopic methods and by comparing their spectroscopic data with previously reported compounds. The absolute configurations of the new briaranes 92–119 were further supported by calculated electronic circular dichroism (ECD) spectra and their enantiomers using the TDDFT-ECD method.70) Additionally, the structures of gemmolide A (92) and gemmacolide AZ (120) were further confirmed by SC-XRD analysis.70)
To further investigate the SAR of these briaranes, junceellolide D (122) was identified as a promising lead compound for anti-osteoclastogenesis. It was found to activate nuclear factor erythroid 2-related factor 2 (Nrf2) while suppressing NF-κBs and mitogen-activated protein kinase (MAPK) signaling pathways, thereby preventing osteoclast-mediated bone destruction.70)
2.6. Ellisella sp. (Family Ellisellidae)Wu et al. isolated 12 8-hydroxybriaranes from the ethanol extract of an octocoral identified as Ellisella sp., collected from the South China Sea.82) These included eight newly discovered compounds, ellisellolides A–H (131–138),82) along with four known analogs: junceellolide N (139),83) fragilisinin H (130),81) fragilide W (140),84) and junceellolide C (141)72,85) (Fig. 6). The structures of the new briaranes 131–138 were elucidated through comprehensive spectroscopic analysis, with their absolute configurations further confirmed by calculated ECD data.82) Notably, the conformation of the 3(E),5(16)-conjugated diene moiety in junceellolide C (141) was revised from an s-trans to an s-cis form based on a nuclear Overhauser effect spectroscopy (NOESY) experiment in a subsequent study.85) Additionally, this compound was found to exhibit anti-hepatitis B virus (HBV) activity.82)
Octocorals of the genus Junceella are recognized as a significant source of briarane-related natural diterpenoids.86–88) In 2020, a new briarane, 17-epi-junceellolide B (142), was identified in the octocoral J. fragilis, collected from Con Co Island, Vietnam.89) Alongside this newly discovered compound, nine previously known analogs were also isolated, including junceellonoids A–D (143–146),90,91) junceellolides A (147), B (148), C (141), and D (122),72) as well as (−)-4-deacetyljunceellolide D (123)73) (Figs. 5–7). The structure of 17-epi-junceellolide B (142) was determined through spectroscopic analysis. Notably, only four briarane derivatives, 17-epi-junceellolide B (148); fragilides S (I) and T (II); and briavioid D (III) (Fig. 7), are known to contain a rare 17β-methyl group in their structures.64,89,92)
Additionally, junceellolide B (148) was identified as a transcription inhibitor of covalently closed circular DNA (cccDNA), making it a promising lead for the development of new anti-HBV agents.93) Furthermore, two chlorinated briaranes, including a newly discovered metabolite, fragilide Y (149),94,95) as well as a known compound, fragilide D (150),96) were isolated from J. fragilis collected off Ximao Island in the South China Sea94) (Fig. 7).
The structure of the newly identified briarane 149 was elucidated using spectroscopic methods; however, the stereochemistry of the functional group 2-((3-methylbutanoyl)oxy)propanoate at C-2 in 149 remains undetermined.94)
Additionally, four new briaranes, fragilides X–Z (151–153)85,95,97,98) and (−)-frajunolide H (154),85) along with eight known analogs, including juncenolide K (155),78,97) fragilide P (156),99) junceellolides B (148), C (141), and D (122),72,85) 12-epi-fragilide G (157),100) junceellonoid A (143),90) and juncin ZI (158),74) were discovered from J. fragilis collected from the waters off Taiwan85,98) (Figs. 5–7).
The structures of isolates 122, 141, 143, 148, and 151–158 were determined through extensive spectroscopic analysis and by comparing their spectroscopic data with those of known analogs. The absolute configurations of 122 (junceellolide D),98) 143 (junceellonoid A),98) 154 ((−)-frajunolide H),85) 155 (juncenolide K),97) 156 (fragilide P),85,98) 157 (12-epi-fragilide G),98) and 158 (juncin ZI)98) were further confirmed by SC-XRD analysis. Additionally, the stereochemistry of the known compounds 155 (juncenolide K),97) 148 (junceellolide B), and 141 (junceellolide C)85) was revised.
Originally, juncenolide K (155) was assigned an 11α,20α-epoxy group with a chair-conformation cyclohexane ring.78) However, SC-XRD and spectroscopic analysis revealed that the 11,20-epoxy group in 155 is actually 11β,20β-oriented, and the cyclohexane ring adopts a twist-boat conformation.97) SC-XRD analysis of 154 ((−)-frajunolide H) and 156 (fragilide P) further revealed that the ∆3(E),5(16)-conjugated diene moieties in these compounds exist in an s-cis form,85) contradicting the initial s-trans assignment for frajunolide H, the enantiomer of 154101) (Fig. 8).
Additionally, NOESY experiments conducted on 148 (junceellolide B) and 141 (junceellolide C) demonstrated that the conformation of the ∆3(E),5(16)-conjugated diene system in both compounds should be revised to an s-cis form.85) Based on these findings, it is suggested that the conformation of all briaranes featuring a 3(E),5(16)-conjugated diene system should be re-evaluated and assigned an s-cis form.85)
2.8. Junceella juncea (Pallas, 1776) (Family Ellisellidae)A total of 45 briaranes, including 16 newly identified compounds, juncelactones A–P (159–174), along with 29 previously known analogs, were isolated from the octocoral Junceella junea collected from the South China Sea in May 2015.102) The known compounds include gemmolides A–C (92–94)70,102,103) and U (112)70); praelolide (175)72,73,80,83,91,93,101,102,104–119); juncins P (176)110) and Z (177)74,99,101); gemmacolides C (178),79) I (179),120) L (180),120) P (181),121) V (129),80) X (182) (=dichotellide T),80,116,118) Y (183),80) AJ (184),122) ZIX (185),75,76) and ZXXVIII (125)75,76); juncenolide J (186)78); junceellolides C (141)72,85) and D (122)72); 12-epi-fragilide G (157)100,123); 11-epi-juncin A (187) (=juncin A)124); umbraculolides A (188)107,125) and E (189)126); fragilide F (190)127); 11β,20β-epoxy-4-deacetoxyjunceellolide D (191)73,128) and 11β,20β-epoxyjunceellolide D (192)73,128); fragilolide J (193)129); and dichotellide U (194)116) (Figs. 5–7, 9).
The structures of all newly identified compounds were determined through extensive spectroscopic analysis. The absolute configurations of juncelactones A (159) and E (163) were further confirmed by SC-XRD analysis, with Flack parameters of x = 0.006 (4) and 0.012 (5), respectively. The absolute configurations of juncelactones B–J (160–168) were elucidated through DP4+ quantum calculations and ECD spectral analysis.102) Notably, praelolide (175) was found to significantly activate Nrf2 nuclear translocation, induce the expression of Nrf2-targeted genes, reduce ROS production, suppress the activation of downstream MAPK/NF-κB signaling, and ultimately inhibit osteoclast differentiation.102) These findings suggest that praelolide could serve as a promising scaffold for developing treatments for osteoclastogenic bone diseases.119) In anti-osteoclastogenesis activity assays, praelolide (175) exhibited a 100% inhibitory effect at a concentration of 10 µM, whereas its 17-epimer, juncelactone B (160), showed only a 12.2% inhibitory effect. Since the only structural difference between these two compounds lies in the stereochemistry at C-17, this suggests that the anti-osteoclastogenesis activity is highly dependent on this configuration. The presence of a β-oriented proton at C-17 may play a crucial role in enhancing the activity.102)
2.9. Erythropodium caribaeorum (Duchassaing & Michelotti, 1860) (Family Erythropodiidae)Two new briaranes, erythrolides W (195) and X (196),130) along with 11 known analogs, erythrolides A (197),131–134) B (198),131–134) D (199),132,133) E (200),132,134) F (201),132) I (202),132) J (203),134) R (204),135) U (205),135) V (206),135) and 16-acetyl erythrolide H (207),132,136) (Fig. 10), were isolated from Erythropodium caribaeorum collected from three environmentally distinct coral reef areas in the South and Southwest Caribbean Sea.130) The structures of the newly identified briaranes 195 and 196 were determined using spectroscopic methods and by comparing their NMR data with those reported in the literature. Metabolic profiling via LC-MS identified three distinct chemotypes of E. caribaeorum from the Colombian Caribbean Sea based on their erythrolide composition.130) Erythrolide A (197) demonstrated selective cytotoxicity against PC3 human prostate cancer cells and MCF7 human breast cancer cells, with IC50 values of 2.45 and 6.77 µM, respectively. Erythrolide D (199) exhibited cytotoxicity against A549 human lung adenocarcinoma cells, with an IC50 value of 2.58 µM.130)
Notably, erythrolide B (198) displayed cytotoxic effects against PC3, MCF7, and A549 tumor cells, with IC50 values of 6.46, 15.21, and 27.09 µM, respectively. In contrast, erythrolide R (204) did not exhibit cytotoxicity against these tumor cell lines, suggesting that the presence of an acetoxy group at C-4 enhances cytotoxicity, as evidenced by the differences in structure and activity between erythrolides 198 and 204. Furthermore, erythrolide B (198) was identified as an apoptosis inducer through annexin flow cytometry analysis and was found to function as a promising tubulin-stabilizing agent.137)
Over the past five years, a total of 207 briarane-type diterpenoids have been isolated from soft corals of the order Scleralcyonacea, including 113 newly identified metabolites. These compounds have been found exclusively in marine environments, particularly in octocorals, and continue to draw significant interest due to their structural complexity and bioactivity. To date, 872 briarane-type diterpenoids have been reported from various marine organisms, with octocorals representing the predominant source. Among these, 422 (48.4%) and 186 (21.3%) compounds have been isolated from corals belonging to the genera Briareum and Junceella, respectively. These metabolites serve as chemotaxonomic markers for these two genera, underlining their importance in the classification and study of marine natural products, although the biological functions of this type of diterpenoids in corals have not yet been clarified.1–7,86,109)
The briarane scaffold is characterized by a highly oxidized bicyclo[8.4.0] ring system with multiple stereocenters and diverse oxygenated functionalities. These structural features make them exceptionally challenging synthetic targets and have spurred the development of novel synthetic strategies. From a synthetic chemistry perspective, the construction of the densely functionalized and stereochemically rich core has required innovative approaches. Notably, Moon and Harned developed a concise synthetic route to the stereotetrad core of briarane diterpenoids, utilizing the unique reactivity of salicylate ester-derived 2,5-cyclohexadienones. Their strategy involved a highly diastereoselective acetylide conjugate addition followed by β-ketoester alkylation, effectively establishing the C-1 quaternary and C-10 tertiary vicinal stereocenters.138)
In addition to this work, several other synthetic efforts have been reported, focusing on either total synthesis or core fragment construction. These advancements continue to refine synthetic accessibility and improve the functionalization of these complex molecules.139–142)
Briarane-type diterpenoids also hold significant promise in the field of chemical biology due to their diverse and potent biological activities. Their unique structures enable them to interact with a variety of molecular targets. A notable example is a derivative of excavatolide B (compound 89), which has been reported as a site-selective, covalent, and orally bioavailable inhibitor of STING-a key regulator in innate immune signaling pathways.143) Such findings underscore the potential of briaranes not only as lead compounds in drug discovery but also as chemical probes for elucidating complex biological mechanisms.
Geographically, the majority of briaranes reported from 2020 to 2024-excluding compounds 1–9 and 195–207 were isolated from octocorals collected in the Indo-Pacific region, particularly the South China Sea. This region is recognized for its exceptional marine biodiversity, positioning it as a vital and largely untapped source of chemical diversity.
Despite their potential, the isolation, structural elucidation, and biological evaluation of briarane-type diterpenoids remain challenging, largely due to their complex polycyclic and highly oxidized frameworks. These obstacles continue to drive research efforts in both natural product chemistry and synthetic methodology. Looking ahead, advancements in analytical technologies such as high-resolution mass spectrometry (HRMS) and NMR spectroscopy are expected to facilitate the discovery and characterization of new briaranes. These developments will likely lead to the identification of novel structures with unique biological activities, further broadening the scope of their application in medicinal chemistry and drug development.
This research was primarily funded by Grants from the National Museum of Marine Biology & Aquarium and the National Science and Technology Council (NSTC 112-2320-B-291-002-MY3, 113-2320-B-291-001, and 112-2811-B-291-002), Taiwan, awarded to P.-J. S. Their generous support is sincerely appreciated.
The authors declare no conflict of interest.
