Briarane Diterpenoids Isolated from Gorgonian Corals between 2011 and 2013

The structures, names, bioactivities and references of 138 briarane-type diterpenoids, including 87 new compounds, are summarized in this review. All the briarane-type compounds mentioned in this review article were obtained from gorgonian corals including the genus Briareum, Dichotella, Junceella and Verrucella. Some of these compounds showed potential bioactivities.


Introduction
This review describes the structures, names, bioactivities and references for all diterpenoid compounds in tabular form. This study reviewed literature from 2011 to 2013 and describes 138 briarane-type diterpenoids (including 87 new compounds) that possess a bicycle [8.4.0] carbon skeleton, and most possess a γ-lactone moiety in their structure (Scheme 1). As in previous reviews [1][2][3][4], we showed the structures, names, bioactivities and references for these briaranes. All briaranes mentioned in this article were isolated from octocorals belonging to the order Gorgonacea, including Briareum asbestinum, Briareum excavatum, Briareum spp., Dichotella fragilis, Dichotella gemmacea, Junceella fragilis, Junceella juncea and Verrucella umbraculum. This survey of briarane-type compounds is presented taxonomically according to genus and species. Scheme 1. The carbon skeleton of briarane-type compounds.

Briareum asbestinum
Gorgonian corals belonging to the genus Briareum play a main role in producing briarane-type natural products. In further studies on the chemical constituents of Caribbean gorgonian B. asbestinum, the most famous species related to briarane metabolites, collected at Hillsboro Ledge, Boca Raton, Florida, yielded nine briareolate ester metabolites, including five new compounds, briareolate esters J-N (1-5) (Table 1) [5,6], and four known analogues, briareolate esters B-D and G [5][6][7][8]. Briareolate esters are a unique group of briaranes that contain a C-19 methyl ester instead of the γ-lactone ring, and compounds of this type have only been found in B. asbestinum. Briaranes 3 and 4 have been  19 20 proven to be the first natural products possessing a 10-membered ring with an (E,Z)-dieneone moiety, and they exhibit cytotoxicity towards BG02 and BxPC-3 cells. SAR (structure-activity-relationship) study confirmed the importance of the (E,Z)-dieneone moiety for bioactivity among briaranes 1-4 [5].

Briareum excavatum
In continuation of the search for new natural products from marine invertebrates collected off the waters of Taiwan at the intersection of the Kuroshio current and the South China Sea surface current, gorgonian B. excavatum, collected at Orchid Island off Taiwan, was examined for its complex and interesting chemical constituents. Eight briarane derivatives, including six new compounds, briacavatolides A-F (6-11) [9,10] (Table 2) and two known metabolites, briaexcavatolide U and briaexcavatin L [9,11,12], were isolated. Briacavatolides C (8) and F (11) were found to show antiviral activity against HCMV using a human embryonic lung (HEL) cell line [9,10]. By comparing the structures of 8 and 10, the 9-acetoxy group was found to be essential for the anti-HCMV activity by SAR study. 10 Briacavatolide E (R 1 = CH 3 , R 2 = OH, Briacavatolide D (R = CH 2 OH) - [10] 11 Briacavatolide F IC 50 (HCMV) = 22 μM [10] a HCMV (human cytomegalovirus).

Dichotella fragilis
Four known briaranes, juncins P and U [20,21], junceellolide D [22] and junceol A [23], were isolated from gorgonian D. fragilis, collected from Meishan, Sanya sea area in the South China Sea [24]. Juncin P and junceellolide D were found to display antifouling activity against the larval settlement of  [24]. Juncin U displayed mild antifouling activity against the larval settlement of B. amphitrite at a concentration of 50.0 μg/mL [24].
It is interesting to note that gemmacolides J (27), V (39) and Y (42) showed significant activities towards A549 cells as compared with the activities of their analogues and the positive control (doxorubicin, IC 50 = 2.8 μM) [25,27]. Gemmacolide Y (42) displayed stronger activity toward MG63 cells than its analogues and the positive control (doxorubicin, IC 50 = 3.2 μM) [27]. SAR study of the active components 27, 39 and 42 and their analogues will potentially lead to the discovery of agents of medical benefit.

Conclusions
In 1977, the first briarane-type natural product, briarein A, was isolated from the Caribbean gorgonian Briareum asbestinum [54]. To date, approximately 600 briarane-type diterpenoids have been isolated from various marine organisms, particularly soft corals belonging to the order Gorgonacea. Compounds of this type of diterpenoid have been proven to possess various bioactivities. Except for the briaranes from B. asbestinum, all the briaranes reported between 2011 and 2013 were obtained from the gorgonian corals distributed in the Indo-Pacific Ocean, particularly from the South China Sea. Because of the structural complexity of the compounds, it is difficult to establish a stable supply of bioactive briaranes by chemical methods. Due to the potential medicinal applications, coral aquaculture to support bioactive briaranes is becoming very attractive [55][56][57][58][59]. For example, briaranes from Briareum excavatum, collected off the waters of Taiwan, were proven to possess significant anti-inflammatory activity [60], and in order to establish a stable supply of bioactive materials, the coral has been cultured successfully using a flow-through sea water system, in the National Museum of Marine Biology and Aquarium, Taiwan for the extraction of additional natural products.