Briarane Diterpenoids Isolated from Octocorals ... - Semantic Scholar

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Feb 17, 2017 - Graduate Institute of Marine Biology, National Dong Hwa University, ... Department of Marine Biotechnology and Resources, National Sun ...
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Briarane Diterpenoids Isolated from Octocorals between 2014 and 2016 Yin-Di Su 1 , Jui-Hsin Su 1,2 , Tsong-Long Hwang 3 , Zhi-Hong Wen 4 , Jyh-Horng Sheu 4, *, Yang-Chang Wu 5,6,7, * and Ping-Jyun Sung 1,2,4,5,8, * 1 2 3

4 5 6 7 8

*

National Museum of Marine Biology and Aquarium, Pingtung 944, Taiwan; [email protected] (Y.-D.S.); [email protected] (J.-H.S.) Graduate Institute of Marine Biology, National Dong Hwa University, Pingtung 944, Taiwan Graduate Institute of Natural Products, College of Medicine, Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University; Research Center for Chinese Herbal Medicine, Research Center for Food and Cosmetic Safety, and Graduate Institute of Health Industry Technology, College of Human Ecology, Chang Gung University of Science and Technology; Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; [email protected] Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 804, Taiwan; [email protected] Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 807, Taiwan Research Center for Natural Products and Drug Development, Kaohsiung Medical University, Kaohsiung 807, Taiwan Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung 404, Taiwan Correspondence: [email protected] (J.-H.S.); [email protected] (Y.-C.W.); [email protected] (P.-J.S.); Tel.: +886-7-525-2000 (ext. 5030) (J.-H.S.); +886-7-312-1101 (ext. 2197) (Y.-C.W.); +886-8-882-5037 (P.-J.S.); Fax: +886-7-525-5020 (J.-H.S.); +886-7-311-4773 (Y.-C.W.); +886-8-882-5087 (P.-J.S.)

Academic Editor: Orazio Taglialatela-Scafati Received: 27 January 2017; Accepted: 15 February 2017; Published: 17 February 2017

Abstract: The structures, names, bioactivities, and references of 124 briarane-type natural products, including 66 new metabolites, isolated between 2014 and 2016 are summarized in this review article. All of the briarane diterpenoids mentioned in this review were isolated from octocorals, mainly from Briareum violacea, Dichotella gemmacea, Ellisella dollfusi, Junceella fragilis, Junceella gemmacea, and Pennatula aculeata. Some of these compounds exhibited potential biomedical activities, including anti-inflammatory activity, antibacterial activity, and cytotoxicity towards cancer cells. Keywords: briarane; octocoral; Briareum; Dichotella; Ellisella; Junceella; Pennatula

1. Introduction Following previous review articles from our research group focused on marine-origin briarane-type natural products [1–5], this review covers the literature from 2014 to January 2017, and describes 124 briarane-related diterpenoids (including 66 new metabolites), most of which are characterized by the presence of a γ-lactone moiety fused to a bicyclo[8.4.0] ring system, obtained from various octocorals (Figure 1), mainly Briareum violacea, Briareum spp. Dichotella gemmacea, Ellisella dollfusi, Junceella fragilis, Junceella gemmacea, and Pennatula aculeata. Many of these compounds exhibited interesting bioactivities in vitro, which might indicate a potential for use in biomedical applications. This survey of briarane-related compounds is presented taxonomically according to genus and species.

Mar. Drugs 2017, 15, 44; doi:10.3390/md15020044

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2

   C‐3/8 cyclization

3

  C‐7/19 cyclization

8

8

7

12

[O]

7

   C‐3/8 cyclization

3

13

  C‐7/19 cyclization 19

14

13 12

[O]

15

11 14 20 11

16 5

1 10 2

6

3

4

9

8

1 10 9 8 18

20 19

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4

16

7 5

6 17 19 7

17 19

O

O O

 

Figure  1.  Possible  biogenetic  origin  of  briarane‐type  metabolites.  The  numbering  system shown  is  Figure 1. Possible biogenetic origin of briarane-type metabolites. The numbering system O shown   is that that presently in use [1].  presently in use [1]. 18

Figure  1.  Possible  biogenetic  origin  of  briarane‐type  metabolites.  The  numbering  system shown  is  that presently in use [1].  2. Alcyonacea 

2. Alcyonacea

2. Alcyonacea 

2.1.2.1. Briareum violacea (Family Briareidae)  Briareum violacea (Family Briareidae) The  taxonomic  position  of  octocorals  affiliated  with  the  genus  Briareum  (=  Asbestia,  2.1. Briareum violacea (Family Briareidae)  The taxonomic position of octocorals affiliated with the genus Briareum (=Asbestia, Pachyclavularia, Pachyclavularia,  and  Solenopodium)  [6]  has  been  found  to  be  situated  near  the  transition  between  and Solenopodium) [6] has been found to be situated nearwith  the transition and The  taxonomic  position  of  octocorals  affiliated  the  genus between Briareum Alcyonacea (=  Asbestia,  Alcyonacea and Gorgonacea, in both taxonomic and chemical terms [6–8]. In 1977, briarein A, the  Gorgonacea, in both taxonomic and chemical terms [6–8]. In 1977, briarein A, the first briarane-type Pachyclavularia,  and  diterpenoid  Solenopodium)  [6]  has  been  to  be  situated  near  the  transition  first  briarane‐type  identified,  was found  isolated  from  the  Caribbean  octocoral  between  Briareum  diterpenoid identified, was isolated from the Caribbean octocoral Briareum asbestinum [9], and since Alcyonacea and Gorgonacea, in both taxonomic and chemical terms [6–8]. In 1977, briarein A, the  asbestinum  [9],  and  since  then  Briareum  has  been  the  main  organism  from  which  briarane‐type  then Briareum has been the main organism from which briarane-type natural products have first  briarane‐type  diterpenoid  identified,  was  isolated  from  the  Caribbean  octocoral  Briareum  natural products have been obtained.  asbestinum  [9],  and  since  then  Briareum  has  been  the  main  organism  from  which  briarane‐type  been obtained. Sixteen  briarane  diterpenoids,  including  10  new  8‐hydroxybriaranes,  briaviolides  A–J  (1–10)  natural products have been obtained.  Sixteen2),  briarane diterpenoids, includingsolenolides  10 new 8-hydroxybriaranes, A–J (1–10) (Figure 2), (Figure  and  six  known  metabolites,  A  [10]  and  D  (= briaviolides briaexcavatolide  E)  [1,10–12],  diterpenoids,  including  10  new  briaviolides  A–J  (1–10)  andexcavatolide  sixSixteen  knownbriarane  metabolites, solenolides A [10] and D 8‐hydroxybriaranes,  (=briaexcavatolide E) [1,10–12], excavatolide A  [13],  briaexcavatolide  I  [12],  4β‐acetoxy‐9‐deacetylstylatulide  lactone,  and  (Figure  2),  and  six  known  metabolites,  solenolides  A  [10]  and  D  (=  briaexcavatolide  E)  [1,10–12],  A [13], briaexcavatolide I [12], 4β-acetoxy-9-deacetylstylatulide lactone, and 9-deacetylstylatulide 9‐deacetylstylatulide lactone [14], were isolated from the octocoral Briareum violacea, collected from  excavatolide  [13],  from briaexcavatolide  [12],  4β‐acetoxy‐9‐deacetylstylatulide  lactone,  and  the waters of Taiwan [15]. The structures of new briaranes 1–10 were established by chemical and  lactone [14], wereA isolated the octocoralI Briareum violacea, collected from the waters of Taiwan [15]. 9‐deacetylstylatulide lactone [14], were isolated from the octocoral Briareum violacea, collected from  and  determination  of  the  absolute  configuration  of  briaviolide  A  (1)  was  Thespectroscopic  structures ofmethods,  new briaranes 1–10 were established by chemical and spectroscopic methods, and the waters of Taiwan [15]. The structures of new briaranes 1–10 were established by chemical and  completed by X‐ray diffraction analysis of its monobenzoyl derivative [15]. At a concentration of 10  determination of the absolute configuration of briaviolide A (1) was completed by X-ray diffraction spectroscopic  methods,  and  determination  of  the moderate  absolute  configuration  of  briaviolide  A  (1)  was  μg/mL,  5  and  9  were  found [15]. to  exert  inhibitory  activities  on briaranes elastase  release  analysis of briaranes  its monobenzoyl derivative At a concentration of 10 µg/mL, 5 and 9 completed by X‐ray diffraction analysis of its monobenzoyl derivative [15]. At a concentration of 10  (inhibition rate = 26.0% and 28.8%, respectively) and superoxide anion production (inhibition rate =  were found to exert moderate inhibitory activities on elastase release (inhibition rate = 26.0% and μg/mL,  briaranes  5  and  9  were  found  to  exert  moderate  inhibitory  activities  on  elastase  release  34.2% and 28.7%, respectively) by human neutrophils [15].  28.8%, respectively) and superoxide anion production (inhibition rate = 34.2% and 28.7%, respectively) (inhibition rate = 26.0% and 28.8%, respectively) and superoxide anion production (inhibition rate =  by 34.2% and 28.7%, respectively) by human neutrophils [15].  human neutrophilsOAc [15]. R1 OAc     O AcO O

O

OAc

  O

OH

R4 R3 R4

R1

R

AcO H

O R2

H R2

R1

 

OH

O R1 R2

3 O O   R2 AcO 1: R1 = α‐Cl, R2 = β‐methyl, R 3 = α‐H, R4 = OH 2: R1 = α‐Cl, R2 = β‐methyl, R3 = α‐H, R 4 = OC(O)Et  O   3: R 2 = β‐methyl, R3 = α‐H, R4 = OAc  1: R11 = β‐OAc, R  = α‐Cl, R2 = β‐methyl, R 3 = α‐H, R4 = OH 1 = α‐Cl, R2 = α‐methyl, R3 = β‐OH, R4 = OH  2: R4: R 1 = α‐Cl, R2 = β‐methyl, R3 = α‐H, R4 = OC(O)Et 

O

AcO

OH

Cl

H AcO H AcO

OH

O

Cl

O O

5: R1 = OAc, R2 = β‐OC(O)CH2CH(CH3)2  O 6: R1 = OH, R2 = α‐OC(O)(CH 2)4CH3  7: R1 = OAc, R 2 = α‐OAc  2 = β‐OC(O)CH2CH(CH3)2  5: R1 = OAc, R

6: R1 = OH, R2 = α‐OC(O)(CH2)4CH3  3: R1 = β‐OAc, R2 = β‐methyl, R3 = α‐H, R4 = OAc  7: R1 = OAc, R2 = α‐OAc  Figure 2. Structures of briaviolides A–J (1–10).  4: R1 = α‐Cl, R2 = α‐methyl, R3 = β‐OH, R4 = OH 

2.2. Briareum sp. 

R R

OAc OH H HO H

O

OH

HO

O O

8: R = OH  9: R = OOH  O 10: R = OAc  8: R = OH  9: R = OOH  10: R = OAc 

Figure 2. Structures of briaviolides A–J (1–10). 

Figure 2. Structures of briaviolides A–J (1–10).

In  continuing  chemical  studies  of  the  constituents  of  an  octocoral  identified  as  Briareum  sp.  2.2. Briareum sp. 

2.2.collected from the southern waters of Taiwan, 22 new briarane derivatives, briarenolides J–Y (11–26)  Briareum sp.

continuing  chemical  studies  of and  the their  constituents  of  an  octocoral based  identified  as  Briareum  sp.  and In  ZI–ZVI  (27–32),  were  obtained,  structures  determined  on  analysis  of  their  In continuing chemical studies of the constituents of an octocoral identified as Briareum sp. collected from the southern waters of Taiwan, 22 new briarane derivatives, briarenolides J–Y (11–26)  spectroscopic data (Figure 3) [16–20]. Briarenolide J (11) was the first 12‐chlorinated diterpenoid to  collected from the southern of Taiwan, 22 structures  new briarane derivatives, briarenolides (11–26) and  ZI–ZVI  (27–32),  were waters obtained,  and  their  determined  based  on  analysis J–Y of  their  1H and  13C NMR chemical shifts of  be isolated from Briareum sp. [16]. The relationships between the  and ZI–ZVI (27–32), were obtained,3,5(16) and their structures determined 3,5based on analysis of their spectroscopic data (Figure 3) [16–20]. Briarenolide J (11) was the first 12‐chlorinated diterpenoid to  2‐hydroxybriaranes  possessing  a  Δ ‐conjugated  diene  moiety  or  a  Δ ‐conjugated  moiety  have  1H and  spectroscopic data (Figure 3) [16–20]. Briarenolide J (11) was the first1312-chlorinated diterpenoid be isolated from Briareum sp. [16]. The relationships between the  C NMR chemical shifts of  been  summarized  [18].  Briarane  11  has  been  shown  to  inhibit  superoxide  anion  generation  and  1 13 3,5(16) 3,5 to be isolated from Briareum sp. [16]. The relationships between the H and C NMR chemical shifts 2‐hydroxybriaranes  possessing  a  Δ ‐conjugated  diene  moiety  or  a  Δ ‐conjugated  moiety  have  elastase  release,  with  IC50  values  of  15.0  and  10.0  μM,  respectively  [16].  In  macrophage  cells,  3,5(16) 3,5 -conjugated summarized  [18].  Briarane  11  has  been  shown  to  inhibit  superoxide  anion  generation  and  of been  2-hydroxybriaranes possessing a ∆ -conjugated diene moiety or a ∆ moiety briaranes 12–14, 17, 20–24, 26, 28, and 32 were found to reduce the level of iNOS to 23.7, 31.7, 49.6,  elastase  with  IC 50  values  of  15.0  and  10.0 shown μM,  respectively  [16].  In  macrophage  cells,  have been release,  summarized [18]. Briarane 11 has been to inhibit superoxide anion generation 58.4, 57.4, 53.5, 41.9, 47.3, 50.1, 54.3, 47.2, and 55.7%, respectively, at a concentration of 10 μM [17– briaranes 12–14, 17, 20–24, 26, 28, and 32 were found to reduce the level of iNOS to 23.7, 31.7, 49.6,  and elastase release, with IC50 values of 15.0 and 10.0 µM, respectively [16]. In macrophage cells, 58.4, 57.4, 53.5, 41.9, 47.3, 50.1, 54.3, 47.2, and 55.7%, respectively, at a concentration of 10 μM [17–

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briaranes 12–14, 17, 20–24, 26, 28, and 32 were found to reduce the level of iNOS to 23.7%, 31.7%, 49.6%, Mar. Drugs 2017, 15, 44  3 of 11  58.4%, 57.4%, 53.5%, 41.9%, 47.3%, 50.1%, 54.3%, 47.2% and 55.7%, respectively, at a concentration of 10 µM [17–20]. Briaranes 15, 17, 21–24, and 26 were found to reduce the level of COX-2 to 53.9%, 59.1%, 20]. Briaranes 15, 17, 21–24, and 26 were found to reduce the level of COX‐2 to 53.9, 59.1, 59.3, 26.1,  59.3%, 26.1%, 35.6%, 58.1% and 55.4%, respectively, at a concentration of 10 µM [18,19]. 35.6, 58.1, and 55.4%, respectively, at a concentration of 10 μM [18,19].  OAc

AcO

OH

R

AcO

O

OH

AcO

O

O

O

R

O Cl

Cl

H

OH AcO

O

HO

OH

OH

H

AcO

H

O

AcO

O

O

AcO

O

 

 

11 

12: R = CH2OAc  14: R = CH2Cl 

O

O

 

13: R = OC(O)Or 

15 

R1

O

O

AcO

 

OH

OAc

H

OH

O R3

OH AcO

OH

OCH3

R2

H O

AcO

Cl

H

O

AcO

O

OH

O

H

O

HO

O

O

 

17: R1 = R2 = OH, R3 = Cl    18: R1 = R2 = OAc, R3 = OH 

16 

19 

OH

R1

AcO

R2

R3

Cl OH

O

OH

R6

H

H

O

HO

R5

O

 

OAc

O

OH

OH

OH

O

O

OH

OH

R2

H

OH R

H

O

AcO

O

AcO

O

OAc

O

OH

O

O   24: R = OAc, 25: R = OC(O)Pr 

23: R1 = CH2OH, R2 = OC(O)Pr 

OH

Cl

H AcO

O

 

22 

OAc

AcO

OAc

AcO

O

OH

O

OH

R1

H AcO

OH

O

R1

OCH3

R2

O

21: R1 = OH, R2 = OAc, R3 = α‐OC(O)Pr, R4 = α‐H, R5 = β‐methyl, R6 = β‐OH 30: R1 = OAc, R2 = H, R3 = β‐OH, R4 = α‐H, R5 = β‐methyl, R6 = α‐OC(O)Pr  31: R1 = OAc, R2 = R3 = H, R4 = β‐OH, R5 = α‐methyl, R6 = α‐OH  32: R1 = OAc, R2 = H, R3 = β‐OAc, R4 = α‐H, R5 = β‐methyl, R6 = β‐OH 

20 

HO

R4 HO

O

Cl

HO HO

H HO

O

  26: R1 = R2 = OAc 

O O

  27 

R

H HO

O O

O

H O O

HO

O

  28: R = OC(O)Pr 

Figure 3. Structures of briarenolides J–Y (11–26) and ZI–ZVI (27–32). 

Figure 3. Structures of briarenolides J–Y (11–26) and ZI–ZVI (27–32).

O

 

29 

 

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3. Gorgonacea 

3.1. Dichotella gemmacea (Family Ellisellidae)

3. Gorgonacea  3.1. Dichotella gemmacea (Family Ellisellidae) 

In 2014, Zhang et al. reported the isolation of seven new briarane derivatives, which were In  2014,  Zhang AS–AY et  al.  reported  isolation  of  seven  new  derivatives, gemmacolides which  were  3.1. Dichotella gemmacea (Family Ellisellidae)  named gemmacolides (33–39)the  (Figure 4), along with 10 briarane  known analogues, named gemmacolides AS–AY (33–39) (Figure 4), along with 10 known analogues, gemmacolides L  L [21], X AH, AO, AQ [24], junceellolides C and D [25], junceellin In (=dichotellide 2014,  Zhang  et T)al. [22,23], reported  the AJ, isolation  of  seven  new  briarane  derivatives,  which  were  [21],  X  (=  dichotellide  T)  [22,23],  AH,  AJ,  AO,  AQ  [24],  junceellolides  C  and  D  [25],  junceellin  (=  (=junceellin A) [25–32], and frajunolide K [33], from the South China Sea gorgonian coral, named gemmacolides AS–AY (33–39) (Figure 4), along with 10 known analogues, gemmacolides L  junceellin A) [25–32], and frajunolide K [33], from the South China Sea gorgonian coral, D. gemmacea  [21],  X  (= [34]. dichotellide  T)  determination [22,23],  AH,  AJ,  [24],  junceellolides  C  and  D  using [25],  junceellin  (=  D. gemmacea Structural ofAO,  newAQ  briaranes 33–39 was conducted spectroscopic [34]. Structural determination of new briaranes 33–39 was conducted using spectroscopic methods,  junceellin A) [25–32], and frajunolide K [33], from the South China Sea gorgonian coral, D. gemmacea  methods, and their absolute configurations were established based on the results of electronic circular and  their  absolute  configurations  were  established  based  on  the  results  of  electronic  circular  [34]. Structural determination of new briaranes 33–39 was conducted using spectroscopic methods,  dichroism (ECD) experiments [34]. Briarane 37 was found to exert a cytotoxic effect towards MG-63 dichroism (ECD) experiments [34]. Briarane 37 was found to exert a cytotoxic effect towards MG‐63  and  their  absolute  configurations  were  established  based  (human osteosarcoma) cells, with an IC of 7.2 µM [34].on  the  results  of  electronic  circular  5050value (human osteosarcoma) cells, with an IC  value of 7.2 μM [34].  dichroism (ECD) experiments [34]. Briarane 37 was found to exert a cytotoxic effect towards MG‐63  (human osteosarcoma) cells, with an IC 50 value of 7.2 μM [34].  R1 OC(O)CH2OC(O)CH2CH(CH3)2 R4

R3 R3 R2 R2

(CH3)2HCCH2(O)CO

R5

AcO (CH3)2HCCH2(O)CO

R5

AcO AcO

R1

R4

OH O

H

O

AcO H

OH

O

AcO

AcO

AcO

H

O

AcO H

OH

(CH3)2HCCH2(O)CO (CH3)2HCCH2(O)CO

O

HO H

O

O OO

HO

Cl

37 

OAc

OAc

OH

OAc

OH OH

Cl H

O

O

37 

O O

Cl

OO

AcO

33: R1 = R2 = OAc, R3 = H, R4 = R5 = OC(O)CH2CH(CH3)2 O 2CH(CH3)2, R5 = OH  34: R1 = R2 = R4 = OAc, R3 = OC(O)CH 33: R11 = R  = R5 2= OAc, R  = OAc, R2 = R 3 = H, R 4 = R5 = OC(O)CH 2CH(CH 3)32)2  35: R 3 = OH, R 4 = OC(O)CH 2CH(CH 34: R1 = R2 = R 4 = OAc, R 3 = OC(O)CH 2CH(CH 3)2, R 5 = OH  5 = Cl  36: R1 = OC(O)CH 2OH, R 2 = OC(O)CH 2CH(CH 3)2, R3 = R 4 = OAc, R 35: R1 = R5 = OAc, R2 = R3 = OH, R4 = OC(O)CH2CH(CH3)2  OAc 36: R1 = OC(O)CH2OH, RAcO 2 = OC(O)CH2CH(CH3)2, R3 = R4 = OAc, R5 = Cl  AcO

OH O

O O

AcO

OC(O)CH2OC(O)CH2CH(CH3)2

AcO

Cl

AcO

O

H

O

AcO H

OH

AcO

 

38 

39

O   Figure 4. Structures of gemmacolides AS–AY (33–39). 39 38  Figure 4. Structures of gemmacolides AS–AY (33–39).

Cl O

Cl

OO

 

O

 

Figure 4. Structures of gemmacolides AS–AY (33–39).  A  new  briarane,  dichotellide  V  (40)  (Figure  5),  along  with  four  known  briarane  analogues,  A new briarane, dichotellide V (40) (Figure 5), along with four known briarane analogues, gemmacolide N [35], dichotellide J [23], junceellin A (= junceellin) [25–32], and junceellolide A [25],  A  new  briarane,  dichotellide  V  (40)  (Figure  5),  along  with  four  known  briarane  analogues,  gemmacolide N [35], dichotellide J [23], junceellin A (=junceellin) [25–32], and junceellolide were isolated from Dichotella gemmacea, collected from Meishan Island, Hainan Province, China [36].  gemmacolide N [35], dichotellide J [23], junceellin A (= junceellin) [25–32], and junceellolide A [25],  A [25], were isolated from Dichotella gemmacea, collected from Meishan Island, Hainan Province, The structure of new briarane 40 was determined by spectroscopic methods, and none of the above  were isolated from Dichotella gemmacea, collected from Meishan Island, Hainan Province, China [36].  compounds  effect 40 on  A549  (human  epithelial  lung  carcinoma),  China [36]. Theexhibited  structure a  ofcytotoxic  new briarane was determined by spectroscopic methods, BGC823  and none The structure of new briarane 40 was determined by spectroscopic methods, and none of the above  (human  cancer),  H1975  a(human  non‐small  lung  cancer),  HeLa  (human  cervix  of the abovegastric  compounds exhibited cytotoxic effect oncell  A549 (human epithelial lung carcinoma), compounds  exhibited  a  cytotoxic  effect  on  A549  (human  epithelial  lung  carcinoma),  BGC823  adenocarcinoma),  MCF7  (human  mammary  gland  adenocarcinoma),  or  U‐937  (human  histiocytic  BGC823 (human gastric cancer), H1975 (human non-small lung cancer), HeLa (human cervix (human  gastric  cancer),  H1975  (human  non‐small  cell  cell lung  cancer),  HeLa  (human  cervix  lymphoma) tumor cells [36].  adenocarcinoma), MCF7 (human mammary gland adenocarcinoma), or U-937 (human histiocytic adenocarcinoma),  MCF7  (human  mammary  gland  adenocarcinoma),  or  U‐937  (human  histiocytic  lymphoma) tumor cells [36]. lymphoma) tumor cells [36].  OAc AcO

(CH3)2HCCH2(O)CO

OAc

AcO

(CH3)2HCCH2(O)CO (CH3)2HCCH2(O)CO (CH3)2HCCH2(O)CO

OC(O)CH2CH(CH3)2 OH

O

H

O

AcO H AcO

OH

OC(O)CH2CH(CH3)2 O O O

Figure 5. Structure of dichotellide V (40).  O Figure 5. Structure of dichotellide V (40).  Figure 5. Structure of dichotellide V (40).

   

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Mar. Drugs 2017, 15, 44  5 of 11  Eight known briaranes, junceellolide D [25], (+)-11β,20β-epoxyjunceellolide D, (−)-11β,20β-epoxy-

4-deacetoxyjunceellolide D [30,37], junceol A [38], juncins H and K [39,40], praelolide [25,29–32,41,42], Eight  known  briaranes,  junceellolide  D  [25],  (+)‐11β,20β‐epoxyjunceellolide  D,  (−)‐11β,20β‐  and junceellin (=junceellin A) [25–32], were obtained from D. gemmacea, collected from Meishan Island, epoxy‐4‐deacetoxyjunceellolide D [30,37], junceol A [38], juncins H and K [39,40], praelolide [25,29– Hainan Province, China in April 2009 [43]. Junceellolide D and praelolide showed antifouling activity 32,41,42],  and  junceellin  (=  junceellin  A)  [25–32],  were  obtained  from  D.  gemmacea,  collected  from  against the settlement of larvae of barnacle Balanus amphitrite with EC50 values of 14.5 and 16.7 µM, Meishan Island, Hainan Province, China in April 2009 [43]. Junceellolide D and praelolide showed  respectively. Junceellolide D, (−)-11β,20β-epoxy-4-deacetoxyjunceellolide D, juncin H, and50praelolide antifouling activity against the settlement of larvae of barnacle Balanus amphitrite with EC  values  exhibited lethality brine shrimp Artemia salina with lethal ratios of 90%, 85%, 60% and 75% of  14.5  and  16.7 towards μM,  respectively.  Junceellolide  D,  (−)‐11β,20β‐epoxy‐4‐deacetoxyjunceellolide  D,  at a concentration of 50 µg/mL [43]. juncin H, and praelolide exhibited lethality towards brine shrimp Artemia salina with lethal ratios of  In addition, seven new briaranes, gemmacolides AZ–BF (41–47) (Figure 6), and eight known 90, 85, 60, and 75% at a concentration of 50 μg/mL [43].  analogues, dichotellides andbriaranes,  O [23], gemmacolide C AZ–BF  [44], juncins P (Figure  [45] and6),  ZIand  [46],eight  junceellolides In  addition,  seven M new  gemmacolides  (41–47)  known  D [25] and K [37], and (−)-4-deacetyljunceellolide D [30], were obtained from D. gemmacea, collected analogues, dichotellides M and O [23], gemmacolide C [44], juncins P [45] and ZI [46], junceellolides  D [25] and K [37], and (−)‐4‐deacetyljunceellolide D [30], were obtained from D. gemmacea, collected  from the South China Sea [47]. The structures of new briaranes 41–47 were determined by spectroscopic from  the  South  China  [47].  The  structures O, of showed new  briaranes  41–47 towards were  determined  methods. Briaranes 41–44,Sea  46, 47, and dichotellide cytotoxicity A549 cells,by  with spectroscopic  methods.  Briaranes  41–44,  46,  47,  and  dichotellide  O,  showed  cytotoxicity  towards  IC50 values of 28.3, 24.7, 34.1, 26.8, 25.8, 13.7 and 25.5 µM, respectively. Briaranes 42, 44, 46, 47, and A549 cells, with IC 50 values of 28.3, 24.7, 34.1, 26.8, 25.8, 13.7, and 25.5 μM, respectively. Briaranes 42,  dichotellide O, showed cytotoxicity towards MG-63 cells, with IC50 values of 15.8, 11.4, 30.6, 34.8 44,  46,  47,  and  dichotellide  O,  showed  cytotoxicity  towards  MG‐63  cells,  with  IC50  values  of  against 15.8,  and 36.8 µM, respectively. Briarane 44 and dichotellide O exhibited antibacterial activity 11.4,  30.6,  34.8,  and  36.8  μM,  respectively.  Briarane  44  and  dichotellide  O  exhibited  antibacterial  the Gram-negative bacterium Escherichia coli, while dichotellide O demonstrated actitity against the activity  against  the  Gram‐negative  bacterium  Escherichia  coli,  while  dichotellide  O  demonstrated  Gram-positive bacterium Bacillus megaterium [47]. actitity against the Gram‐positive bacterium Bacillus megaterium [47].    R1

R4 R3

R5 OH

R2

O

H AcO

O O

 

41: R1 = R2 = OAc, R3 = H, R4 = OC(O)CH2CH(CH3)2, R5 = OH  42: R1 = R4 = OAc, R2 = R3 = OC(O)CH2CH(CH3)2, R5 = OH  43: R1 = OC(O)CH2OC(O)CH2CH(CH3)2, R2 = R4 = OAc, R3 = OC(O)CH2CH(CH3)2, R5 = OH  44: R1 = R2 = R3 = OAc, R4 = OC(O)CH2CH(CH3)2, R5 = OCH3  45: R1 = OC(O)CH2OC(O)CH2CH(CH3)2, R2 = OC(O)CH2CH(CH3)2, R3 = R4 = OAc, R5 = OCH3  46: R1 = R2 = OAc, R3 = OH, R4 = R5 = OC(O)CH2CH(CH3)2  47: R1 = R4 = OAc, R2 = OH, R3 = R5 = OC(O)CH2CH(CH3)2 

Figure 6. Gemmacolides AZ–BF (41–47).   

Figure 6. Gemmacolides AZ–BF (41–47).

3.2. Ellisella dollfusi (Family Ellisellidae) 

3.2. Ellisella dollfusi (Family Ellisellidae)

Zhou and  coworkers  isolated  seven  briaranes,  including  two  new  compounds,  dollfusilins  A  Zhou and coworkers isolated seven briaranes, including two new compounds, dollfusilins A (48) and B (49) (Figure 7), along with five known analogues, brianthein W [14,48,49], funicolide E  (48)[49],  and9‐deacetylbriareolide  B (49) (Figure 7), along five known analogues, brianthein [14,48,49], funicolide EA  [49], H  with [14,50,51],  9‐deacetylstylatulide  lactone W [14],  and  umbraculolide  9-deacetylbriareolide H [14,50,51], 9-deacetylstylatulide lactone [14], and umbraculolide A [29,52], [29,52], from the organic extract of gorgonian coral Ellisella dollfusi, collected from the Xisha Sea area  from extractSea  of gorgonian coral Ellisella dollfusi, collected from49  the Xisha Sea area ofthrough  the South of the the organic South  China  [53].  The  structures  of  new  briaranes  48  and  were  determined  comprehensive analysis of spectroscopic data. Brianthein W exhibited an effect of delayed hatching  China Sea [53]. The structures of new briaranes 48 and 49 were determined through comprehensive and  notochord  growth data. malformation  toxicity  towards  Danio  rerio  embryos  IC50  analysis of spectroscopic Brianthein W exhibited anzebrafish  effect of delayed hatching andwith  notochord values  of  30.6  and  18.9  μg/mL  in  48  h,  respectively.  Funicolide  E  displayed  egg  coagulation  and  growth malformation toxicity towards zebrafish Danio rerio embryos with IC50 values of 30.6 and of  33.6  μg/mL  (24  h) toxicity and  toxicity  towards  zebrafish  embryos, egg with  EC50  values  18.9delayed  µg/mLhatching  in 48 h, respectively. Funicolide E displayed coagulation and delayed hatching 29.8 μg/mL, respectively [53].  towards zebrafish embryos, with EC values of 33.6 µg/mL (24 h) and 29.8 µg/mL, respectively [53]. 50

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6 of 11 

Mar. Drugs 2017, 15, 44 

OAc

AcO

AcO

OAc

AcO

AcO

6 of 11 

OAc OAc OAc OAc

H

O

H O

H

O

O

H

O O

48

O O

49O

O

48

49

Figure 7. Structures of dollfusilins A (48) and B (49).  Figure 7. Structures of dollfusilins A (48) and B (49). Figure 7. Structures of dollfusilins A (48) and B (49). 

3.3. Junceella fragilis (Family Ellisellidae)  3.3. Junceella fragilis (Family Ellisellidae)  Gorgonian corals belonging to the genus Junceella have also been found to be major sources of  Gorgonian corals belonging to the[54,55].  genus The  Junceella have also been collected  found to from  be major sources Gorgonian corals belonging to the genus Junceella have also been found to be major sources of  briarane‐related  natural  diterpenoids  gorgonian  J.  fragilis,  the  South  ofbriarane‐related  briarane-related natural diterpenoids [54,55]. gorgonian J. fragilis, collected from the South natural  diterpenoids  [54,55].  The The gorgonian  J.  fragilis,  collected  from  the  South  China Sea, was found to contain 12 new briaranes,  fragilisinins A–L (50–61) [56] (Figure 8), along  China Sea, was found to contain 12 new briaranes, fragilisinins A–L (50–61) [56] (Figure 8), along with China Sea, was found to contain 12 new briaranes,  with  seven  known  analogues,  (+)‐junceellolide  fragilisinins A–L (50–61) [56] (Figure 8), along  A  [30],  junceellolide  B  [25],  junceol  A  [38],  seven known analogues, (+)-junceellolide A [30], junceellolide B [25], junceol A [38], junceellonoid with  seven  known  analogues,  (+)‐junceellolide  A  [30],  junceellolide  B  [25],  junceol  A  [38],  junceellonoid D [57,58], fragilide C [59], and frajunolides A [60] and E [33]. The structures of new  Djunceellonoid D [57,58], fragilide C [59], and frajunolides A [60] and E [33]. The structures of new  [57,58], fragilide [59],determined  and frajunolides A [60] and Emethods.  [33]. The Briaranes  structures58–61  of newwere  briaranes 50–61 briaranes  50–61  C were  by  spectroscopic  the  first  briaranes  50–61 by were  determined  by  spectroscopic  methods.  58–61  were  the  briarane first  were determined spectroscopic methods. Briaranes 58–61 wereBriaranes  the first iodine-containing iodine‐containing briarane derivatives to be isolated. The absolute configuration of briarane 50 was  iodine‐containing briarane derivatives to be isolated. The absolute configuration of briarane 50 was  confirmed by single‐crystal X‐ray diffraction data [56]. Briaranes 54, 55, 59, (+)‐junceellolide A, and  derivatives to be isolated. The absolute configuration of briarane 50 was confirmed by single-crystal confirmed by single‐crystal X‐ray diffraction data [56]. Briaranes 54, 55, 59, (+)‐junceellolide A, and  junceellonoid  D  showed  potent  antifouling  activities  against A, the  settlement  of  barnacle  Balanus  X-ray diffraction data [56]. Briaranes 54, 55, 59, (+)-junceellolide and junceellonoid D showed potent junceellonoid  D  showed  potent  antifouling ofactivities  settlement  of  barnacle  Balanus  amphitrite larvae, with EC 50 values of 14.0, 12.6, 11.9, 5.6, and 10.0 μM (LC 50 /EC 50 = >13, >14.5, >11.5,  antifouling activities against the settlement barnacleagainst  Balanusthe  amphitrite larvae, with EC50 values of amphitrite larvae, with EC 50 values of 14.0, 12.6, 11.9, 5.6, and 10.0 μM (LC50/EC50 = >13, >14.5, >11.5,  >33.3, >20), respectively [56].  14.0, 12.6, 11.9, 5.6, and 10.0 µM (LC50 /EC50 = >13, >14.5, >11.5, >33.3, >20), respectively [56]. >33.3, >20), respectively [56].  R R

3.3. Junceella fragilis (Family Ellisellidae)

R4

AcO AcO R1 AcO AcO

R4

1

R2

R2

Cl O

AcO

AcO

  4 = Cl  51: R1 = OAc, R2 = H, R3 = R5 = OH, R 52: R 1 = R2 = OAc, R 3 = H, R 4 = Cl, R45 = Cl   = OH  1 = OAc, R 2 = H, R 3 = R5 = OH, R 51: R 60: R 1 = R 5 = OAc, R 2 = I, R43 = Cl, R  = H, R54 = OH   = OCH3  52: R 1 = R 2 = OAc, R 3 = H, R 1 = OC(O)CH 2CH3, R 2 = I, R 3 = H, R 4 = Cl, R 61: R60: R 1 = R5 = OAc, R 2 = I, R 3 = H, R 4 = OCH 3  5 = OAc  61: R1 = OC(O)CH2CH3, R2 = I, R3 = H, R4 = Cl, R5 = OAc 

OAc

AcO

OAc OCH3

R R

OH H HAcO AcO

OH

H

 

54: R = OCH3, 57: R = OH  O   54: R = OCH3, 57: R = OH 

OCH3

O

O

O

O O

AcO

55  O 55 

OCH3

OH

OH

HAcO

O O

AcO

OAc

OAc

OCH3

OH

O

 

O

59: R1 = I, R2 = H, R3 = R4 = OAc  AcO

R4

O O

R5

 

50: R1 = R4 = H, R2 = R3 = OH   53: R 2 = R 4 = H, R 3 = OH  50: R1 = OAc, R 1 = R4 = H, R 2 = R 3 = OH  58: R 1 = I, R22 = R 53: R 1 = OAc, R  = R44 = H, R  = H, R33 = OAc   = OH  1 = I, R 2 = H, R 3 = R 4 = OAc  59: R 58: R 1 = I, R 2 = R 4 = H, R 3 = OAc 

OAc

O

H R 5

O

O

OAc

R4

O

H

O

Cl

O O

R3

R3 R3

O

O

H R 3

2

R1

AcO

O

H

AcO

R1 R2

AcO

Figure 8. Structures of fragilisinins A–L (50–61).  Figure 8. Structures of fragilisinins A–L (50–61). 

H

OH

O

HAcO

O O

AcO

56  O 56 

Figure 8. Structures of fragilisinins A–L (50–61). 3.4. Junceella gemmacea (Family Ellisellidae)  3.4. Junceella gemmacea (Family Ellisellidae)  Four  gemmacea new  briaranes,  3.4. Junceella (Familyjunceellolides  Ellisellidae) M–P  (62–65)  (Figure  9)  [61],  along  with  seven  known  Four  new  briaranes,  A–D  junceellolides  M–P  (62–65)  (Figure  9)  [61],  along  with  seven  known  briaranes,  junceellolides  [25],  junceellin  A  [25–32],  praelolide  [25,29–32,41,42],  and  juncin  ZI  Four new briaranes, junceellolides (62–65) (Figure 9)[25,29–32,41,42],  [61], alongChina  with seven briaranes,  junceellolides  A–D  [25],  junceellin  A  [25–32],  praelolide  and  juncin  ZI  [46],  were  isolated  from  the  gorgonian  J. M–P gemmacea,  collected  from  the  South  Sea  [61]. known The  briaranes, A–D [25], configurations,  junceellin A [25–32], praelolide [25,29–32,41,42], and juncin [46],  were junceellolides isolated  from  the  gorgonian  J.  gemmacea,  collected  from  the 62–65,  South  China  Sea  [61].  The  structures,  including  the  absolute  of  new  briaranes  were  deduced  on  the  ZIstructures,  [46], of  were isolatedthe  from the gorgonian J.electronic circular dichroism  gemmacea, from the South China [61]. including  absolute  configurations,  of  new  collected briaranes  62–65,  were  deduced  on Sea the  basis  spectroscopic  analyses,  particularly  (ECD)  experiments,  and  The structures, including the absolute configurations, of new briaranes 62–65, were deduced basis  of  spectroscopic  analyses,  particularly  electronic circular dichroism  (ECD)  experiments,  and  on from biogenetic correlations among briaranes 62–65.  from biogenetic correlations among briaranes 62–65. 

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the basis of spectroscopic analyses, particularly electronic circular dichroism (ECD) experiments, andMar. Drugs 2017, 15, 44  from biogenetic correlations among briaranes 62–65. 7 of 11  Mar. Drugs 2017, 15, 44 

OAc

AcO

OAc

AcO

R OH

O

H

O

AcO H

OH

AcO

O O

OAc

AcO

Cl OH

R O

7 of 11 

OAc

AcO

O

H

O

AcO H

OH

65 

O

O O O

AcO

62: R = OAc, 63: R = Cl, 64: R = OCH3 

Cl

O

Figure 9. Structures of junceellolides M–P (62–65).  62: R = OAc, 63: R = Cl, 64: R = OCH 3  Figure 9. Structures of junceellolides M–P65 (62–65). Figure 9. Structures of junceellolides M–P (62–65). 

3.5. Junceella sp. (Family Ellisellidae) 

3.5. Junceella sp. (Family Ellisellidae)

3.5. Junceella sp. (Family Ellisellidae)  Three  known  briaranes,  junceellin  (=  junceellin  A)  [25–32],  praelolide  [25,29–32,41,42],  and  Three known briaranes, junceellin (=junceellin A) from  [25–32], praelolide junceellolide  A  [25],  were  claimed  to  have  been  obtained  a  gorgonian  coral [25,29–32,41,42], Junceella  sp.,  Three  known  briaranes,  junceellin  junceellin  A)  [25–32],  praelolide  [25,29–32,41,42],  and sp., andcollected off the Vietnam Thu Island in May 2010 [62]. In the antimicrobial activity test, junceellin  junceellolide A [25], were claimed to(=  have been obtained from a gorgonian coral Junceella junceellolide  A  [25],  were  claimed  to  have  been  obtained  from  a  gorgonian  coral  Junceella  sp.,  collected off the Vietnam Island in May activity  2010 [62]. In thethe  antimicrobial activity test, junceellin and  praelolide  exhibited Thu weak  antibacterial  against  bacterium  Vibrio  parahaemolyticus.  collected off the Vietnam Thu Island in May 2010 [62]. In the antimicrobial activity test, junceellin  andJunceellolide A was also found to display weak antibacterial activity against the bacterium Candida  praelolide exhibited weak antibacterial activity against the bacterium Vibrio parahaemolyticus. and  praelolide  exhibited  weak  antibacterial  activity  against  the  bacterium  Vibrio  parahaemolyticus.  Junceellolide albicans [62]. A was also found to display weak antibacterial activity against the bacterium Junceellolide A was also found to display weak antibacterial activity against the bacterium Candida  Candida albicans [62]. albicans [62].  4. Pennatulacea 

4. Pennatulacea

4. Pennatulacea  Pennatula aculeata (Family Pennatulidae) 

Pennatula aculeata (Family Pennatulidae)

Investigation  of  the  chemical  constituents  of  P.  aculeata,  collected  from  Dinawan  Island  in  Pennatula aculeata (Family Pennatulidae)  Investigation of afforded  the chemical constituents of P. aculeata, collectedC  from Island in The  Sabah, Sabah,  Malaysia,  novel  briarane  2‐acetoxyverecynarmin  (66) Dinawan [63]  (Figure  10).  Investigation  of  the  chemical  constituents  of  P.  aculeata,  collected  from  Dinawan  Island  in  structure  of  the novel new  briarane briarane  2-acetoxyverecynarmin 66  was  elucidated  by  analysis  of  (Figure spectroscopic  data,  and  this  Malaysia, afforded C (66) [63] 10). The structure of the Sabah,  Malaysia,  afforded  novel  briarane  2‐acetoxyverecynarmin  C  (66)  [63]  (Figure  10).  The  compound showed moderate inhibitory activity towards COX‐1 and COX‐2, with IC 50  values of 44.3  new briarane 66 was elucidated by analysis of spectroscopic data, and this compound showed moderate structure  of  the  new  briarane  66  was  elucidated  by  analysis  of  spectroscopic  data,  and  this  and 47.3 μM, respectively. The 2‐acetoxy group in 66 was found to be located on the α‐face, relative  inhibitory activity towards COX-1 and COX-2, with IC50 values of 44.3 and 47.3 50µM, respectively. compound showed moderate inhibitory activity towards COX‐1 and COX‐2, with IC  values of 44.3  to Me‐15 and H‐10, which is a rare occurrence in briarane‐related analogues.    Theand 47.3 μM, respectively. The 2‐acetoxy group in 66 was found to be located on the α‐face, relative  2-acetoxy group in 66 was found to be located on the α-face, relative to Me-15 and H-10, which is a rare occurrence in briarane-related analogues. OAc to Me‐15 and H‐10, which is a rare occurrence in briarane‐related analogues.    O OAc O

HO HO

H O H O

 

Figure 10. Structure of 2‐acetoxyverecynarmin C (66).   

5. Conclusions 

Figure 10. Structure of 2‐acetoxyverecynarmin C (66).  Figure 10. Structure of 2-acetoxyverecynarmin C (66).

5. Conclusions  Since  briarein  A,  the  first  briarane‐type  natural  product,  was  prepared  from  the  Caribbean  octocoral  Briareum  asbestinum  in  1977  [9],  over  600  briarane‐type  diterpenoids  have  been  isolated  Since  briarein  A,  the  first  briarane‐type  natural  product,  was  prepared  from  the  Caribbean  from  a  wide  variety  of  marine  life  to  date.  A natural large  portion  of  these  natural  compounds  been  Since briarein A,asbestinum  the first in  briarane-type product, was prepared frombeen  the has  Caribbean octocoral  Briareum  1977  [9],  over  600  briarane‐type  diterpenoids  have  isolated  prepared from soft corals belonging to the orders Alcyonacea and Gorgonacea. Compounds of this  octocoral asbestinum in life  1977 over 600 briarane-type diterpenoids have been from  a  Briareum wide  variety  of  marine  to [9], date.  A  large  portion  of  these  natural  compounds  has isolated been  type  of  diterpenoid  have  been  demonstrated  to  possess  various  bioactivities  in  vitro,  such  as  from a wide variety of marine life to date. A large portion of these natural compounds has been prepared from soft corals belonging to the orders Alcyonacea and Gorgonacea. Compounds of this  anti‐inflammatory activity, antibacterial activity, and cytotoxicity towards cancer cells. For example,  prepared soft corals to the orders Alcyonacea and Gorgonacea. Compounds type  of from diterpenoid  have belonging been  demonstrated  to  possess  various  bioactivities  in  vitro,  such  as  of one  of  the  compounds  of  this  type,  excavatolide  B  [13],  has  been  proven  to  possess  extensive  thisanti‐inflammatory activity, antibacterial activity, and cytotoxicity towards cancer cells. For example,  type of diterpenoid have been demonstrated to possess various bioactivities in vitro, such as biomedical  bioactivities,  such  as  anti‐inflammatory,  analgesic,  the  attenuation  of  rheumatoid  one  of  the  compounds  this  type,  excavatolide  [13],  has  been  proven  to  possess  extensive  anti-inflammatory activity,of  antibacterial activity, andB cytotoxicity towards cancer cells. For example, arthritis  activities,  anticancer,  and  the  modulation  of  the  electrophysiological  characteristics  and  biomedical  bioactivities,  such  as  anti‐inflammatory,  analgesic,  the  attenuation  of  rheumatoid  one of the compounds of this type, excavatolide B [13], has been proven to possess extensive biomedical calcium  homeostasis  in  atrial  myocytes  [64–67].  Due  to  the  structural  diversity  and  biomedical  arthritis  activities,  and  the  analgesic, modulation  of attenuation the  electrophysiological  characteristics  and  bioactivities, such as anticancer,  anti-inflammatory, the of rheumatoid arthritis activities, bioactivities,  there  has  been  little  synthetic  work  on  briarane  analogues  [68,69].  It  is  interesting  to  calcium  and homeostasis  in  atrial ofmyocytes  [64–67].  Due  to characteristics the  structural  and diversity  and homeostasis biomedical  in anticancer, the modulation the electrophysiological calcium note  that  all  briaranes  reported  as  having  been  isolated  between  2014  and  2016  were  all  collected  bioactivities,  there  has  been  little  synthetic  work  on  briarane  analogues  [68,69].  It  is  interesting  to  from octocorals distributed in the Indo‐Pacific Ocean, particularly from the South China Sea.  note  that  all  briaranes  reported  as  having  been  isolated  between  2014  and  2016  were  all  collected  from octocorals distributed in the Indo‐Pacific Ocean, particularly from the South China Sea. 

5. Conclusions

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atrial myocytes [64–67]. Due to the structural diversity and biomedical bioactivities, there has been little synthetic work on briarane analogues [68,69]. It is interesting to note that all briaranes reported as having been isolated between 2014 and 2016 were all collected from octocorals distributed in the Indo-Pacific Ocean, particularly from the South China Sea. Acknowledgments: This research was supported by grants from the National Museum of Marine Biology and Aquarium; the National Dong Hwa University; the National Sun Yat-sen University; and the National Research Program for Biopharmaceuticals, Ministry of Science and Technology (Grant Nos. MOST 105-2325-B-291-001, 105-2811-B-291-003, 104-2320-B-291-001-MY3, and 104-2325-B-291-001), Taiwan, awarded to Jyh-Horng Sheu, Yang-Chang Wu, and Ping-Jyun Sung. Author Contributions: Yin-Di Su contributed in terms of writing the manuscript. Jyh-Horng Sheu, Yang-Chang Wu, and Ping-Jyun Sung conceived and designed the format of the manuscript. All of the authors contributed in terms of critical reading and discussion of the manuscript. Conflicts of Interest: The authors declare no conflicts of interest.

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