marine drugs Review
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.
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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
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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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OAc
AcO
AcO
OAc
AcO
AcO
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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
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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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