Secondary Metabolites of Genus Acanthella: History
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Contributor:
Sabrin R. M. Ibrahim
,
Kholoud F. Ghazawi
,
Samar F. Miski
,
Duaa Fahad ALsiyud
,
Shaimaa G. A. Mohamed
,
Gamal A. Mohamed

Marine sponges are multicellular and primitive animals that potentially represent a wealthy source of novel drugs. The genus Acanthella (family Axinellidae) is renowned to produce various metabolites with various structural characteristics and bioactivities, including nitrogen-containing terpenoids, alkaloids, and sterols. Different metabolites were separated and characterized from different species of this genus using various spectroscopic and chromatographic techniques. The isolated metabolites are categorized according to their chemical classes into sesquiterpenes, diterpenes, alkaloids, steroid compounds, and others. Additionally, their reported biosynthetic and synthetic studies are also highlighted whenever applicable.

  • Acanthella
  • Axinellidae
  • nitrogen-containing terpenoids
  • Life below water

1. Sesquiterpenes

The reported investigations revealed the purification of various classes of sesquiterpenes that are substituted by isonitrile or isothiocyanate functionalities, including mono-, bi-, and tri-cyclic skeletons with 3-, 5-, 6-, and/or 7-membered rings (Figure 1 and Table 1). Frequently, formamide derivatives were reported along with both isothiocyanate and/or isonitrile moieties. Isonitrile-containing metabolites have been reported from some species belonging to Penicillium and Axinella genera [1]. Several reports stated their characterization from Acanthella. It was reported that A. cavernosa (Dendy, 1922) can convert cyanide and thiocyanate for isocyanide and isothiocyanate biosynthesis, which could be attributed to the presence of rhodanese or the equivalent enzyme [2]. Therefore, thiocyanate was postulated to be the precursor for the isothiocyanate moiety in terpenes by direct utilization or oxidative desulphurization of cyanide, conversion to isocyanide terpenes, and reinsertion of sulfur [2].
Figure 1. Classes of sesquiterpenes reported from the genus Acanthella.
Table 1. Sesquiterpenes from the genus Acanthella (molecular weight and formulae, chemical class, species, and sampling locations).
Compound Name Mol. Wt. Mol. Formula Species Sampling Locations Ref.
Aromadendrane-type sesquiterpenes          
Axisonitrile-2 (1) 231 C16H25N A. cavernosa Hachijo-Jima Island, Japan [3]
(+)-Axamide 2 (2) 249 C16H27NO A. cavernosa Coast of Ximao Island, Hainan, China [4]
l-Isocyanoaromadendrane (3) 231 C16H25N A. acuta Near Banyuls, France [5][6]
  - - A. pulcherrima Weed Reef, Darwin, Australia [6]
  - - A. acuta Near Banyuls, France [7]
  - - A. cavernosa Tani’s Reef, Mooloolaba, Australia [8]
  - - A. cavernosa Tani’s Reef or Coral Gardens dive sites [9]
Isonitrile 2 (4) 231 C16H25N A. acuta Bay of Naples, southern Italy [10]
(+)-Axisothiocyanate 2 (5) 263 C16H25NS A. cavernosa Hachijo-jima Island, Japan [11]
  - - Acanthella sp. Ximao Sea, Hainan, China [12]
  - - A. cavernosa Tani’s Reef or Coral Gardens dive sites [9]
l-Isothiocyanatearomadendrane (6) 263 C16H25NS A. acuta Near Banyuls, France [7]
  - - A. cavernosa Tani’s Reef, Mooloolaba, Australia [8]
1-Isocyanatearomadendrane (7) 247 C16H25NO A. acuta Near Banyuls, France [7]
  - - A. cavernosa Tani’s Reef or Coral Gardens dive sites [9]
1-Isothiocyanatoaromadendrane (8) 263 C16H25NS A. acuta Bay of Naples, southern Italy [10]
  - - A. cavernosa Tani’s Reef or Coral Gardens dive sites [9]
(+)-10R-Isothiocyanatoalloaromadendrane (9) 263 C16H25NS A. cavernosa Hachijo-jima Island, Japan [11]
  - - Acanthella sp. Ximao Sea, Hainan, China [12]
  - - Acanthella sp. Yalong Bay, Hainan, China [13]
  - - A. cavernosa Coast of Ximao Island, Hainan, China [4]
10α-Isothiocyanoalloaromadendrane (10) 263 C16H25NS A. pulcherrima Weed Reef, Darwin, Australia [6]
  - - A. cavernosa Tani’s Reef or Coral Gardens dive sites [9]
  - - Acanthella sp. Ximao Sea, Hainan, China [12]
  - - A. cavernosa Tani’s Reef, Mooloolaba, Australia [8]
Ximaocavernosin O (11) 368 C24H36N2O A. cavernosa Coast of Ximao Island, Hainan, China [4]
ent-4β,10α-Dihydroxyaromadendrane (12) 238 C15H26O2 A. cavernosa Coast of Ximao Island, Hainan, China [14]
Palustrol (13) 222 C15H26O A. acuta Near Banyuls, France [5]
  - - A. acuta Near Banyuls, France [7]
10S-Viridiflorol (14) 222 C15H26O A. cavernosa Hachijo-jima Island, Japan [11]
10R-Viridiflorol (15) 222 C15H26O A. cavernosa Hachijo-jima Island, Japan [11]
(+)-Ximaocavernosin P (16) 234 C15H22O2 A. cavernosa Coast of Ximao Island, Hainan, China [14]
Spiroaxane-type sesquiterpenes          
Axisonitrile-3 (17) 231 C16H25N A. acuta Near Banyuls, France [5]
  - - A. cavernosa Thailand [15]
  - - A. klethra Pelorus Island, Queensland, Australia [16]
  - - A. klethra Vicinities of Phantom and Pelom Islands, Queensland, Australia [17]
  - - A. cavernosa Heron Island, Great Barrier Reef, Australia [2]
  - - A. cavernosa Heron Island, Great Barrier Reef, Australia [18]
  - - Acanthella sp. Ximao Sea, Hainan, China [12]
  - - A. cavernosa Tani’s Reef, Mooloolaba, Australia [8]
Isonitrile 1 (18) 245 C17H27N A. acuta Bay of Naples, southern Italy [10]
3-Oxoaxisonitrile-3 (19) 245 C16H23NO Acanthella sp. Ximao Sea, Hainan, China [12]
Axisonitrile-4 (20) 231 C16H25N A. acuta Sidi Elghdamssi island, Monastir region, Tunisia [19]
Axisocyanate-3 (21) 247 C16H25NO A. cavernosa Tani’s Reef, Mooloolaba, Australia [8]
(+)-Axisothiocyanate (22) 263 C16H25NS A. cavernosa Coast of Ximao Island, Hainan, China [4]
Axisothiocyanate 3 (23) 263 C16H25NS A. klethra Pelorus Island, Queensland, Australia [16]
  - - A. klethra Vicinities of Phantom and Pelom Islands, Queensland, Australia [17]
  - - Acanthella sp. Queen Charlotte Island chain off the coast of British Columbia. [20]
  - - A. cavernosa Hachijo-jima Island, Japan [11]
  - - A. cavernosa Heron Island, Great Barrier Reef, Australia [2]
  - - A. cavernosa Heron Island, Great Barrier Reef, Australia [18]
Ximaocavernosin H (24) 277 C16H22NOS A. cavernosa Coast of Ximao Island, Hainan, China [4]
Ximaocavernosin I (25) 279 C16H25NOS A. cavernosa Coast of Ximao Island, Hainan, China [4]
Ximaocavernosin J (26) 279 C16H25NOS A. cavernosa Coast of Ximao Island, Hainan, China [4]
Ximaocavernosin K (27) 263 C16H25NO2 A. cavernosa Coast of Ximao Island, Hainan, China [4]
Ximaocavernosin L (28) 265 C16H27NO2 A. cavernosa Coast of Ximao Island, Hainan, China [4]
Ximaocavernosin M (29) 265 C16H27NO2 A. cavernosa Coast of Ximao Island, Hainan, China [4]
Ximaocavernosin N (30) 368 C24H36N2O A. cavernosa Coast of Ximao Island, Hainan, China [4]
(–)-Axamide 3 (31) 249 C16H27NO A. cavernosa Coast of Ximao Island, Hainan, China [4]
Axamide 3 (32) 249 C16H27NO A. cavernosa Hachijo-jima Island, Japan [11]
Isothiocyanate 1 (33) 277 C17H27NS A. acuta Bay of Naples, southern Italy [10]
Eudesmane-type sesquiterpenes          
Acanthellin-1 (34) 231 C16H25N A. acuta Bay of Naples, southern Italy [1]
  - - A. acuta Near Banyuls, France [5]
  - - A. acuta Bay of Taranto near Porto Cesareo, Southern Italy [21]
  - - A. acuta Sidi Elghdamssi Island, Monastir region, Tunisia [19]
Acanthene B (35) 263 C16H25NS Acanthella sp. Queen Charlotte Island chain off the coast of British Columbia. [20]
  - - Acanthella sp. Ximao Sea, Hainan, China [12]
  - - A. cavernosa Tani’s Reef or Coral Gardens dive sites [9]
Acanthine B (36) 263 C16H25NS A. cavernosa Coast of Ximao Island, Hainan, China [4]
Acanthene C (37) 249 C16H27NO Acanthella sp. Queen Charlotte Island chain off the coast of British Columbia. [20]
Axiriabiline A (38) 249 C16H27NO A. cavernosa Xidao Island, Hainan, China [22]
6α-Isocyano-5αH,7αH,10α-eudesm-4(14)-ene) (39) 231 C16H25N A. acuta Bay of Taranto near Porto Cesareo, Southern Italy [21]
  - - A. acuta Bay of Naples, southern Italy [10]
11-Isocyano-7βH-eudesm-5-ene (40) 231 C16H25N Acanthella sp. Queen Charlotte Island chain off the coast of British Columbia. [20]
11-Formamido-7βH-eudesm-5-ene (41) 249 C16H27NO A. cavernosa Xidao Island, Hainan, China [22]
11-Isothiocyano-7βH-eudesm-5-ene (42) 263 C16H25NS A. pulcherrima Weed Reef, Darwin, Australia [6]
  - - A. klethra Pelorus Island, Queensland, Australia [16]
  - - A. klethra Vicinities of Phantom and Pelom Islands, Queensland, Australia [17]
  - - Acanthella sp. Queen Charlotte Island chain off the coast of British Columbia. [20]
  - - A. cavernosa Heron Island, Great Barrier Reef, Australia [2]
6α-Isothiocyano-5αH,7αH,10α-eudesm-4(14)-ene (43) 263 C16H25NS A. acuta Bay of Taranto near Porto Cesareo, Southern Italy [21]
  - - A. acuta Bay of Naples, southern Italy [10]
  - - Acanthella sp. Queen Charlotte Island chain off the coast of British Columbia. [20]
(lR,5R,6R,8R)-Dec[4.4.0]ane-1,5-dimethyl-8-(1′-methylethenyl)-5-isothiocyanate (44) 263 C16H25NS A. klethra Pelorus Island, Queensland, Australia [16]
  - - A. klethra Vicinities of Phantom and Pelom Islands, Queensland, Australia [17]
  - - Acanthella sp. Queen Charlotte Island chain off the coast of British Columbia. [20]
(lR,5R,6R,8S)-Dec[4.4.0]ane-1,5-dimethyl-8-(1′-methylethenyl)-5-isothiocyanate (45) 263 C16H25NS A. klethra Pelorus Island, Queensland, Australia [16]
  - - A. klethra Vicinities of Phantom and Pelom Islands, Queensland, Australia [17]
  - - A. cavernosa Heron Island, Great Barrier Reef, Australia [18]
Cadinene-type sesquiterpenes          
10-Isothiocyanato-4-cadinene (46) 263 C16H25NS A. cavernosa Heron Island, Great Barrier Reef, Australia [18]
  - - A. cavernosa Tani’s Reef or Coral Gardens dive sites [9]
10-Isothiocyanato-4-amorphene (47) 263 C16H25NS A. cavernosa Heron Island, Great Barrier Reef, Australia [18]
  - - A. cavernosa Several locations off the Japanese coast [23]
  - - Acanthella sp. Ximao Sea, Hainan, China [12]
  - - A. cavernosa Tani’s Reef or Coral Gardens dive sites [9]
Isomer-10-isothiocyanato-4-amorphene (48) 263 C16H25NS A. cavernosa Heron Island, Great Barrier Reef, Australia [18]
(+)-Ximaocavernosin A (49) 295 C16H25NO2S A. cavernosa Coast of Ximao Island, Hainan, China [14]
(±)-Ximaocavernosin A (50) 279 C16H25NOS A. cavernosa Coast of Ximao Island, Hainan, China [4]
(±)-Ximaocavernosin B (51) 279 C16H25NOS A. cavernosa Coast of Ximao Island, Hainan, China [4]
(±)-Ximaocavernosin C (52) 279 C16H25NOS A. cavernosa Coast of Ximao Island, Hainan, China [4]
(+)-Ximaocavernosin D (53) 293 C17H27NOS A. cavernosa Coast of Ximao Island, Hainan, China [4]
(±)-Ximaocavernosin E (54) 295 C16H25NO2S A. cavernosa Coast of Ximao Island, Hainan, China [4]
(+)-Ximaocavernosin F (55) 309 C17H27NO2S A. cavernosa Coast of Ximao Island, Hainan, China [4]
(±)-Ximaocavernosin G (56) 277 C16H23NOS A. cavernosa Coast of Ximao Island, Hainan, China [4]
(±)-Axinisothiocyanate J (57) 279 C16H25NOS A. cavernosa Coast of Ximao Island, Hainan, China [4]
(±)-Axinisothiocyanate D (58) 295 C16H25NO2S A. cavernosa Coast of Ximao Island, Hainan, China [4]
Axinisothiocyanate A (59) 295 C16H25NO2S A. cavernosa Coast of Ximao Island, Hainan, China [4]
ent-Epicubenol (60) 222 C15H26O A. pulcherrima Weed Reef, Darwin, Australia [6]
Isothiocyanate 4 (61) 263 C16H25NS A. pulcherrima Weed Reef, Darwin, Australia [6]
Epipolasin-A enantiomer-2 (62) 263 C16H25NS A. pulcherrima Weed Reef, Darwin, Australia [6]
10α-Isocyano-4-amorphene (63) 231 C16H25N A. cavernosa Hachijo-Jima Island, Japan [3]
  - - A. cavernosa Several locations off the Japanese coast [23]
10-Isocyano-4-cadinene (64) 231 C16H25N A. cavernosa Heron Island, Great Barrier Reef, Australia [18]
  - - A. cavernosa Several locations off the Japanese coast [23]
  - - A. cavernosa Tani’s Reef or Coral Gardens dive sites [9]
10-Formamido-4-cadinene (65) 249 C16H27NO A. cavernosa Several locations off the Japanese coast [23]
  - - A. cavernosa Xidao Island, Hainan, China [22]
(+)-α-Muurolene (66) 204 C15H24 A. cavernosa Hachijo-jima Island, Japan [11]
T-cadinol (67) 222 C15H26O A. cavernosa Several locations off the Japanese coast [23]
(+)-Maninsigin D (68) 234 C15H22O2 A. cavernosa Coast of Ximao Island, Hainan, China [14]
  234 C15H22O2 A. cavernosa Coast of Ximao Island, Hainan, China [14]
(-)-Maninsigin D (69) 234 C15H22O2 A. cavernosa Coast of Ximao Island, Hainan, China [14]
(+)-Ximaocavernosin Q (70) 234 C15H22O2 A. cavernosa Coast of Ximao Island, Hainan, China [14]
(-)-Ximaocavernosin Q (71) 234 C15H22O2 A. cavernosa Coast of Ximao Island, Hainan, China [14]
Cadalene (72) 198 C15H18 A. cavernosa Coast of Ximao Island, Hainan, China [14]
trans-4,5-Dihydroxycorocalane (73) 234 C15H22O2 A. cavernosa Coast of Ximao Island, Hainan, China [14]
Axane-type sesquiterpenes          
Cavernoisonitrile (74) 245 C16H23NO A. cavernosa Hachijo-Jima Island, Japan [3]
(-)-Cavernothiocyanate (75) 263 C16H25NS A. cavernosa Hachijo-Jima Island, Japan [3]
  - - A. cavernosa Hachijo-jima Island, Japan [11]
1β-H,7α-methyl,8α-H,9β-methyl-Cavernothiocyanate (76) 263 C16H25NS A. cavernosa Hachijo-jima Island, Japan [11]
Bisabolene-type sesquiterpenes          
7-Isocyano-7,8-dihydro-α-bisabolene (77) 231 C16H25N A. cavernosa Hachijo-Jima Island, Japan [3]
Epimaaliane-type sesquiterpenes          
(+)-Epipolasin-A (78) 263 C16H25NS A. pulcherrima Weed Reef, Darwin, Australia [6]
  - - A. cavernosa Heron Island, Great Barrier Reef, Australia [2]
Epipolasin-A enantiomer-1 (79) 263 C16H25NS A. pulcherrima Weed Reef, Darwin, Australia [6]
  - - Acanthella sp. Ximao Sea, Hainan, China [12]
5-Formamide-isonitrile (80) 249 C16H27NO Acanthella sp. Queen Charlotte Island chain off the coast of British Columbia. [20]
Isonitrile 4 (81) 231 C16H25N Acanthella sp. Queen Charlotte Island chain off the coast of British Columbia. [20]
Maaliol (82) 222 C15H26O A. pulcherrima Weed Reef, Darwin, Australia [6]
Acanthene A (83) 240 C15H25Cl Acanthella sp. Queen Charlotte Island chain off the coast of British Columbia. [20]
Gurjunene          
(+)-Aristolone (84) 218 C15H22O A. cavernosa Coast of Ximao Island, Hainan, China [14]
  - - A. cavernosa South China Sea [24]
(+)-9-Aristolene (85) 204 C15H24 A. cavernosa Hachijo-jima Island, Japan [11]
Isonitrile 3 (86) 231 C16H25N A. acuta Bay of Naples, southern Italy [10]
Isothiocyanate 3 (87) 263 C16H25NS A. acuta Bay of Naples, southern Italy [10]

1.1. Aromadendrane-Type Sesquiterpenes

In 1987, l-isocyanoaromadendrane (3) was reported as a novel isonitrile sesquiterpene from the fish toxic CH2Cl2 fraction of A. acuta using SiO2CC (silica gel column chromatography), assigned by spectral and chemical methods [5].
Furthermore, 5 and 9 were isolated from Japanese A. cavernosa by SiO2 CC and RP-HPLC and identified by different spectroscopic methods [11]. Ximaocavernosin O (11) was isolated from an A. cavernosa Et2O fraction using silica gel/MCI/Sephadex LH-20/(RP)-HPLC/chiral-phase HPLC and was characterized by spectroscopy, X-ray diffraction, and QM-NMR analyses as well as Mosher’s method and TDDFT-ECD calculations [4]. Compound 11 is similar to 2 and was formerly reported from nudibranch Hexabranchus sanguineus with a C-10 phenyl urea fragment instead of a C-10 formamide in 2 [4]. New aromadendrane-type sesquiterpenoids, 16 and 12, were purified from the Hainan A. cavernosa using SiO2/Sephadex LH-20 CC/chiral-phase HPLC by Shen et al.. Their configurations were elucidated based on spectral, TDDFT-ECD, and X-ray analyses and optical rotation measurements. Compound 16 with a 2S/4S/5R/6S/7S configuration ([α]D +169.6]) is identical to 2β-hydroxyaromadendr-1(10)-en-9-one ([α]D _186]) except for the optical rotation (Figure 2) [4].
Figure 2. Aromadendrane-type sesquiterpenes (1–16) reported from the genus Acanthella.

1.2. Spiroaxane-Type Sesquiterpenes

Spiroaxane skeletons containing sesquiterpenes are of rare natural occurrence. Compound 19, a new sesquiterpene isocyanide with a spiroaxane (spiro [25][26] decane) skeleton was obtained from Chinese Acanthella sp., which is a 3-oxo derivative of 17 [12]. Additionally, 23 is a spiroaxane sesquiterpene with a C-6 isocyanate and was purified and characterized by Jumaryatno et al. from A. cavernosa specimens collected from Coral gardens/Gneerings reef/Mooloolaba/Australia and from A. klethra collected from Pelorus Island, Queensland, in addition to 17 [8][16].
Additionally, 23–30 were isolated from A. cavernosa Et2O fractions using silica gel/MCI/Sephadex LH-20/(RP)-HPLC/chiral-phase HPLC and characterized by spectral, X-ray diffraction, and QM-NMR analyses as well as Mosher’s method and TDDFT-ECD calculations [4]. Compounds 23–30 are spiroaxane derivatives involving compounds with C-6 isothiocyanate (e.g., 23–25) and formamide or a 1-phenethyl urea fragment (e.g., 26–30) [4] (Figure 3). In 2019, Wu et al. reported the purification of axamide-3 (32) from the acetone fraction of A. cavernosa collected from Xidao Island (Hainan Province, China) which was characterized by NMR spectral data and optical rotation [22].
Figure 3. Spiroaxane-type sesquiterpenes (17–33) reported from the genus Acanthella.

1.3. Eudesmane-Type Sesquiterpenes

Acanthellin-1 (34) is a bicyclic sesquiterpene with isopropylidene and isonitrile moieties. It was separated as an optically active oil from the ether fraction of the acetone extract of A. acuta collected from the Bay of Naples using SiO2CC, and was characterized by NMR and chemical methods, as well as optical rotation [1] (Figure 4). A chromatographic investigation of A. klethra collected from Pelorus Island, Queensland, yielded sesquiterpenoids with isothiocyanate and isonitrile groups, i.e., 42, 44, and 45, that were assigned by spectral and X-ray analyses. Compounds 42, 44, and 45 are of eudesmane-type and are related to 34. Compounds 45 and 44 are different in stereo-configuration at C-7 [16][17]. Additionally, 39 and 43 are in the bicyclic cis-eudesmane class of sesquiterpenes, possessing isocyanate and isothiocyanate functionalities, respectively, and were purified and specified from A. acuta [21], whereas 35 is a stereoisomer of 5 [20].
Figure 4. Eudesmane-type sesquiterpenes (34–45) reported from the genus Acanthella.
Axiriabiline A (38) was obtained from the acetone fraction of A. cavernosa collected from Xidao Island (Hainan Province, China) and characterized by NMR spectral data and optical rotation [22]. Burgoyne et al. (1993) purified two new sesquiterpenoid acanthenes B and C (35 and 37) along with 40 and 42–44 from the hexane fraction of unidentified Acantbella species using SiO2 flash CC/HPLC. The compounds were characterized by spectral analyses [20].

1.4. Cadinene-Type Sesquiterpenes

In 2000, Clark et al. isolated a new sesquiterpene, 46, that has a 1R/6R/7S/10R configuration and C-10 isothiocyanato functionality and [α]D +3 [18]. In addition, Nogata et al. purified a new sesquiterpene, 65, and the known 67 from A. cavernosa EtOH extracts utilizing SiO2/Sephadex LH-20/ODS HPLC. These compounds were assigned based on spectral data and chemical transformations [23] (Figure 5). Compound 65 has a C-10 formamido functionality instead of the C-10-OH in 67 [23].
Figure 5. Cadinene-type sesquiterpenes (46–57) reported from the genus Acanthella.
New cadinane-type sesquiterpenoids, ximaocavernosins A–G (49–56), were isolated from A. cavernosa Et2O fractions using SiO2/MCI/Sephadex LH-20/(RP)-HPLC/chiral-phase HPLC and characterized by spectroscopy, X-ray diffraction, and QM-NMR analyses as well as Mosher’s method and TDDFT-ECD calculations [4]. Compounds 49–56 have cadinane frameworks with a Δ5,6 double bond and a C-10 isothiocyanate but differ in stereochemistry and oxidation patterns [4]. In 2019, Wu et al. reported the purification of 10-formamido-4-cadinene (65) from the acetone fraction of A. cavernosa collected from Xidao Island (Hainan Province, China), which was characterized by NMR spectral data and optical rotation [22]. New cadinane-type sesquiterpenoids, 49 and 68–73, were purified from Hainan A. cavernosa using SiO2/Sephadex LH-20 CC/chiral-phase HPLC (Figure 6). Their configurations were elucidated based on spectral, TDDFT-ECD, and X-ray analyses and optical rotation measurements. Maninsigin D and ximaocavernosin Q were obtained as racemic forms, which were separated into their enantiomers [(+)-68/(−)-69 and (+)-70/(−)-71] using chiral-phase HPLC [14].
Figure 6. Cadinene-type sesquiterpenes (58–73) reported from the genus Acanthella.

1.5. Other Sesquiterpenes

New axane sesquiterpenoids, 74 and 75, in addition to 77, were separated from the antifungal hexane fraction of A. cavernosa collected from the Hachijo-Jima Islands using flash CC/sephadex LH-20/HPLC. They were elucidated based on spectral data [27]. Compound 74 is a rare oxygenated tricyclic sesquiterpene cyanide belonging to axane-type sesquiterpenes [27]. Furthermore, 66, 75, 76, and 85 were isolated by SiO2 CC and RP-HPLC and identified by alpha-D, spectral data, and chemical methods from Japanese A. cavernosa [11]. Additionally, the new epimaaliane sesquiterpene 79, along with 78, were specified from the antimicrobial acetone extracts of A. pulcherrima using spectral and optical rotation measurements. Compound 79 is an enantiomer of 78 with an opposite [α]D value and differs at the ring junction [6]. Burgoyne et al. purified epimaaliane-type sesquiterpenes 80 and 81 from the hexane fraction of an unidentified Acantbella species using SiO2 flash CC and HPLC. The compounds were characterized by spectral analyses [20] (Figure 7).
Figure 7. Other sesquiterpenes (74–87) reported from the genus Acanthella.
Notably, Shen et al. proposed that 12, 16, 49, 68–73, and 84 originate from E,E-farnesyl diphosphate (E,E-FPP), as illustrated in Scheme 1 [14].
Scheme 1. Biosynthesis pathway of 12, 16, 49, 68–73, and 84 [14].

2. Diterpenoids

Diterpenoids are among the common metabolites reported from various Acanthella species. These compounds are characterized by the existence of nitrogenous functionalities such as isothiocyanato, isocyano, and/or formamido groups. These diterpenes are classified into two major classes, kalihinanes and biflorane derivatives, according to the 8C side chain (Figure 8 and Table 2). Kalihinanes have a decalin frame structure with C-7-attached dihydropyran, tetrahydropyran, or tetrahydofuran moiety. Additionally, these rings may carry various substituents such as OH, Cl, isothiocyanato, isocyano, and formamido groups or chlorine. They include kalihinenes, kalihinols, and kalihipyranes. Kalihinols are spilt into two main categories, tetrahydrofuran (I) and tetrahydropyran (II) groups, according to the C-7 substitution. Commonly, they have trans-decalin framework with a C-4 or C-5 tertiary alcohol and an isocyanate moiety at C-10 and/or C-5. The first group has a tetrahydrofuran moiety featuring NCS, NC, or Cl at C-15, or the gem-dimethyl is substituted by an isopropenyl moiety, whereas the tetrahydropyran group possesses Cl atom at C-14. Kalihinenes have a Δ4-trisubstituted double bond and possess similar structural features to kalihinols, while biflorane diterpenoids are a class of kalihinane diterpenes featuring a linear eight-carbon open chain substituent at C-7. Biosynthetically, these metabolites are proposed to result from the cyclization of the biflorane skeleton (trans or cis form) and geranylgeranyl pyrophosphate [28]. Their stereochemistry has been determined using spectroscopic, X-ray and/or CD analyses, as well as chemical and computational methods.
Figure 8. Classes of diterpenes reported from genus Acanthella.
Table 2. Diterpenes from the genus Acanthella (molecular weight and formulae, chemical class, species, and sampling locations).
Compound Name Mol. Wt. Mol. Formula Species Sampling Locations Ref.
Kalihinols          
Kalihinol A (88) 392 C22H33ClN2O2 Acanthella sp. Apra Harbor, Guam, western side of the USA [29]
  - - Acanthella sp. Apra Harbor, Guam, western side of the USA [30]
  - - A. caruenosa Fiji, South Pacific Ocean [31]
  - - A. klethra Kuchinoerabu Island of the Satsunan Archipelago, Japan [27]
  - - A. cavernosa Seychelles and Desnceufs Islands [32]
  - - A. cavernosa Fiji, South Pacific Ocean [28]
  - - A. cavernosa Yakushima Island, southwest of Tokyo [33][34]
  - - Acanthella sp. Coral reef of Ishigaki Island, Okinawa, Japa [35]
  - - A. cavernosa Dibud, Philippines [36]
  - - A. cavernosa Shallow water reef in Sanya Bay, Hainan Island, China [37]
  - - Acanthella sp. Ximao Sea, Hainan, China [12]
  - - Acanthella sp. Yalong Bay, Hainan, China [13]
  - - A. cavernosa Xisha Islets, South China Sea [38]
  - - A. cavernosa South China Sea [24]
trans 10β-Formamidokalihinol A (89) 410 C22H35ClN2O3 A. cavernosa Hachijo-jima Island, Japan [11]
  - - A. cavernosa Shallow water reef in Sanya Bay, Hainan Island, China [37]
  - - A. cavernosa Xisha Islets, South China Sea [38]
cis 10β-Formamidokalihinol A (90) 410 C22H35ClN2O3 A. cavernosa Shallow water reef in Sanya Bay, Hainan Island, China [37]
10β-Formamido-5-isocyanatokalihinol A (91) 426 C22H35ClN2O4 A. cavernosa Hachijo-jima Island, Japan [11]
  - - A. cavernosa Xidao Island, Hainan, China [22]
10β-Formamido-5β-isothiocyanatokalihinol A (92) 442 C22H35ClN2O3S A. cavernosa Hachijo-jima Island, Japan [11]
  - - A. cavernosa Xisha Islets, South China Sea [38]
  - - A. cavernosa Xidao Island, Hainan, China [22]
Bisformamidokalihinol A (93) 428 C22H37ClN2O4 A. cavernosa Xidao Island, Hainan, China [22]
Kalihinol B (94) 392 C22H33ClN2O2 Acanthella sp. Apra Harbor, Guam, western side of the USA [30]
  - - Acanthella sp. Queen Charlotte Island chain off the coast of British Columbia. [20]
  - - A. klethra Kuchinoerabu Island of the Satsunan Archipelago, Japan [27]
  - - A. cavernosa Seychelles and Desnceufs Islands [32]
Isokalihinol B (95) 392 C22H33ClN2O2 A. klethra Kuchinoerabu Island of the Satsunan Archipelago, Japan [27]
  - - A. cavernosa Seychelles and Desnceufs Islands [32]
  - - A. cavernosa Beau Vallon Beach, Mahé, Seychelles [39]
Kalihinol C (96) 328 C20H28N2O2 Acanthella sp. Apra Harbor, Guam, western side of the USA [30]
  - - A. cavernosa Seychelles and Desnceufs Islands [32]
Kalihinol D (97) 392 C22H33ClN2O2 Acanthella sp. Apra Harbor, Guam, western side of the USA [30]
  - - A. cavernosa Seychelles and Desnceufs Islands [32]
  - - Acanthella sp. Yalong Bay, Hainan, China [13]
Kalihinol E (98) 392 C22H35ClN2O3 Acanthella sp. Apra Harbor, Guam, western side of the USA [30]
  - - A. cavernosa Seychelles and Desnceufs Islands [32]
  - - A. cavernosa Hachijo-jima Island, Japan [11]
  - - A. cavernosa Xisha Islets, South China Sea [38]
  - - A. cavernosa South China Sea [24]
10β-Formamidokalihinol E (99) 410 C22H33ClN2O2 A. cavernosa Hachijo-jima Island, Japan [11]
Kalihinol F (100) 383 C23H33N3O2 Acanthella sp. Apra Harbor, Guam, western side of the USA [30]
  - - A. caruenosa Fiji, South Pacific Ocean [31]
  - - Acanthella sp. Apra Harbor, Guam, western side of the USA [40]
  - - Acanthella sp. Queen Charlotte Island chain off the coast of British Columbia. [20]
  - - A. klethra Kuchinoerabu Island of the Satsunan Archipelago, Japan [27]
  - - A. cavernosa Seychelles and Desnceufs Islands [32]
  - - A. cavernosa Beau Vallon Beach, Mahé, Seychelles [39]
  - - Acanthella sp. Coast of Cape Sada, Ehime Prefecture, Japan [41]
  - - A. cavernosa Dibud, Philippines [36]
Isokalihinol F (101) 383 C23H33N3O2 A. cavernosa Fiji, South Pacific Ocean [31]
  - - A. cavernosa Seychelles and Desnceufs Islands [32]
  - - A. cavernosa Beau Vallon Beach, Mahé, Seychelles [39]
  - - A. cavernosa Fiji, South Pacific Ocean [28]
  - - A. cavernosa Heron Island, Great Barrier Reef, Australia [18]
8-Hydroxy-isokalihinol F (102) 399 C23H33N3O3 A. cavernosa Heron Island, Great Barrier Reef, Australia [18]
10-epi-Isokalihinol F (103) 383 C23H33N3O2 A. cavernosa Beau Vallon Beach, Mahé, Seychelles [39]
trans 10-Formamido-kalihinol F (104) 401 C23H35N3O3 A. cavernosa Dibud, Philippines [36]
cis 10-Formamido-kalihinol F (105) 401 C23H35N3O3 A. cavernosa Dibud, Philippines [36]
trans 15-Formamido-kalihinol F (106) 401 C23H35N3O3 A. cavernosa Dibud, Philippines [36]
cis 15-Formamido-kalihinol F (107) 401 C23H35N3O3 A. cavernosa Dibud, Philippines [36]
Kalihinol G (108) 415 C23H33N3O2S Acanthella sp. Apra Harbor, Guam, western side of the USA [30]
  - - A. cavernosa Seychelles and Desnceufs Islands [32]
  - - Acanthella sp. Coral reef of Ishigaki Island, Okinawa, Japan [35]
  - - A. cavernosa Dibud, Philippines [36]
10-Isothiocyanatokalihinol G (109) 447 C23H33N3O2S2 A. cavernosa Xisha Islets, South China Sea [38]
5,10-bis-Isothiocyanatokalihinol G (110) 479 C23H33N3O2S3 Acanthella sp. Coral reef of Ishigaki Island, Okinawa, Japan [35]
Kalihinol H (111) 415 C23H33N3O2S Acanthella sp. Apra Harbor, Guam, western side of the USA [30]
  - - A. cavernosa Seychelles and Desnceufs Islands [32]
  - - Acanthella sp. Coral reef of Ishigaki Island, Okinawa, Japan [35]
Isokalihinol H (112) 415 C23H33N3O2S A. cavernosa Beau Vallon Beach, Mahé, Seychelles [39]
10-epi-Isokalihinol H (113) 415 C23H33N3O2S A. cavernosa Beau Vallon Beach, Mahé, Seychelles [39]
Kalihinol I (114) 456 C22H33ClN2O2S2 A. cavernosa Thailand [15]
  - - A. cavernosa Seychelles and Desnceufs Islands [32]
  - - Acanthella sp. Coral reef of Ishigaki Island, Okinawa, Japan [35]
10-epi-Kalihinol I (115) 456 C22H33ClN2O2S2 Acanthella sp. Coral reef of Ishigaki Island, Okinawa, Japan [35]
  - - A. cavernosa Xisha Islets, South China Sea [38]
  - - A. cavernosa South China Sea [24]
Kalihinol J (116) 442 C22H35ClN2O3S A. cavernosa Thailand [15]
  - - A. cavernosa Seychelles and Desnceufs Islands [32]
  - - A. cavernosa Dibud, Philippines [36]
Kalihinol M (117) 442 C22H35ClN2O3S A. cavernosa Xisha Islets, South China Sea [38]
Kalihinol N (118) 442 C22H35ClN2O3S A. cavernosa Xisha Islets, South China Sea [38]
Kalihinol O (119) 424 C22H33ClN2O2S A. cavernosa Xisha Islets, South China Sea [38]
Kalihinol P (120) 424 C22H33ClN2O2S A. cavernosa Xisha Islets, South China Sea [38]
Kalihinol Q (121) 424 C22H33ClN2O2S A. cavernosa Xisha Islets, South China Sea [38]
Kalihinol R (122) 456 C22H33ClN2O2S2 A. cavernosa Xisha Islets, South China Sea [38]
Kalihinol S (123) 410 C22H35ClN2O3 A. cavernosa Xisha Islets, South China Sea [38]
Kalihinol T (124) 424 C22H33ClN2O2S A. cavernosa Xisha Islets, South China Sea [38]
Kalihinol X (125) 424 C22H33ClN2O2S Acanthella sp. Apra Harbor, Guam, western side of the USA [30]
  - - A. cavernosa Fiji, South Pacific Ocean [31]
  - - A. cavernosa Thailand [15]
  - - A. cavernosa Seychelles and Desnceufs Islands [32]
  - - A. cavernosa Dibud, Philippines [36]
  - - Acanthella sp. Yalong Bay, Hainan, China [13]
10-epi-Kalihinol X (126) 424 C22H33ClN2O2S Acanthella sp. Yalong Bay, Hainan, China [13]
  - - A. cavernosa Xisha Islets, South China Sea [38]
  - - A. cavernosa South China Sea [24]
Kalihinol Y (127) 365 C21H32ClNO2 Acanthella sp. Apra Harbor, Guam, western side of the USA [30]
  - - Acanthella caruenosa Fiji, South Pacific Ocean [31]
  - - A. cavernosa Thailand [15]
  - - A. cavernosa Seychelles and Desnceufs Islands [32]
  - - Acanthella sp. Coral reef of Ishigaki Island, Okinawa, Japan [35]
  - - A. cavernosa Dibud, Philippines [36]
Kalihinone Ya (128) 367 C20H30ClNO3 Acanthella sp. Apra Harbor, Guam, western side of the USA [30]
Δ9-Kalihinol Y (129) 365 C21H32ClNO2 Acanthella sp. Coral reef of Ishigaki Island, Okinawa, Japan [35]
Kalihinol Z (130) 392 C22H33ClN2O2 Acanthella sp. Apra Harbor, Guam, western side of the USA [30]
  - - A. cavernosa Fiji, South Pacific Ocean [31]
  - - A. cavernosa Seychelles and Desnceufs Islands [32]
Kalihiacyloxyamide A (131) 468 C25H41ClN2O4 A. cavernosa Xisha Island, South China Sea [42]
Kalihiacyloxyamide B (132) 468 C25H41ClN2O4 A. cavernosa Xisha Island, South China Sea [42]
Kalihiacyloxyamide C (133) 552 C30H49ClN2O5 A. cavernosa Xisha Island, South China Sea [42]
Kalihiacyloxyamide D (134) 552 C30H49ClN2O5 A. cavernosa Xisha Island, South China Sea [42]
Kalihiacyloxyamide E (135) 586 C33H47ClN2O5 A. cavernosa Xisha Island, South China Sea [42]
Kalihiacyloxyamide F (136) 586 C33H47ClN2O5 A. cavernosa Xisha Island, South China Sea [42]
Kalihiacyloxyamide G (137) 518 C30H50N2O5 A. cavernosa Xisha Island, South China Sea [42]
Kalihiacyloxyamide H (138) 518 C30H50N2O5 A. cavernosa Xisha Island, South China Sea [42]
Kalihinene          
Kalihinene (139) 340 C22H32N2O A. klethra Kuchinoerabu Island of the Satsunan Archipelago, Japan [27]
  - - A. cavernosa Beau Vallon Beach, Mahé, Seychelles [39]
  - - A. cavernosa Fiji, South Pacific Ocean [28]
  - - Acanthella sp. Coral reef of Ishigaki Island, Okinawa, Japan [35]
  - - A. cavernosa Dibud, Philippines [36]
  - - Acanthella sp. Ximao Sea, Hainan, China [12]
1-epi-Kalihinene (140) 340 C22H32N2O A. cavernosa Beau Vallon Beach, Mahé, Seychelles [39]
  - - A. cavernosa Heron Island, Great Barrier Reef, Australia [18]
15-Isothiocyanato-l-epi-kalihinene (141) 372 C22H32N2OS A. cavernosa Beau Vallon Beach, Mahé, Seychelles [39]
1,10-diepi-Kalihinene (142) 340 C22H32N2O A. cavernosa Beau Vallon Beach, Mahé, Seychelles [39]
Kalihinene A (143) 340 C22H32N2O A. cavernosa Seychelles and Desnceufs Islands [32]
  - - A. cavernosa Xisha Islets, South China Sea [43]
Kalihinene B (144) 340 C22H32N2O A. cavernosa Seychelles and Desnceufs Islands [32]
Kalihinene E (145) 367 C21H34ClNO2 A. cavernosa Xisha Islets, South China Sea [43]
Kalihinene F (146) 331 C21H33NO2 A. cavernosa Xisha Islets, South China Sea [43]
Kalihinene X (147) 367 C21H34ClNO2 A. cavernosa Yakushima Island, southwest of Tokyo [33][34]
  - - A. cavernosa Xisha Islets, South China Sea [43]
Kalihinene Y (148) 367 C21H34ClNO2 A. cavernosa Yakushima Island, southwest of Tokyo [33][34]
  - - A. cavernosa Xisha Islets, South China Sea [43]
Kalihinene Z (149) 367 C21H34ClNO2 A. cavernosa Yakushima Island, southwest of Tokyo [33][34]
10-Formamidokalihinene (150) 358 C22H34N2O2 A. cavernosa Yakushima Island, southwest of Tokyo [33][34]
  - - A. cavernosa Fiji, South Pacific Ocean [28]
  - - A. cavernosa Xisha Islets, South China Sea [43]
15-Formamidokalihinene (151) 358 C22H34N2O2 A. cavernosa Yakushima Island, southwest of Tokyo [33]
  - - A. cavernosa Fiji, South Pacific Ocean [28]
  - - A. cavernosa Xisha Islets, South China Sea [43]
10,l5-bis-Formamidokalihinene (152) 376 C22H36N2O3 A. cavernosa Fiji, South Pacific Ocean [28]
6-Hydroxy-kalihinene (153) 356 C22H32N2O2 A. cavernosa Fiji, South Pacific Ocean [28]
  - - Acanthella sp. Coral reef of Ishigaki Island, Okinawa, Japan [35]
6-Hydroxy-15-Formamidokalihinene (154) 374 C22H34N2O3 A. cavernosa Fiji, South Pacific Ocean [28]
6-Hydroxy-10-Formamidokalihinene (155) 374 C22H34N2O3 A. cavernosa Fiji, South Pacific Ocean [28]
6-Hydroxy-10-Formamido-15-thyocyano-kalihinene (156) 406 C22H34N2O3S A. cavernosa Fiji, South Pacific Ocean [28]
Kalihioxepanes          
Kalihioxepane A (157) 365 C21H32ClNO2 A. cavernosa Xisha Island, South China Sea [44]
Kalihioxepane B (158) 365 C21H32ClNO2 A. cavernosa Xisha Island, South China Sea [44]
Kalihioxepane C (159) 383 C21H34ClNO3 A. cavernosa Xisha Island, South China Sea [44]
Kalihioxepane D (160) 383 C21H34ClNO3 A. cavernosa Xisha Island, South China Sea [44]
Kalihioxepane E (161) 383 C21H34ClNO3 A. cavernosa Xisha Island, South China Sea [44]
Kalihioxepane F (162) 365 C21H32ClNO2 A. cavernosa Xisha Island, South China Sea [44]
Kalihioxepane G (163) 365 C21H32ClNO2 A. cavernosa Xisha Island, South China Sea [44]
Kalihipyran (164) 311 C21H29NO A. cavernosa Beau Vallon Beach, Mahé, Seychelles [39]
  - - A. cavernosa Heron Island, Great Barrier Reef, Australia [18]
Kalihipyrans          
Kalihipyran A (165) 329 C21H31NO2 A. cavernosa Yakushima Island, southwest of Tokyo [33]
Kalihipyran B (166) 365 C21H32ClNO2 A. cavernosa Yakushima Island, southwest of Tokyo [33]
Kalihipyran C (167) 329 C21H31NO2 A. cavernosa Xisha Islets, South China Sea [43]
Biflorane diterpenes          
Biflora-4,9,15-triene (168) 272 C20H32 A. cavernosa Yakushima Island, southwest of Tokyo [33]
  - - A. cavernosa Hachijo-jima Island, Japan [11]
Cavernene A (169) 315 C21H33NO A. cavernosa Xisha Islets, South China Sea [43]
Cavernene B (170) 317 C21H35NO A. cavernosa Xisha Islets, South China Sea [43]
Cavernene C (171) 317 C21H35NO A. cavernosa Xisha Islets, South China Sea [43]
Cavernene D (172) 331 C21H33NO2 A. cavernosa Xisha Islets, South China Sea [43]
Isocyanobifloradiene epoxide A (173)
11,12-epoxy-10-isocyano-4,14-bifloradiene (173)		 313 C21H31NO A. cavernosa Heron Island, Great Barrier Reef, Australia [18]
Isocyanobifloradiene epoxide B (174)
11,18-epoxy-10-isocyano-4,14-bifloradiene (174)		 313 C21H31NO A. cavernosa Heron Island, Great Barrier Reef, Australia [18]

2.1. Kalihinols

Kalihinol A (88) was the first reported member of this diterpenoid class in 1984 [29] (Table 2). It is a tricyclic diterpenoid belonging to group II, containing isocyano, hydroxyl, and chlorine moieties. It was separated from the CCl4 extract of Acanthella sp. and characterized by NMR and X-ray analyses [29] and its configuration was assigned as 1S/4R/5R/6S/7S/10S/11R/14S using the CD exciton chirality method [45] (Figure 9).
Figure 9. Kalihinol diterpenes (88–102) reported from the genus Acanthella.
In 1987, Chang et al. purified and characterized isocyano-diterpenoids kalihinols A–H (88, 94, 96–98, 100, 108, and 111) and X–Z (125, 127, and 130) from Acanthella sp. obtained from Guam and Fiji using spectral and X-ray analyses. They differ in the C-7 attached moiety; the tetrahydropyran with C-14 chlorine (e.g., 25, 88, 98, 130, and 127); or the tetrahydro-furanyl moiety, with 15-NC (e.g., 97 and 100), 15-NCS (e.g., 108), 15-C1 (e.g., 94), or isopropenyl replacing gem-dimethyl (e.g., 96) [30] (Figure 10).
Figure 10. Kalihinol diterpenes (103–117) reported from the genus Acanthella.
Additionally, 101 was isolated as colorless needles from A. carvenosa by flash chromatography and HPLC. It resembles 100 with a difference in the substitution at C4 and C5 [31]. Additionally, new members of the kalihinols family, 114 and 116, along with 125 and 127, were purified from A.cavernosa collected from Thailand by SiO2 CC and HPLC and identified by extensive NMR data. Compound 114 is similar to 125 with a C-5-N-formyl instead of the isothiocyanoate moiety in 125 [15]. Compounds 117 and 118 are two novel C-4 formamido analogs of isokalihinols reported from the South China Sea specimen of A. cavernosa. They have a trans-decalin ring at C-7 of the tetrahydrofuran and tetrahydropyran rings, respectively. Compound 117 possesses a C-15 chlorine atom and a C-10 isothiocyanato group, whereas 118 is an example of tetrahydropyran-type isokalihinol. They have 1S/4S/5S/6S/7S/10S/11R/14S and 1S/4S/5S/6S/7S/10S/11R/14R configurations, respectively [38]. From Okinawan Acanthella sp., new members of kalihinane-type diterpenes, 110, 115, and 129, were purified from the EtOAc fraction using SiO2 CC and HPLC. Compound 129 is of tetrahydropyran type and is closely similar to 127, with a trisubstituted olefinic bond in 129 instead of the exo-methylene group in 127, while 110 and 115 have three and two isothiocyano groups, respectively [35] (Figure 11).
Figure 11. Kalihinol diterpenes (118–130) reported from the genus Acanthella.
In 1994, Trimurtulu et al. reported new diterpene isonitriles, 103 and 113, from A. carvenosa collected from The Seychelles. Compound 103 differs from 101 in the trans-decalin ring system configuration, whereas 113 has an isothiocyanate group instead of one of the C-10 isonitrile groups of 103 [39]. Besides, Xu et al. reported new diterpenoids, kalihinols O–T (119–124), together with 88, 98, 109, 115, and 126, from A. cavernosa in the South China Sea using SiO2 and Sephadex LH-20 CC [38]. Their structures and stereo-structures were determined by NMR/CD/X-ray analyses [38]. Compound 119 is structurally similar to 98, with a C-10 isothiocyanate instead of a C-10 isonitrile in 98, whereas 120 is an isocyanato analog of 88 and 123 is a C-5 formamide analog of 126. Furthermore, 121 and 122 are the C-14 epimers of 120 and 115, respectively, and 124 is the C-15-isothiocyanato analog of 97 [38]. Clark et al. in 2000, purified a new kalihinol-type diterpenoid, 8-OH-isokalihinol F (102), from A. cavernosa obtained from Heron Island, Great Barrier Reef, Australia, which was structurally similar to 101 with an additional C-8 OH [18]. In addition, new formamide analogs, 104 and 106, were purified by Bugni et al. in 2004 from two Philippine A. cavernosa specimens. They featured formamide moieties at C-10 and C-15, respectively, instead of the isonitrile in 100 [36]. Furthermore, a new kalihinol diterpene, 126, was isolated from Hainan Acanthella sp. by SiO2 and Sephadex LH-20 CC and was assigned as a C-10 epimer of 127 [13]. Additionally, new α-acyloxy-amide-substituted diterpenoids, kalihiacyloxyamides A–H (131–138), were separated from South China Sea A. cavernosa EtOAc fractions using SiO2/Rp-18 CC/RP-HPLC that were elucidated based on spectral, X-ray, and CD analyses (Figure 12). These metabolites featured isobutyl amide (e.g., 131 and 132), iso-amyl ester (e.g., 133, 134, 137, and 138), and phenethyl ester (e.g., 135 and 136) groups [42].
Figure 12. Kalihinol diterpenes (131–138) reported from the genus Acanthella.

2.2. Kalihinenes

The first member of this group is kalihinene (139), which was purified from an A. klethra EtOH extract using SiO2 CC/Develosil ODS-5 CC/HPLC and assigned by NMR and X-ray analyses [27]. Furthermore, compounds 143 and 144 were reported as novel monounsaturated kalihinane class diterpenes derived from A. Cavernosa toxic CH2Cl2 extracts against Artemia salina and Lebistes reticulatus using VLC/Flash/Rp-18 CC. These two compounds are diastereoisomers of 139 that feature a trans-decalin skeleton instead of the trans-decalin skeleton of kalihinene. On the other hand, 143 and 144 are epimers at C-10 [32]. Additionally, 145 and 146 are tertrahydropyran/trans-decalin and tetrahydrofuran/cis-decalin analogs bearing formamido groups at C-10 and C-15, respectively (Figure 13). Kalihinene E (145) is a C-14 epimer of 148 with 1S/6S/7S/10S/11R/14R configuration [43]. In 1994, Rodríguez et al. purified new diterpenoids belonging to kalihinene and 6-OH kalihinene groups (148 and 150–156), along with 139 from A. cavernosa collected from a Fijian location. These compounds were characterized based on spectral and X-ray analyses as well as biogenetic evidence [28]. Additionally, 140–142 are new metabolites reported from A. carvenosa collected from The Seychelles [39]. Compound 140 is a C-1 isomer of 139, 141 has C-15 isothiocyanate instead of C-15 isonitrile in 140, and 142 is an isomer of 140 and 139 [39].
Figure 13. Kalihinene diterpenes (139–156) reported from the genus Acanthella.

2.3. Kalihipyrans and Kalihioxepanes

Kalihipyran (164) is a tricyclic kalihinene-type diterpene with a C-7 isopropenyl-containing dihydropyran moiety and a C-10 isonitrile [39]. Compound 167 is an isomer of 165 with cis-decalin [43], while 166 has a C-15 chlorine atom [33][34]. In 2022, Wang et al. purified new kalihinane diterpenoids, kalihioxepanes A–G (157–163), from South China Sea A. cavernosa by the means of SiO2/Sephadex LH-20/HPLC. The structures were elucidated by spectral and X-ray analyses, in addition to quantum chemical calculation methods [44] (Figure 14).
Figure 14. Kalihioxepanes (157–163) and kalihipyrans (164–167) diterpenes reported from the genus Acanthella.
These metabolites possess a rare C-7-attached oxepane ring with a C-14 Cl atom. Compounds 157–160 have a trans decalin skeleton; however, 161–163 have a cis-decalin skeleton with C-10 isonitrile (e.g., 157 and 158) and formamide (e.g., 159–163) groups [44]. Wang et al. proposed that 157–163 are biosynthesized using geranylgeraniol as a precursor (Scheme 2). The latter undergoes a series of reactions, including cyclization, double-bond migration, nucleophilic addition, and oxidation reactions, to give epoxide biflorane (A, the key intermediate). Nucleophilic substitution of biflorane forms 157 and 158. After that, hydration generates 159–161 which are then dehydrated to give 162 and 163, respectively [44].
Scheme 2. Biosynthesis of kalihioxepanes A–G (157–163) [44].

2.4. Biflorane Diterpenes

From the Japanese A. cavernosa, biflora-4,9,15-triene (168) was separated, which is a rare biflorane diterpene related to 66, by replacing the methyl hydrogen of the isopropyl group of 66 with a prenyl group [11]. In 2012, Xu et al. reported 169–172 from CH2Cl2 extracts of South China Sea A. cavernosa, bearing a C-10 formamide group that varied in the decalin moiety (cis or trans) configuration and nature of C-7-linked side chain [43] (Figure 15). Their structures were assigned by spectral and X-ray analyses. Compounds 169, 170, and 172 are trans-decalin derivatives, with a C-7 isoprenoid unit, a mono-olefinic isoprenoid sidechain, and a trisubstituted epoxide in the side chain, respectively. In contrast, 171 had a cis-decalin moiety [43].
Figure 15. Biflorane (168–174) diterpenes reported from the genus Acanthella.
Investigation of A. cavernosa DCM/MeOH extracts led to the separation of two oxirane analogs with a trans-decalin framework, 173 and 174, featuring a trisubstituted epoxide and a terminal epoxide group in the side chain, respectively. Compound 174 was suggested to be a precursor of the kalihipyran skeleton [18]. Clark et al. proposed that the biosynthesis of pyranyl and furanyl kalihinols involves epoxidation of the bifloradiene precursor’s terminal double bond by a nucleophilic attack at either epoxide end by a cyanide ion to form a hydroxyisocyanide. The latter initiates cyclisation to afford a bicyclic system (Scheme 3). Compounds 173 and 174 are alternative epoxidation products. Compound 174 was suggested to be a precursor of the kalihipyran skeleton [18].
Scheme 3. Biosynthesis of 140, 164, and 174 [18].

3. Alkaloids

Several reports have stated the isolation of different classes of alkaloids from this genus. It is noteworthy that bromopyrrole alkaloids are the dominant type reported from the species of this genus. Oroidin 177 is the first member of pyrrole 2-aminoimidazole alkaloids. These alkaloids were reported to have significant bioactivities, as well as chemical defense against predator fish.
In 2010, Hammami et al. purified a novel bromopyrolimidazole analog, 178, along with 177 from Tunisian A. acuta diethyl ether extracts [19]. Four bromo-pyrrole alkaloids, including novel alkaloid hanishin (179) in addition to 175–177, were isolated from A. carteri collected from the northern coast of Hanish Island, Yemen, South Red Sea, by Mancini et al. Compounds 177 and 179 are members of the oroidin family of alkaloids that are considered condensation products of prolines. Compound 179 was proposed to be derived from aminoimidazolinone (I) or amino acid (II) intermediates through 1N-C9 cyclization with subsequent side-chain oxidative breakdown [46] (Scheme 4).
Scheme 4. Proposed biosynthesis of 179 [46].
Mattia et al. purified 180 as a brominated alkaloid from Red Sea A. Aurantiaca BuOH extracts. The compound features an aminooxodihydroimidazole ring linked to a pyrroloazepine group via a double bond (Figure 16) [47]. Compounds 180 and 181 were obtained from A. aurantiaca BuOH extracts using Sephadex LH-20 and crystallization and were characterized by spectral and X-ray analyses [48]. In 2014, Macabeo and Guce reported the bromopyrrole-imidazole alkaloids 182–184 from CH2Cl2-MeOH extracts of A. carteri from The Philippines [49], while 185 is a pyrrole alkaloid isolated from the n-BuOH fraction of Acanthella sp. using Sephadex LH-20/Rp-18 CC [50].
Figure 16. Alkaloids (175–185) reported from genus Acanthella.
A series of synthetic reactions including Suzuki–Miyaura coupling and debromination resulted in natural analogs 186 and 187, in addition to new synthetic derivatives (−)-4-bromo-5-phenylphakellin and (−)-4,5-diphenylphakellin. It was found that the C-5 Br substitution with phenyl or H led to a loss in activity, revealing that the C-5 Br is important for α2B adrenoceptor agonistic activity (Scheme 5) [51].
Scheme 5. Semisynthesis of (−)-dibromophakellin (188) derivatives [51].
Furthermore, 190 was purified from A. carteri using Sephadex LH-20/SiO2 CC, giving a bright-orange color with a diazotized benzidine. The compound was characterized by NMR and X-ray analyses, as well as chemical methods. Compound 190 is a 6R/10S brominated alkaloid with a fused C-C pyrrole linkage to the cyclic guanidine core belonging to the 189 series [52].
In 2002, Wiese and his group reported the synthesis of 190 using dihydrooroidin that is converted to 188 (Scheme 6). Then, thermal rearrangement of 188 in the presence of K2CO3 produces 190 [53].
Scheme 6. Synthesis of 190 using dihydrooroidin [53].
Additionally, Grkovic et al. were able to separate tricyclic-guanidine-containing alkaloids, including a new analog mirabilin K (192), along with 191 and 193, from A. cavernosa collected in Southwestern Australia using diol flash chromatography/Rp-18/HPLC. The compounds were characterized by spectroscopic analyses and optical rotation measurements. Compound 192 has a 4S*/7S*/9R*/11S*/12R* configuration, which differs from 191 in the C9-CH3 group and with the presence of a N-substituted methine group (Figure 17) [54]. Furthermore, 194 and 195 were obtained by Fan et al. from the acetone extracts of A. cavernosa collected from the South China Sea [24].
Figure 17. Alkaloids (186–195) reported from the genus Acanthella.
Diketopiperazines, including the rare cyclo(L-Phe-L-Thr) and cyclo(L-Tyr-L-Ile) (196–202), along with decarboxylated amino acid 207 and deoxyribonucleotides 203–206, were reported and characterized from Fijian A. cavernosa (Figure 18). Their L-L absolute configuration was assigned based on an NMR and CD comparison with synthetic L-L analogs, as well as optical rotation measurements [55].
Figure 18. Alkaloids (196–207) reported from the genus Acanthella.

4. Steroid Compounds

In 2008, Qui et al. reported the purification of three new nor-steroids, 208–210, along with the known steroids 211–214 from the petroleum ether fraction of A. cavernosa obtained from Hainan Island, China, using SiO2 CC/HPLC. The new steroids are related to A-ring-contracted steroid analogs featuring carbonyl and ketone groups located at C-3 and C-4; they differ in their C-17 side chains [56] (Figure 19). In addition, 215 was obtained from the acetone extract of the same sponge collected from the South China Sea [24].
Figure 19. Steroid compounds (208–215) reported from the genus Acanthella.

5. Other Metabolites

Compound 216 was separated from A. vulgata acetone extracts using an MgO column and crystallization from petroleum ether. The compound belongs to carotenoids, as it has a polyene chain with terminal aromatic moieties on both ends [57] (Figure 20). Mancini et al. were able to purify and characterize 219, a novel methyl-branched glycerol enol ether, and the related linear analog 218 from A. carteri obtained from Southern Red Sea Hanish Islands by utilizing flash CC/HPLC and spectral and chemical methods [58]. Compound 219 has an additional methyl group at C-2 of the sidechain compared to 218, and both have a 2`S configuration [58]. In 2010, Hammami et al. separated the sesterterpene 217 and cerebrosides 220–222 from Tunisian A. acuta diethyl ether extracts [19], whereas 226 was purified from the Chinese A. cavernosa by Fan et al. [24].
Figure 20. Other metabolites (216–226) reported from the genus Acanthella.

This entry is adapted from the peer-reviewed paper 10.3390/md21040257

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