A Review of Sponge-Derived Diterpenes: 2009–2022

Abstract

Sponges are a vital source of pharmaceutically active secondary metabolites, of which the main structural types are alkaloids and terpenoids. Many of these compounds exhibit biological activities. Focusing specifically on diterpenoids, this article reviews the structures and biological activities of 228 diterpenes isolated from more than 33 genera of sponges from 2009 to 2022. The Spongia sponges produce the most diterpenoid molecules among all genera, accounting for 27%. Of the 228 molecules, 110 exhibit cytotoxic, antibacterial, antifungal, antiparasitic, anti-inflammatory, and antifouling activities, among others. The most prevalent activity is cytotoxicity, present in 54 molecules, which represent 24% of the diterpenes reported. These structurally and biologically diverse diterpenoids highlight the vast, yet largely untapped, potential of marine sponges in the discovery of new bioactive molecules for medicinal use.

1. Introduction

Sponges are important multicellular animals, exhibiting a vast diversity and widespread distribution. More than a decade ago, there were already about 15,000 species of sponges that had been described [1]. The number of natural products derived from sponges is substantial, with over 200 new molecules discovered each year [2,3,4]. Compounds derived from sponges exhibit a rich diversity, encompassing terpenoids [5], sterols, alkaloids [6], ceramides, macrolides, peptides, and others. Among these, alkaloids and terpenoids are the most abundant, accounting for 50% of the total [7]. Diterpenoids represent a class of structurally diverse terpenes with various biological activities.

There have been some reviews on the separation, structural elucidation, and biological activity evaluation of diterpenoids. From 1984 to 2009, Hanson James R. published a series of reviews on newly discovered diterpenes every year [8,9,10,11]. Since 2011, Hanson began publishing reviews on diterpenoids from terrestrial sources [12]. Reviews on diterpenoids from marine sources are relatively fewer.

We have consistently focused on the diterpene compounds derived from marine sources. In our review of marine-derived diterpenes, we found that fungi and sponges are primary sources of these compounds. Previously, we summarized the diterpenes from marine fungi [13]. Here, we provide another review focusing on the diterpenes from marine sponges.

There are some review articles on sponge-derived natural products. Two articles summarize the chemical and biological diversity of compounds from sponges over a decade, with the timespans being 2009–2018 [7] and 2011–2020 [14], respectively. Some reviews focus on specific types of sponges, such as molecules from the order Dictyoceratida [15], the families Hymedesmiidae [16] and Latrunculiidae [17], and the genera Amphimedon [18], Aaptos [19], Callyspongia [20], Haliclona [21], Petrosia [22], Phorbas [23], Reniera [24], Stelletta [25], and Suberea [26]. Other reviews focus on compounds with specific activities, like sponge-derived molecules with antimalarial/antiprotozoal activity [27] and natural products from Red Sea sponges with cytotoxic activity [28]. A review critically analyzed drugs/drug candidates inspired by natural sponge products [29]. There are also reviews focusing on specific types of compounds, such as alkaloids from sponges [6]. Diterpenes sourced from sponges have not been reviewed yet.

In this article, the structures and bioactivities of 228 newly discovered diterpenoids from more than 33 genera of sponges reported by 73 publications covering 14 years, from 2009 to 2022, are summarized.

2. The Characteristics of Diterpenes from Sponges

From 2009 to 2022, there were 73 reports on 228 new diterpenoids from sponges. Among these compounds, 62 were from the genus Spongia, accounting for 27% of the total, while 33, 17, 16, 13, 13, and 11 were from the genera Agelas, Acanthella, Hamigera, Darwinella, Dysidea, and Dendrilla, respectively (Figure 1A). In addition, 26 other genera of sponges have also yielded diterpenoids, with each contributing fewer than 10 molecules (Figure 1B). Among these, 12 genera have each produced a single diterpenoid. Furthermore, there are five diterpenoids that originate from sponges that have not yet been identified at the genus level.

Among these diterpenes, 110 have demonstrated a variety of bioactivities, constituting 48% of the overall number of reported compounds. The literature has reported 138 bioactivity data entries for these compounds, with 17, 4, and 1 compounds exhibiting two, three, and four different types of bioactivities, respectively. Cytotoxic activities against various tumor cell lines are considered to be a single type of activity.

The most frequently reported activity was cytotoxicity against tumor cells, with 54 molecules showing this activity, accounting for 39% of the activity entries and 24% of all reported molecules (Figure 2). The number of compounds with antibacterial activity ranked second, with 22 molecules, among which 6 had antituberculosis activity. The numbers of molecules with anti-inflammatory, antiparasitic, antifouling, antifungal, and osteoclast-inhibitory activities were 13, 12, 11, 7, and 6, respectively. Among the 12 molecules with antiparasitic activity, 9 were active against Plasmodium species, whereas 3 were active against the leishmaniasis parasite. The activities of 13 molecules were categorized as other types, including radiation sensitization activity, antioxidant activity, inhibitory activity against specific target proteins such as Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b), antiviral activity, and so on.

3. Isolation, Structure, and Bioactivities of Diterpenes from Sponges

3.1. Acanthella

A total of 17 diterpenes were obtained from Acanthella sponges. Seven formamido-diterpenes—cavernenes A–D, kalihinenes E–F, and kalihipyran C (1–7, Figure 3)—were isolated from the South China Sea sponge Acanthella cavernosa [30]. The cytotoxicity of these compounds was evaluated using five human cancer cell lines (human colon cancer cell line HCT-116, human lung epithelial cell line A549, human cervical carcinoma cell line HeLa, human hepatocellular carcinoma cell line QGY-7701, and human mammary cancer cell line MDA-MB-231).

Compounds 1 and 2 showed cytotoxic activities against HCT-116 cells, with IC₅₀ (50% inhibitory concentration) values of 6.31 and 8.99 µM, respectively (Table 1). Compound 5 showed cytotoxic activity against HCT-116, HeLa, QGY-7701, and MDA-MB-231 cells, with IC₅₀ values of 14.36, 13.36, 17.78, and 12.84 µM, respectively.

A nitrogen-containing kalihinane-type diterpenoid, bisformamidokalihinol A (8, Figure 3), was obtained from the Acanthella cavernosa sponge [31]. Eight diterpenoids, kalihinols M–T (9–16, Figure 3), were isolated from the South China Sea sponge Acanthella cavernosa [32]. Kalihinols M–N, with a formamide functionality at C-4, extended the structural breadth of this diterpenoid family. Kalihinols O–R showed cytotoxic activity against HCT-116 cells, with IC₅₀ values of 5.97, 10.68, 20.55, and 13.44 µM, respectively. Kalihinol P displayed cytotoxic activity against H1299 cells, with an IC₅₀ value of 26.21 µM. Kalihinols O–T displayed significant antifouling activity against Balanus amphitrite larvae, with EC₅₀ values of 1.43, 0.72, 1.48, 1.16, 0.53, and 0.74 µM, respectively. A kalihinol diterpene, 10-epi-kalihinol X (17, Figure 3), was obtained from the Hainan sponge Acanthella sp. [33]. Compound 17 exhibited in vitro cytotoxicity against the human lung adenocarcinoma cell line A549, with an IC₅₀ value of 9.30 µg/mL.

Table 1. Sponge-derived diterpenes with various bioactivities.

Compound Number	Compound Name	Producing Sponge	Activity	Reference
			Cytotoxicity to cancer cell lines
1–2	Cavernenes A–B	Acanthella cavernosa	Cytotoxicity against the HCT-116 cell line, with IC50 values of 6.31 and 8.99 µM, respectively	[30]
5	Kalihinene E	Acanthella cavernosa	Cytotoxicity against the HCT-116, HeLa, QGY-7701, and MDA-MB-231 cell lines, with IC50 values of 14.36, 13.36, 17.78, and 12.84 µM, respectively	[30]
11	Kalihinol O	Acanthella cavernosa	Cytotoxicity against HCT-116 cells, with an IC50 value of 5.97 µM	[32]
12	Kalihinol P	Acanthella cavernosa	Cytotoxicity against HCT-116 and H1299 cells, with IC50 values of 10.68 and 26.21 µM, respectively	[32]
13–14	Kalihinols Q–R	Acanthella cavernosa	Cytotoxicity against HCT-116 cells, with IC50 values of 20.55 and 13.44 µM, respectively	[32]
17	10-Epi-kalihinol X	Acanthella sp.	Cytotoxicity against the A549 cell line, with an IC50 value of 9.30 µg/mL	[33]
20	Axistatin 1	Agelas axifera Hentschel	Cytotoxicity against P388, BXPC-3, MCF-7, SF-268, NCI-H460, KM20L2, and DU-145 cells, with GI50 (50% growth inhibition) values of 19.8, 4.8, 5.7, 3.6, 4.6, 4.1, and 4.8 µM, respectively	[34]
21	Axistatin 2	Agelas axifera Hentschel	Cytotoxicity against P388, BXPC-3, MCF-7, SF-268, NCI-H460, KM20L2, and DU-145 cells, with GI50 values of 22.8, 5.5, 6.8, 3.9, 4.3, 4.1, and 5.0 µM, respectively	[34]
22	Axistatin 3	Agelas axifera Hentschel	Cytotoxicity against P388, BXPC-3, MCF-7, SF-268, NCI-H460, KM20L2, and DU-145 cells, with GI50 values of 8.9, 6.0, 5.8, 3.5, 5.4, 6.9, and 7.5 µM, respectively	[34]
27	Nemoechine G	Agelas aff. nemoechinata	Cytotoxicity against Jurkat cell lines, with an IC50 of 17.1 µM	[35]
28	Nemoechine D	Agelas aff. nemoechinata	Cytotoxicity against the human promyelocytic leukemia HL-60 cell line, with an IC50 value of 9.9 µM	[36]
36	(+)-Agelasine B	Agelas mauritiana	Cytotoxicity toward the cancer cell lines PC9, A549, HepG2, MCF-7, and U937, with IC50 values of 5.08, 14.07, 9.76, 7.64, and 4.49 µM, respectively	[37]
40	Iso-agelasine C	Agelas nakamurai	Cytotoxicity against HL-60, K562, and HCT-116 cell lines, with IC50 values of 25.3, 28.9, and 38.8 µM, respectively	[38]
41	Iso-agelasidine B	Agelas nakamurai	Cytotoxicity against HL-60 and K562 cell lines, with IC50 values of 33.0 and 39.2 µM, respectively	[38]
42	(−)-Agelasine D	Agelas nakamurai	Cytotoxicity against L5178Y mouse lymphoma cells, with an IC50 value of 4.03 µM	[39]
43	(−)-Agelamide D	Agelas nakamurai	Cytotoxicity against L5178Y mouse lymphoma cells, with an IC50 value of 12.5 µM	[39,40,41]
42	(−)-Agelasine D	Agelas nakamurai	Cytotoxic to Hep3B cells, with a GI50 of 9.9 µM	[41]
43	(−)-Agelamide D	Agelas nakamurai	Cytotoxic to Hep3B cells, with a GI50 of 12.0 µM	[41]
99	NN *	Dysidea cf. arenaria	Cytotoxicity against NBT-T2 rat bladder epithelial cells, with an IC50 value of 1.9 µg/mL	[42]
103–104	NN	Dysidea cf. arenaria	Cytotoxicity against NBT-T2 rat bladder epithelial cells, with IC50 values of 1.8 and 4.2 µg/mL, respectively	[42]
105–108	NN	Dysidea cf. arenaria	Cytotoxicity against the NBT-T2 cell line, with IC50 values of 3.1, 1.9, 8.4, and 3.1 µM, respectively	[43]
112	2,5-Dihydroxy-homoverrucos-(3)-ene	Halichondria sp.	Cytotoxicity against the human multiple myeloma cell line RPMI-8266, with an IC50 of 49.0 µM	[44]
113	2-Hydroxy-5-oxo-homoverrucos-(3)-ene	Halichondria sp.	Cytotoxicity against RPMI-8266 cells, with an IC50 of 65.8 µM	[44]
114	5,18-Dihydroxy-homoverrucosane	Halichondria sp.	Cytotoxicity against RPMI-8266 cells, with an IC50 of 32.7 µM	[44]
115	5-Hydroxy-18-aldehyde-homoverrucosane	Halichondria sp.	Cytotoxicity against RPMI-8266 cells, with an IC50 of 49.3 µM	[44]
116	Halioxepine	Haliclona sp.	Cytotoxicity against NBT-T2 cells, with an IC50 of 4.8 µg/mL	[45]
124–125, 127–128,130	Hamigerans M–Q	Hamigera tarangaensis	Cytotoxicity against the HL-60 cell line, with IC50 values of 6.9, 19.5, 14.7, 21.3, and 33.3 µM, respectively	[46]
126	18-Epi-hamigeran N	Hamigera tarangaensis	Cytotoxicity against the HL-60 cell line, with an IC50 value of 14.1 µM	[46]
129	18-Epi-hamigeran P	Hamigera tarangaensis	Cytotoxicity against the HL-60 cell line, with an IC50 value of 11.6 µM	[46]
136	3β-Hydroxyspongia-13(16),14-diene-2-one	Hyattella aff. intestinalis	Cytotoxicity against NBT-T2 cells, with an IC50 value of 24.1 µM	[47]
143	6,10,18-Triacetoxy-2E,7E-dolabelladien	Luffariella variabilis	Cytotoxicity against the MDA-MB-231 cell line, with an IC50 value of 11.57 µM	[48]
145	NN	Pseudoaxinella flava	Cytotoxicity against the PC3 cell line, with an IC50 value of 7 µM	[49]
172	3β-Hydroxyspongia-13(16),14-dien-2-one	Spongia tubulifera	Activity against A549, human skin melanoma A2058, hepatocyte carcinoma HepG2, and pancreas carcinoma MiaPaca-2 cell lines, with IC50 values of 88.1, 71.4, 91.3, and 90.0 µM, respectively	[50]
191	Epoxynorspongian E	Spongia sp.	Activity against the PC3 and PBL-2H3 cell lines, with IC50 values of 24.8 and 27.2 µM, respectively	[51]
199	2β,3α,19-Triacetoxy-17-hydroxyspongia-13(16),14-diene	Spongia officinalis Linnaeus, 1759	Cytotoxicity against the K562 cell line, with an IC50 value of 7.3 µM	[52]
206	Ceylonamide G	Spongia sp.	Inhibited the growth of DU145 cells in two-dimensional monolayer culture, with an IC50 of 6.9 µM; also effective on spheroids of a three-dimensional DU145 cell culture model with a minimum effective concentration of 10 µM	[53]
209–211	Gracilins J–L	Spongionella sp.	Cytotoxic activity against K562 cells and normal human peripheral blood mononuclear cells (PBMCs), with IC50 values of 15 and 30, 8.5 and 9, and 2.65 and 3 µM, respectively	[54]
212	3′-Norspongiolactone	Spongionella sp.	Cytotoxic activity against K562 cells and normal PBMCs, with IC50 values of 12 and 30 µM, respectively	[54]
213	Spongionellol A	Spongionella sp.	Activity in the cell lines PC3, PC3-DR, DU145, DU145-DR, 22Rv1, VCaP, and LNCaP, with IC50 values of 0.96, 1.23, 0.94, 1.53, 2.64, 1.30, and 1.02 µM, respectively	[55]
224	Luakuliide A	Unidentified	Activity against HL-60 cells, with an IC50 value of 21.7 µM	[56]
227	Chromodorolide D	Unidentified	Cytotoxicity against the NBT-T2 cell line, with an IC50 value of 5.6 µg/mL	[57]
228	NN	Unidentified	Cytotoxicity against the NBT-T2 cell line, with an IC50 value of 12 µg/mL	[57]
			Antibacterial activity
25	10-Hydro-9-hydroxyagelasine F	Agelas nakamurai	Inhibited the growth of Mycobacterium smegmatis, with inhibition zones of 10 mm at 20 µg/disc	[58]
33	(+)-10-Epiagelasine B	Agelas citrina	Active against Staphylococcus aureus ATCC 29213, S. aureus USA300LAC, Streptococcus pneumoniae ATCC 49619, S. pneumoniae 549 CHUAC, Enterococcus faecalis ATCC 29212, E. faecalis 256 CHUAC, and E. faecium 214 CHUAC, with MIC (minimum inhibitory concentration) values of 1, 2, 4, 8, 4, 4, and 4 µg/mL, respectively	[59]
36	(+)-Agelasine B	Agelas mauritiana	Active against a panel of methicillin-resistant S. aureus (MRSA) clinical strains 2010-260, 2010-210, 2010-292, and 2010-300, as well as a methicillin-susceptible S. aureus strain H608, with MIC90 values of 2, 1, 2, 1, and 2 µg/mL, respectively	[37]
40	Iso-agelasine C	Agelas nakamurai	Antibacterial activities against Proteusbacillus vulgaris, with an MIC value of 18.75 µg/mL	[38]
46–49	Agelasines O–R	Agelas sp.	Inhibited the growth of S. aureus and Bacillus subtilis, with MIC values of 16 and 16, 32 and 32, 8 and 8, and 8 and 8 µg/mL, respectively	[60]
51	Agelasine T	Agelas sp.	Inhibited the growth of S. aureus and B. subtilis, with MIC values of 16 and 16 µg/mL, respectively	[60]
66	Eleganstone A	Dactylospongia elegans	Antibacterial activity against Escherichia coli, B. subtilis, and S. aureus, with an MIC value of 64 µg/mL	[61]
67	(1R*,2E,4R*,8E,10S*, 11S*,12R*)-10,18-diacetoxydolabella-2,8-dien-6-one	Dactylospongia elegans	Antibacterial activity against E. coli, B. subtilis, and S. aureus, with an MIC value of 64 µg/mL	[61]
85	Dendrillin B	Dendrilla antarctica	Achieved 90% eradication at 100 µg/mL in the MRSA biofilm assay	[62]
88	Darwinolide	Dendrilla membranosa	Cytotoxicity against MRSA, with an MIC of 132.9 μM, and activity against the biofilm formation of the same MRSA strain, with an IC50 value of 33.2 µM	[63]
138	Monamphilectine A	Hymeniacidon sp.	Showed 43% and 38% of the bactericidal strength of the β-lactam antibiotics carbenicillin and amphicillin, respectively, against E. coli at a concentration of 150 nM	[64]
203	Spongenolactone A	Spongia sp.	Exhibited 46%, 47%, and 93% inhibition against S. aureus at 50, 100, and 200 µM, respectively	[65]
204	Spongenolactone B	Spongia sp.	Displayed 24%, 42%, and 40% inhibition against S. aureus at 50, 100, and 200 µM, respectively	[65]
			Antituberculosis activity
57–59	Macfarlandins F–H	Chelonaplysilla sp.	Inhibited Mycobacterium tuberculosis, with MIC values of >20, 49, and >20 µg/mL, respectively	[66]
138	Monamphilectine A	Hymeniacidon sp.	Activity against M. tuberculosis H37Rv, with an MIC value of 15.3 µg/mL	[64]
219	7-Methylaminoisoneoamphilecta-1(14),15-diene	Svenzea flava	Activity against M. tuberculosis H37Rv, with an MIC value of 15 µg/mL	[67]
220	7-Formamidoisoneoamphilecta-1(14),15-diene	Svenzea flava	Activity against M. tuberculosis H37Rv, with an MIC value of 32 µg/mL	[67]
			Antifungal activity
40	Iso-agelasine C	Agelas nakamurai	Activity against Candida albicans, with an MIC value of 4.69 µg/mL	[38]
41	Iso-agelasidine B	Agelas nakamurai	Activity against C. albicans, with an MIC value of 2.34 µg/mL	[38]
46	Agelasine O	Agelas sp.	Inhibited the growth of Trichophyton mentagrophytes and Cryptococcus neoformans, with IC50 values of 32 and 16 µg/mL, respectively	[60]
47	Agelasine P	Agelas sp.	Inhibited the growth of C. neoformans, with an IC50 value of 32 µg/mL	[60]
48–49	Agelasines Q–R	Agelas sp.	Inhibited the growth of Aspergillus niger, T. mentagrophytes, C. albicans, and C. neoformans, both with IC50 values of 16, 16, 16, and 8 µg/mL, respectively	[60]
51	Agelasine T	Agelas sp.	Inhibited the growth of C. neoformans, with an IC50 value of 16 µg/mL	[60]
			Antiparasitic activity
60	8-Isocyanoamphilecta-11(20),15-diene	Ciocalapata sp.	Activity against Plasmodium falciparum K1, with an IC50 value of 0.98 µM	[68]
61	(1S,3S,4R,7S,8S,11S,12S,13S,15R,20R)-7-Formamido-20-isocy-anoisocycloamphilectane	Cymbastela hooperi	Inhibitory effects on three strains of P. falciparum (FCR3F86, W2, and D6), with an average IC50 value of 0.5 µg/mL	[69]
62	(1S,3S,4R,7S,8S,11S,12S,13S,15R,20R)-7,20-Diformamidoisocy-cloamphilectane	Cymbastela hooperi	Inhibitory effects on P. falciparum FCR3F86, with an IC50 value of 14.8 µg/mL	[69]
83	Membranoid B	Dendrilla antarctica	Activity against Leishmania donovani (IC50 0.8 µM), with no discernible cytotoxicity against uninfected J774A.1 cells	[70]
84	Membranoid D	Dendrilla antarctica	Activity against L. donovani (IC50 1.4 µM), with no discernible cytotoxicity against uninfected J774A.1 cells	[70]
85	Dendrillin B	Dendrilla antarctica	Activity against the leishmaniasis parasite, with an IC50 value of 3.5 µM	[62]
92	Diacarperoxide H	Diacarnus megaspinorhabdosa	Activity against P. falciparum (W2 clones) in vitro, with an IC50 value of 12.9 µM	[71]
93	Diacarperoxide I	Diacarnus megaspinorhabdosa	Activity against P. falciparum (W2 and D6 clones) in vitro, with IC50 values of 4.8 and 7.9 µM, respectively	[71]
94	Diacarperoxide J	Diacarnus megaspinorhabdosa	Activity against P. falciparum (W2 and D6 clones) in vitro, with IC50 values of 1.8 and 1.6 µM, respectively	[71]
138	Monamphilectine A	Hymeniacidon sp.	Activity against a chloroquine-resistant (CQ-R) P. falciparum W2 strain, with an IC50 value of 0.60 µM	[64]
217–218	Monamphilectines B–C	Svenzea flava	Activity against P. falciparum, with IC50 values of 44.5 and 43.3 nM, respectively	[72]
			Anti-inflammatory activity
133–134	Hipposponlachnins A–B	Hippospongia lachne	Inhibitory activity on the release of β-hexosaminidase in DNP-IgE-stimulated RBL-2H3 cells, with IC50 values of 49.37 and 23.91 µM, respectively	[73]
141	Erectcyanthin B	Hyrtios erectus	Inhibited 5-LOX, COX-2, and COX-1, with IC50 values of 0.88, 0.98, and 1.09 mM, respectively	[74]
193	Sponalactone	Spongia officinalis	Inhibitory activity on the lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 macrophages, with an IC50 value of 32 µM	[75]
194	17-O-acetylepispongiatriol	Spongia officinalis	Inhibitory activity on the LPS-induced NO production in RAW264.7 macrophages, with an IC50 value of 15 µM	[75]
195	17-O-acetylspongiatriol	Spongia officinalis	Inhibitory activity on the LPS-induced NO production in RAW264.7 macrophages, with an IC50 value of 12 µM	[75]
196	15α,16α-Dimethoxy-15,16-dihydroepispongiatrio	Spongia officinalis	Inhibitory activity on the LPS-induced NO production in RAW264.7 macrophages, with an IC50 value of 22 µM	[75]
197	15α-Ethoxyepispongiatriol-16(15H)-one	Spongia officinalis	Inhibitory activity on the LPS-induced NO production in RAW264.7 macrophages, with an IC50 value of 12 µM	[75]
198	17-Dehydroxysponalactone	Spongia sp.	Inhibited superoxide anion generation (91%) and elastase release (90%) at 10 µM, with IC50 values of 3.37 and 4.07 µM, respectively	[76]
203–205	Spongenolactones A–C	Spongia sp.	Inhibitory activity against superoxide anion generation in fMLF/CB-stimulated human neutrophils, with IC50 values of 16.5, 13.1, and 17.4 µM, respectively	[65]
221	Tedanol	Tedania ignis	Showed anti-inflammatory activity through the inhibition of carrageenan-induced paw edema in mice	[77]
			Antifouling activity
11–16	Kalihinols O–T	Acanthella cavernosa	Activity against Balanus amphitrite larvae, with EC50 (50% effective concentration) values of 1.43, 0.72, 1.48, 1.16, 0.53, and 0.74 µM, respectively	[32]
42	(−)-Agelasine D	Agelas nakamurai	Inhibited the growth of planktonic forms of the biofilm-forming bacteria Staphylococcus epidermidis (MIC < 0.0877 µM), but did not inhibit biofilm formation	[39]
43	(−)-Agelamide D	Agelas nakamurai	Inhibited only the biofilm formation but not the growth of S. epidermidis	[39]
81	9,11-Dihydrogracilin A	Dendrilla antarctica	Reduced the area covered by the fouling organisms	[78]
82	9,11-Dihydrogracillinone A	Dendrilla antarctica	Reduced the area covered by the fouling organisms	[78]
139	Hymerhabdrin A	Hymerhabdia sp.	Toxic against larvae of the barnacle Balanus amphitrite, with an IC50 of 3.6 µg/mL	[79]
			Inhibition of osteoclasts
153–154	Ceylonamides A–B	Spongia ceylonensis	Inhibitory effects on RANKL-induced osteoclastogenesis in RAW264 macrophages, with IC50 values of 13 and 18 µM, respectively	[80]
160	Ceylonin A	Spongia ceylonensis	Inhibited the RANKL-induced formation of multinuclear osteoclasts in RAW264 cells by 70% (50 µM), in a dose-dependent manner, without cytotoxicity	[81]
163–165	Ceylonins D–F	Spongia ceylonensis	Inhibited the RANKL-induced formation of multinuclear osteoclasts by 28%, 47%, and 31%, respectively	[81]
			Others
43	(−)-Agelamide D	Agelas nakamurai	Enhanced the radiation sensitivity of Hep3B cells; enhanced the efficacy of radiotherapy in a hepatocellular carcinoma (HCC) xenograft mouse model	[41]
53–55	Agelasines W–Y	Astrosclera willeyana	Inhibited the Cbl-b protein that negatively regulates T-cell activation, with IC50 values of 57, 72, and 66 µM, respectively	[82]
116	Halioxepine	Haliclona sp.	Activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH), with an IC50 of 3.2 µg/mL	[45]
141	Erectcyanthin B	Hyrtios erectus	Scavenged DPPH and ABTS+, with IC50 values of 0.45 and 0.40 mM, respectively	[74]
141	Erectcyanthin B	Hyrtios erectus	Activity against 3-hydroxy-3-methylglutaryl-coenzyme A reductase, with an IC50 value of 0.07 mM	[74]
144	Niphateolide A	Niphates olemda	Inhibited the p53-Hdm2 (human Mdm2) interaction, with an IC50 value of 16 µM	[83]
146	Raspadiene	Raspailia bouryesnaultae	Inhibited the replication of HSV-1 (KOS and 29R strains) at 100 µg/mL by 83% and 74%, respectively	[84]
151	18-Nor-3,5,17-trihydroxyspongia-3,13(16),14-trien-2-one	Spongia sp.	Inhibited aromatase in a dose-dependent manner, with an IC50 value of 34.4 µM	[85]
151	18-Nor-3,5,17-trihydroxyspongia-3,13(16),14-trien-2-one	Spongia sp.	Doubled the quinone reductase 1 (QR1) activity in cultured Hepa 1c1c7 cells at 11.2 µM	[85]
209	Gracilin J	Spongionella sp.	Restored mitochondrial activity of neurons to control levels of 98.9% ± 4.7% (p < 0.001) at 0.1 µM, reversing the 28.6% ± 3.4% decrease caused by 200 µM H2O2 treatment	[86]
214	26-O-etfhylstrongylophorine-14	Strongylophora strongilata	Inhibiting protein tyrosine phosphatase 1B (PTP1B), associated with type 2 diabetes, with an IC50 value of 8.7 µM	[87]

* Not named.

Table 1. Sponge-derived diterpenes with various bioactivities.

Compound Number	Compound Name	Producing Sponge	Activity	Reference
			Cytotoxicity to cancer cell lines
1–2	Cavernenes A–B	Acanthella cavernosa	Cytotoxicity against the HCT-116 cell line, with IC50 values of 6.31 and 8.99 µM, respectively	[30]
5	Kalihinene E	Acanthella cavernosa	Cytotoxicity against the HCT-116, HeLa, QGY-7701, and MDA-MB-231 cell lines, with IC50 values of 14.36, 13.36, 17.78, and 12.84 µM, respectively	[30]
11	Kalihinol O	Acanthella cavernosa	Cytotoxicity against HCT-116 cells, with an IC50 value of 5.97 µM	[32]
12	Kalihinol P	Acanthella cavernosa	Cytotoxicity against HCT-116 and H1299 cells, with IC50 values of 10.68 and 26.21 µM, respectively	[32]
13–14	Kalihinols Q–R	Acanthella cavernosa	Cytotoxicity against HCT-116 cells, with IC50 values of 20.55 and 13.44 µM, respectively	[32]
17	10-Epi-kalihinol X	Acanthella sp.	Cytotoxicity against the A549 cell line, with an IC50 value of 9.30 µg/mL	[33]
20	Axistatin 1	Agelas axifera Hentschel	Cytotoxicity against P388, BXPC-3, MCF-7, SF-268, NCI-H460, KM20L2, and DU-145 cells, with GI50 (50% growth inhibition) values of 19.8, 4.8, 5.7, 3.6, 4.6, 4.1, and 4.8 µM, respectively	[34]
21	Axistatin 2	Agelas axifera Hentschel	Cytotoxicity against P388, BXPC-3, MCF-7, SF-268, NCI-H460, KM20L2, and DU-145 cells, with GI50 values of 22.8, 5.5, 6.8, 3.9, 4.3, 4.1, and 5.0 µM, respectively	[34]
22	Axistatin 3	Agelas axifera Hentschel	Cytotoxicity against P388, BXPC-3, MCF-7, SF-268, NCI-H460, KM20L2, and DU-145 cells, with GI50 values of 8.9, 6.0, 5.8, 3.5, 5.4, 6.9, and 7.5 µM, respectively	[34]
27	Nemoechine G	Agelas aff. nemoechinata	Cytotoxicity against Jurkat cell lines, with an IC50 of 17.1 µM	[35]
28	Nemoechine D	Agelas aff. nemoechinata	Cytotoxicity against the human promyelocytic leukemia HL-60 cell line, with an IC50 value of 9.9 µM	[36]
36	(+)-Agelasine B	Agelas mauritiana	Cytotoxicity toward the cancer cell lines PC9, A549, HepG2, MCF-7, and U937, with IC50 values of 5.08, 14.07, 9.76, 7.64, and 4.49 µM, respectively	[37]
40	Iso-agelasine C	Agelas nakamurai	Cytotoxicity against HL-60, K562, and HCT-116 cell lines, with IC50 values of 25.3, 28.9, and 38.8 µM, respectively	[38]
41	Iso-agelasidine B	Agelas nakamurai	Cytotoxicity against HL-60 and K562 cell lines, with IC50 values of 33.0 and 39.2 µM, respectively	[38]
42	(−)-Agelasine D	Agelas nakamurai	Cytotoxicity against L5178Y mouse lymphoma cells, with an IC50 value of 4.03 µM	[39]
43	(−)-Agelamide D	Agelas nakamurai	Cytotoxicity against L5178Y mouse lymphoma cells, with an IC50 value of 12.5 µM	[39,40,41]
42	(−)-Agelasine D	Agelas nakamurai	Cytotoxic to Hep3B cells, with a GI50 of 9.9 µM	[41]
43	(−)-Agelamide D	Agelas nakamurai	Cytotoxic to Hep3B cells, with a GI50 of 12.0 µM	[41]
99	NN *	Dysidea cf. arenaria	Cytotoxicity against NBT-T2 rat bladder epithelial cells, with an IC50 value of 1.9 µg/mL	[42]
103–104	NN	Dysidea cf. arenaria	Cytotoxicity against NBT-T2 rat bladder epithelial cells, with IC50 values of 1.8 and 4.2 µg/mL, respectively	[42]
105–108	NN	Dysidea cf. arenaria	Cytotoxicity against the NBT-T2 cell line, with IC50 values of 3.1, 1.9, 8.4, and 3.1 µM, respectively	[43]
112	2,5-Dihydroxy-homoverrucos-(3)-ene	Halichondria sp.	Cytotoxicity against the human multiple myeloma cell line RPMI-8266, with an IC50 of 49.0 µM	[44]
113	2-Hydroxy-5-oxo-homoverrucos-(3)-ene	Halichondria sp.	Cytotoxicity against RPMI-8266 cells, with an IC50 of 65.8 µM	[44]
114	5,18-Dihydroxy-homoverrucosane	Halichondria sp.	Cytotoxicity against RPMI-8266 cells, with an IC50 of 32.7 µM	[44]
115	5-Hydroxy-18-aldehyde-homoverrucosane	Halichondria sp.	Cytotoxicity against RPMI-8266 cells, with an IC50 of 49.3 µM	[44]
116	Halioxepine	Haliclona sp.	Cytotoxicity against NBT-T2 cells, with an IC50 of 4.8 µg/mL	[45]
124–125, 127–128,130	Hamigerans M–Q	Hamigera tarangaensis	Cytotoxicity against the HL-60 cell line, with IC50 values of 6.9, 19.5, 14.7, 21.3, and 33.3 µM, respectively	[46]
126	18-Epi-hamigeran N	Hamigera tarangaensis	Cytotoxicity against the HL-60 cell line, with an IC50 value of 14.1 µM	[46]
129	18-Epi-hamigeran P	Hamigera tarangaensis	Cytotoxicity against the HL-60 cell line, with an IC50 value of 11.6 µM	[46]
136	3β-Hydroxyspongia-13(16),14-diene-2-one	Hyattella aff. intestinalis	Cytotoxicity against NBT-T2 cells, with an IC50 value of 24.1 µM	[47]
143	6,10,18-Triacetoxy-2E,7E-dolabelladien	Luffariella variabilis	Cytotoxicity against the MDA-MB-231 cell line, with an IC50 value of 11.57 µM	[48]
145	NN	Pseudoaxinella flava	Cytotoxicity against the PC3 cell line, with an IC50 value of 7 µM	[49]
172	3β-Hydroxyspongia-13(16),14-dien-2-one	Spongia tubulifera	Activity against A549, human skin melanoma A2058, hepatocyte carcinoma HepG2, and pancreas carcinoma MiaPaca-2 cell lines, with IC50 values of 88.1, 71.4, 91.3, and 90.0 µM, respectively	[50]
191	Epoxynorspongian E	Spongia sp.	Activity against the PC3 and PBL-2H3 cell lines, with IC50 values of 24.8 and 27.2 µM, respectively	[51]
199	2β,3α,19-Triacetoxy-17-hydroxyspongia-13(16),14-diene	Spongia officinalis Linnaeus, 1759	Cytotoxicity against the K562 cell line, with an IC50 value of 7.3 µM	[52]
206	Ceylonamide G	Spongia sp.	Inhibited the growth of DU145 cells in two-dimensional monolayer culture, with an IC50 of 6.9 µM; also effective on spheroids of a three-dimensional DU145 cell culture model with a minimum effective concentration of 10 µM	[53]
209–211	Gracilins J–L	Spongionella sp.	Cytotoxic activity against K562 cells and normal human peripheral blood mononuclear cells (PBMCs), with IC50 values of 15 and 30, 8.5 and 9, and 2.65 and 3 µM, respectively	[54]
212	3′-Norspongiolactone	Spongionella sp.	Cytotoxic activity against K562 cells and normal PBMCs, with IC50 values of 12 and 30 µM, respectively	[54]
213	Spongionellol A	Spongionella sp.	Activity in the cell lines PC3, PC3-DR, DU145, DU145-DR, 22Rv1, VCaP, and LNCaP, with IC50 values of 0.96, 1.23, 0.94, 1.53, 2.64, 1.30, and 1.02 µM, respectively	[55]
224	Luakuliide A	Unidentified	Activity against HL-60 cells, with an IC50 value of 21.7 µM	[56]
227	Chromodorolide D	Unidentified	Cytotoxicity against the NBT-T2 cell line, with an IC50 value of 5.6 µg/mL	[57]
228	NN	Unidentified	Cytotoxicity against the NBT-T2 cell line, with an IC50 value of 12 µg/mL	[57]
			Antibacterial activity
25	10-Hydro-9-hydroxyagelasine F	Agelas nakamurai	Inhibited the growth of Mycobacterium smegmatis, with inhibition zones of 10 mm at 20 µg/disc	[58]
33	(+)-10-Epiagelasine B	Agelas citrina	Active against Staphylococcus aureus ATCC 29213, S. aureus USA300LAC, Streptococcus pneumoniae ATCC 49619, S. pneumoniae 549 CHUAC, Enterococcus faecalis ATCC 29212, E. faecalis 256 CHUAC, and E. faecium 214 CHUAC, with MIC (minimum inhibitory concentration) values of 1, 2, 4, 8, 4, 4, and 4 µg/mL, respectively	[59]
36	(+)-Agelasine B	Agelas mauritiana	Active against a panel of methicillin-resistant S. aureus (MRSA) clinical strains 2010-260, 2010-210, 2010-292, and 2010-300, as well as a methicillin-susceptible S. aureus strain H608, with MIC90 values of 2, 1, 2, 1, and 2 µg/mL, respectively	[37]
40	Iso-agelasine C	Agelas nakamurai	Antibacterial activities against Proteusbacillus vulgaris, with an MIC value of 18.75 µg/mL	[38]
46–49	Agelasines O–R	Agelas sp.	Inhibited the growth of S. aureus and Bacillus subtilis, with MIC values of 16 and 16, 32 and 32, 8 and 8, and 8 and 8 µg/mL, respectively	[60]
51	Agelasine T	Agelas sp.	Inhibited the growth of S. aureus and B. subtilis, with MIC values of 16 and 16 µg/mL, respectively	[60]
66	Eleganstone A	Dactylospongia elegans	Antibacterial activity against Escherichia coli, B. subtilis, and S. aureus, with an MIC value of 64 µg/mL	[61]
67	(1R*,2E,4R*,8E,10S*, 11S*,12R*)-10,18-diacetoxydolabella-2,8-dien-6-one	Dactylospongia elegans	Antibacterial activity against E. coli, B. subtilis, and S. aureus, with an MIC value of 64 µg/mL	[61]
85	Dendrillin B	Dendrilla antarctica	Achieved 90% eradication at 100 µg/mL in the MRSA biofilm assay	[62]
88	Darwinolide	Dendrilla membranosa	Cytotoxicity against MRSA, with an MIC of 132.9 μM, and activity against the biofilm formation of the same MRSA strain, with an IC50 value of 33.2 µM	[63]
138	Monamphilectine A	Hymeniacidon sp.	Showed 43% and 38% of the bactericidal strength of the β-lactam antibiotics carbenicillin and amphicillin, respectively, against E. coli at a concentration of 150 nM	[64]
203	Spongenolactone A	Spongia sp.	Exhibited 46%, 47%, and 93% inhibition against S. aureus at 50, 100, and 200 µM, respectively	[65]
204	Spongenolactone B	Spongia sp.	Displayed 24%, 42%, and 40% inhibition against S. aureus at 50, 100, and 200 µM, respectively	[65]
			Antituberculosis activity
57–59	Macfarlandins F–H	Chelonaplysilla sp.	Inhibited Mycobacterium tuberculosis, with MIC values of >20, 49, and >20 µg/mL, respectively	[66]
138	Monamphilectine A	Hymeniacidon sp.	Activity against M. tuberculosis H37Rv, with an MIC value of 15.3 µg/mL	[64]
219	7-Methylaminoisoneoamphilecta-1(14),15-diene	Svenzea flava	Activity against M. tuberculosis H37Rv, with an MIC value of 15 µg/mL	[67]
220	7-Formamidoisoneoamphilecta-1(14),15-diene	Svenzea flava	Activity against M. tuberculosis H37Rv, with an MIC value of 32 µg/mL	[67]
			Antifungal activity
40	Iso-agelasine C	Agelas nakamurai	Activity against Candida albicans, with an MIC value of 4.69 µg/mL	[38]
41	Iso-agelasidine B	Agelas nakamurai	Activity against C. albicans, with an MIC value of 2.34 µg/mL	[38]
46	Agelasine O	Agelas sp.	Inhibited the growth of Trichophyton mentagrophytes and Cryptococcus neoformans, with IC50 values of 32 and 16 µg/mL, respectively	[60]
47	Agelasine P	Agelas sp.	Inhibited the growth of C. neoformans, with an IC50 value of 32 µg/mL	[60]
48–49	Agelasines Q–R	Agelas sp.	Inhibited the growth of Aspergillus niger, T. mentagrophytes, C. albicans, and C. neoformans, both with IC50 values of 16, 16, 16, and 8 µg/mL, respectively	[60]
51	Agelasine T	Agelas sp.	Inhibited the growth of C. neoformans, with an IC50 value of 16 µg/mL	[60]
			Antiparasitic activity
60	8-Isocyanoamphilecta-11(20),15-diene	Ciocalapata sp.	Activity against Plasmodium falciparum K1, with an IC50 value of 0.98 µM	[68]
61	(1S,3S,4R,7S,8S,11S,12S,13S,15R,20R)-7-Formamido-20-isocy-anoisocycloamphilectane	Cymbastela hooperi	Inhibitory effects on three strains of P. falciparum (FCR3F86, W2, and D6), with an average IC50 value of 0.5 µg/mL	[69]
62	(1S,3S,4R,7S,8S,11S,12S,13S,15R,20R)-7,20-Diformamidoisocy-cloamphilectane	Cymbastela hooperi	Inhibitory effects on P. falciparum FCR3F86, with an IC50 value of 14.8 µg/mL	[69]
83	Membranoid B	Dendrilla antarctica	Activity against Leishmania donovani (IC50 0.8 µM), with no discernible cytotoxicity against uninfected J774A.1 cells	[70]
84	Membranoid D	Dendrilla antarctica	Activity against L. donovani (IC50 1.4 µM), with no discernible cytotoxicity against uninfected J774A.1 cells	[70]
85	Dendrillin B	Dendrilla antarctica	Activity against the leishmaniasis parasite, with an IC50 value of 3.5 µM	[62]
92	Diacarperoxide H	Diacarnus megaspinorhabdosa	Activity against P. falciparum (W2 clones) in vitro, with an IC50 value of 12.9 µM	[71]
93	Diacarperoxide I	Diacarnus megaspinorhabdosa	Activity against P. falciparum (W2 and D6 clones) in vitro, with IC50 values of 4.8 and 7.9 µM, respectively	[71]
94	Diacarperoxide J	Diacarnus megaspinorhabdosa	Activity against P. falciparum (W2 and D6 clones) in vitro, with IC50 values of 1.8 and 1.6 µM, respectively	[71]
138	Monamphilectine A	Hymeniacidon sp.	Activity against a chloroquine-resistant (CQ-R) P. falciparum W2 strain, with an IC50 value of 0.60 µM	[64]
217–218	Monamphilectines B–C	Svenzea flava	Activity against P. falciparum, with IC50 values of 44.5 and 43.3 nM, respectively	[72]
			Anti-inflammatory activity
133–134	Hipposponlachnins A–B	Hippospongia lachne	Inhibitory activity on the release of β-hexosaminidase in DNP-IgE-stimulated RBL-2H3 cells, with IC50 values of 49.37 and 23.91 µM, respectively	[73]
141	Erectcyanthin B	Hyrtios erectus	Inhibited 5-LOX, COX-2, and COX-1, with IC50 values of 0.88, 0.98, and 1.09 mM, respectively	[74]
193	Sponalactone	Spongia officinalis	Inhibitory activity on the lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 macrophages, with an IC50 value of 32 µM	[75]
194	17-O-acetylepispongiatriol	Spongia officinalis	Inhibitory activity on the LPS-induced NO production in RAW264.7 macrophages, with an IC50 value of 15 µM	[75]
195	17-O-acetylspongiatriol	Spongia officinalis	Inhibitory activity on the LPS-induced NO production in RAW264.7 macrophages, with an IC50 value of 12 µM	[75]
196	15α,16α-Dimethoxy-15,16-dihydroepispongiatrio	Spongia officinalis	Inhibitory activity on the LPS-induced NO production in RAW264.7 macrophages, with an IC50 value of 22 µM	[75]
197	15α-Ethoxyepispongiatriol-16(15H)-one	Spongia officinalis	Inhibitory activity on the LPS-induced NO production in RAW264.7 macrophages, with an IC50 value of 12 µM	[75]
198	17-Dehydroxysponalactone	Spongia sp.	Inhibited superoxide anion generation (91%) and elastase release (90%) at 10 µM, with IC50 values of 3.37 and 4.07 µM, respectively	[76]
203–205	Spongenolactones A–C	Spongia sp.	Inhibitory activity against superoxide anion generation in fMLF/CB-stimulated human neutrophils, with IC50 values of 16.5, 13.1, and 17.4 µM, respectively	[65]
221	Tedanol	Tedania ignis	Showed anti-inflammatory activity through the inhibition of carrageenan-induced paw edema in mice	[77]
			Antifouling activity
11–16	Kalihinols O–T	Acanthella cavernosa	Activity against Balanus amphitrite larvae, with EC50 (50% effective concentration) values of 1.43, 0.72, 1.48, 1.16, 0.53, and 0.74 µM, respectively	[32]
42	(−)-Agelasine D	Agelas nakamurai	Inhibited the growth of planktonic forms of the biofilm-forming bacteria Staphylococcus epidermidis (MIC < 0.0877 µM), but did not inhibit biofilm formation	[39]
43	(−)-Agelamide D	Agelas nakamurai	Inhibited only the biofilm formation but not the growth of S. epidermidis	[39]
81	9,11-Dihydrogracilin A	Dendrilla antarctica	Reduced the area covered by the fouling organisms	[78]
82	9,11-Dihydrogracillinone A	Dendrilla antarctica	Reduced the area covered by the fouling organisms	[78]
139	Hymerhabdrin A	Hymerhabdia sp.	Toxic against larvae of the barnacle Balanus amphitrite, with an IC50 of 3.6 µg/mL	[79]
			Inhibition of osteoclasts
153–154	Ceylonamides A–B	Spongia ceylonensis	Inhibitory effects on RANKL-induced osteoclastogenesis in RAW264 macrophages, with IC50 values of 13 and 18 µM, respectively	[80]
160	Ceylonin A	Spongia ceylonensis	Inhibited the RANKL-induced formation of multinuclear osteoclasts in RAW264 cells by 70% (50 µM), in a dose-dependent manner, without cytotoxicity	[81]
163–165	Ceylonins D–F	Spongia ceylonensis	Inhibited the RANKL-induced formation of multinuclear osteoclasts by 28%, 47%, and 31%, respectively	[81]
			Others
43	(−)-Agelamide D	Agelas nakamurai	Enhanced the radiation sensitivity of Hep3B cells; enhanced the efficacy of radiotherapy in a hepatocellular carcinoma (HCC) xenograft mouse model	[41]
53–55	Agelasines W–Y	Astrosclera willeyana	Inhibited the Cbl-b protein that negatively regulates T-cell activation, with IC50 values of 57, 72, and 66 µM, respectively	[82]
116	Halioxepine	Haliclona sp.	Activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH), with an IC50 of 3.2 µg/mL	[45]
141	Erectcyanthin B	Hyrtios erectus	Scavenged DPPH and ABTS+, with IC50 values of 0.45 and 0.40 mM, respectively	[74]
141	Erectcyanthin B	Hyrtios erectus	Activity against 3-hydroxy-3-methylglutaryl-coenzyme A reductase, with an IC50 value of 0.07 mM	[74]
144	Niphateolide A	Niphates olemda	Inhibited the p53-Hdm2 (human Mdm2) interaction, with an IC50 value of 16 µM	[83]
146	Raspadiene	Raspailia bouryesnaultae	Inhibited the replication of HSV-1 (KOS and 29R strains) at 100 µg/mL by 83% and 74%, respectively	[84]
151	18-Nor-3,5,17-trihydroxyspongia-3,13(16),14-trien-2-one	Spongia sp.	Inhibited aromatase in a dose-dependent manner, with an IC50 value of 34.4 µM	[85]
151	18-Nor-3,5,17-trihydroxyspongia-3,13(16),14-trien-2-one	Spongia sp.	Doubled the quinone reductase 1 (QR1) activity in cultured Hepa 1c1c7 cells at 11.2 µM	[85]
209	Gracilin J	Spongionella sp.	Restored mitochondrial activity of neurons to control levels of 98.9% ± 4.7% (p < 0.001) at 0.1 µM, reversing the 28.6% ± 3.4% decrease caused by 200 µM H2O2 treatment	[86]
214	26-O-etfhylstrongylophorine-14	Strongylophora strongilata	Inhibiting protein tyrosine phosphatase 1B (PTP1B), associated with type 2 diabetes, with an IC50 value of 8.7 µM	[87]

* Not named.

3.2. Acanthodendrilla

Only two diterpenes were reported to be generated by the Acanthodendrilla sponges. These two molecules are spongian diterpenes, named 3β-acetoxy-15-hydroxyspongia-12-en and 3-methylspongia-3,12-dien-16-one (18–19, Figure 4). They were isolated from the marine sponge Acanthodendrilla sp., collected in Pulau-Pulau [88]. Compounds 18 and 19 represent new chemical entities of the known spongian diterpene family. Compound 18 is a new 3-acetoxyspongia, while compound 19 represents an unreported rearranged 3-methylspongia-3-en. This is the first report of spongian diterpenes from the Acanthodendrilla genus. The cytotoxic potential of compounds 18 and 19 against A549, MDA-MB-231, human colorectal carcinoma cells (HT-29), and human pancreatic adenocarcinoma cells (PSN1) was evaluated. Both compounds proved to be inactive in the tested cancer cell lines. Their GC₅₀ values (drug concentration causing a 50% reduction in the net protein increase) were over 27.5 and 33.3 µM, respectively, for all cell lines.

3.3. Agelas

Agelas sponges are prevalent in tropical and subtropical marine environments and are a significant source of bioactive natural products. The sponges of the genus Agelas have yielded a diverse array of metabolites, with 355 new ones reported between 1971 and 2021 [89]. Among over 19 species of Agelas sponges, A. mauritiana and A. oroides are the most prolific, yielding 45 and 36 metabolites respectively [90]. Specifically, regarding diterpenes, from 2009 to 2022, a total of 33 molecules were isolated from Agelas sponges, a number second only to those isolated from the genus Spongia.

Three pyrimidine diterpenes, named axistatins 1–3 (20–22, Figure 4), were isolated from the Palauan marine sponge Agelas axifera Hentschel [34]. All of the isolated compounds were found to be inhibitors of cancer cell growth. Axistatins 1–3 showed inhibition against the murine lymphocytic leukemia P388, pancreatic adenocarcinoma BXPC-3, breast adenocarcinoma MCF-7, CNS glioblastoma SF-268, lung large-cell carcinoma NCI-H460, colon adenocarcinoma KM20L2, and prostate carcinoma DU-145 cell lines, with GI₅₀ values of 19.8, 22.8, and 8.9; 4.8, 5.5, and 6.0; 5.7, 6.8, and 5.8; 3.6, 3.9, and 3.5; 4.6, 4.3, and 5.4; 4.1, 4.1, and 6.9; and 4.8, 5.0, and 7.5 µM, respectively. Axistatins 1–3 also exhibited antimicrobial activity. A brief review has introduced promising anti-CNS-tumor active substances derived from marine sponges that were published between 1994 and 2014 [91]. Axistatins 1–3 are among the eight compounds featured in this review.

Three N-methyladenine-containing diterpenes, named 2-oxoagelasines A and F (23–24, Figure 4) and 10-hydro-9-hydroxyagelasine F (25), were isolated from the Okinawan marine sponge Agelas nakamurai Hoshino. Antibacterial experiments were performed on Mycobacterium smegmatis NBRC 3207 using the paper disc method. Compound 25 inhibited the growth of M. smegmatis, with an inhibition zone of 10 mm at 20 µg/disc [58].

Two N-methyladenine-containing diterpenes, nemoechines F–G (26–27, Figure 4), were isolated from the South China Sea sponge Agelas aff. nemoechinata. Compound 27 exhibited cytotoxicity against Jurkat cell lines, with an IC₅₀ value of 17.1 µM [35].

Diterpenoid alkaloids are complex natural compounds that are primarily derived from specific plant genera and marine organisms, exhibiting a range of biological activities, from medicinal applications to potent neurotoxicity [92]. Marine sponges have also been reported to produce different diterpenoid alkaloids. From the South China Sea sponge Agelas aff. nemoechinata, a diterpene-adenine alkaloid called nemoechine D (28, Figure 4) was obtained [36]. It showed cytotoxicity against the HL-60 cell line, with an IC₅₀ value of 9.9 µM.

Three diterpene alkaloids, agelasidines E–F and agelasine N (29–31, Figure 5), were isolated from the Caribbean sponge Agelas citrina [93]. This represents the first report of natural products from the sponge A. citrina. Three diterpene alkaloids, (+)-8-epiagelasine T, (+)-10-epiagelasine B, and (+)-12-hydroxyagelasidine C (32–34, Figure 5), were also obtained from A. citrina [59]. The evaluation of antimicrobial activity against the Gram-positive pathogens S. aureus, Streptococcus pneumoniae, and Enterococcus faecalis showed that compound 33 was active against all of the tested strains, with MIC values in the range of 1–8 µg/mL.

Five diterpene alkaloids, (−)-8′-oxo-agelasine B, (+)-agelasine B, (+)-8′-oxo-agelasine C, agelasine V, and (+)-8′-oxo-agelasine E (35–39, Figure 5), were isolated from the sponge Agelas mauritiana [37]. Compounds 35 and 37–39 are the second examples of 8′-oxo-agelasine analogs. Compound 36 not only exhibited cytotoxicity toward the cancer cell lines PC9, A549, HepG2, MCF-7, and U937, with IC₅₀ values of 4.49–14.07 µM, but also showed antibacterial activities against a panel of clinical MRSA isolates, with MIC values of 1–2 µg/mL (Table 1).

Two diterpene alkaloids, iso-agelasine C and iso-agelasidine B (40–41, Figure 5), were isolated from the South China Sea sponge Agelas nakamurai [38]. Compound 40 showed cytotoxicity against the HL-60, K562, and HCT-116 cell lines, with IC₅₀ values of 25.3, 28.9, and 38.8 µM, respectively. Compound 41 showed cytotoxicity against the HL-60 and K562 cell lines, with IC₅₀ values of 33.0 and 39.2 µM, respectively. Compound 40 also exhibited antibacterial activities against Proteusbacillus vulgaris, with an MIC value of 18.75 µg/mL. Moreover, compounds 40 and 41 showed antifungal activities against Candida albicans, with MIC values of 4.69 and 2.34 µg/mL, respectively. Another two diterpene alkaloids, (−)-agelasine D and (−)-ageloxime D (42–43, Figure 6), were also obtained from the Agelas nakamurai sponge [39]. They exhibited cytotoxicity against L5178Y mouse lymphoma cells, with IC₅₀ values of 4.03 and 12.5 µM, respectively. Moreover, compound 42 inhibited the growth of planktonic forms of the biofilm-forming bacteria Staphylococcus epidermidis (MIC < 0.0877 µM), but it did not inhibit biofilm formation, whereas compound 43 showed the opposite activity profile and inhibited only biofilm formation but not bacterial growth.

It is worth mentioning that the reported compound 43, named (−)-ageloxime D, was revised as (+)-N-[4-amino-6-(methylamino)pyrimidin-5-yl]-N-copalylformamide, which was produced via hydrolysis of agelasine D [40]. It was later renamed (−)-agelamide D [41]. (−)-Agelasine D was more cytotoxic to Hep3B cells than (−)-agelamide D, with their GI₅₀ values being 9.9 and 12.0 µM, respectively [41]. It was found that (−)-agelamide D enhanced the radiation sensitivity of Hep3B cells, reducing their ability to form colonies and boosting the rate of apoptosis [41]. It also upregulated the expression of protein kinase RNA-like endoplasmic reticulum kinase/inositol-requiring enzyme 1α/activating transcription factor 4 (PERK/eIF2α/ATF4), a pivotal pathway in the unfolded protein response (UPR) across various HCC cell lines, thereby intensifying the UPR signaling triggered by radiation. In vivo xenograft studies validated that (−)-agelamide D amplified the suppressive effect of radiation on tumor growth, without causing systemic toxicity. Immunohistochemistry confirmed that (−)-agelamide D elevated ATF4 expression and the incidence of apoptosis induced by radiation, aligning with the in vitro observations.

Diterpene alkaloids were also found from an Okinawan marine sponge (Agelas sp.) [94]. Agelamasine A (44, Figure 6) is the first diterpene alkaloid with a rearranged (4→2)-abeo-clerodane skeleton from a marine source, while agelamasine B (45, Figure 6) is a clerodane diterpene alkaloid. Agelasines O–U (46–52, Figure 6) are also diterpene alkaloids isolated from the Okinawan marine sponge Agelas sp. [60]. Agelasines O–R were the third examples of diterpene alkaloids with a 9-N-methyladenine and a pyrrole unit. Agelasine O has a halimane skeleton, while agelasines P–R have a clerodane skeleton. Agelasines S–U are new diterpene alkaloids with a 9-N-methyladenine unit consisting of a halimane skeleton, a labdane skeleton, and a clerodane skeleton, respectively. Agelasines O–R and T showed antimicrobial activities against several bacterial and fungal strains (Table 1).

3.4. Astrosclera

The Astrosclera sponges yielded three diterpenes in total. The three N-methyladenine-containing diterpenes, agelasines W–Y (53–55, Figure 7), were isolated from a specimen of Astrosclera willeyana collected in 1997 and frozen ever since. Agelasines W–Y have bicyclic terpenoid skeletons with a prenyl side chain that terminates with an N-methyladenine subunit. In terms of activity, these three compounds can inhibit the Cbl-b protein, with IC₅₀ values of 57, 72, and 66 µM, respectively [82]. Cbl-b negatively regulates T-cell activation and, thus, lowers the immune system’s reaction to cancer cells. Agelasines W–Y could be promising immunotherapy agents for enhancing antitumor immunity by inhibiting the Cbl-b protein.

3.5. Cacospongia

Two unusual C₁₇ γ-lactone norditerpenoids (a pair of inseparable enantiomers, 56a and 56b, Figure 7) were obtained from the marine sponge Cacospongia sp. as a mixture [95]. They bore the 4S,5S and 4R,5R absolute configurations, respectively. It should be noted that since these two compounds exist in the form of a mixture, they have been counted as one when tallying the number of diterpenes from different genera of sponges.

3.6. Chelonaplysilla

The Chelonaplysilla sponges yielded three diterpenes in total. These three diterpenes, macfarlandins F–H (57–59, Figure 7), were obtained from a sample of the marine sponge Chelonaplysilla sp. collected in Samoa [66]. Structurally, macfarlandins F and H are the first members of this family to have oxygenation at C-2, and macfarlandins G and H are the first to have a monocyclic δ-lactone heterocycle attached to their decalin ring system. In addition, macfarlandin G exhibited activity against Mycobacterium tuberculosis, with an MIC of 49 µg/mL, whereas macfarlandins F and H both exhibited MICs > 20 µg/mL.

3.7. Ciocalapata

Only one diterpene was reported to be produced by the Ciocalapata sponge. This molecule is a rare isonitrile diterpene named 8-isocyanoamphilecta-11(20),15-diene (60, Figure 7), which was isolated from a cryopreserved sample of a Ciocalapata sp. sponge [68]. The antimalarial activity of isonitrile terpenoids has long been reported. Coincidentally, compound 60 possesses strong activity against Plasmodium falciparum K1, with an IC₅₀ value of 0.98 µM.

3.8. Cymbastela

The total number of diterpenes reported from the Cymbastela sponges is five. These five diterpene formamides (61–65, Figure 7) were obtained from the tropical marine sponge Cymbastela hooperi [69]. Compound 61 ((1S,3S,4R,7S,8S,11S,12S,13S,15R,20R)-7-formamido-20-isocyanoisocycloamphilectane) contains both formamide and isonitrile functionalities, which is not usual for natural products. Through in vitro antiplasmodial bioassays, compound 61 was found to have better activity (IC₅₀ 0.5 µg/mL) than compound 62 ((1S,3S,4R,7S,8S,11S,12S,13S,15R,20R)-7,20-diformamidoisocycloamphilectane) (IC₅₀ 14.8 µg/mL), whereas compounds 63–65 were inactive.

3.9. Dactylospongia

The Dactylospongia sponges yielded two diterpenes in total. These two diterpenes were isolated from the marine sponge Dactylospongia elegans. Eleganstone A (66, Figure 8) is a rare diterpene with a 5/6/4/5 fused tetracyclic ring skeleton, and compound 67 belongs to the dolabellane diterpenes, which had not been discovered from the genus Dactylospongia previously [61]. The antibacterial activity of these two compounds was evaluated, and their MIC values were 64 µg/mL against E. coli, B. subtilis, and S. aureus.

3.10. Darwinella

The Darwinella sponges yielded 13 diterpenes in total. Nine nitrogenous spongian diterpenes—oxeatamide A (68, Figure 8), iso-oxeatamide A (69), oxeatamides B-G (70–75), and oxeatamide A 23-methyl ester (76)—were isolated from the sponge Darwinella oxeata [96]. They were tested for cytotoxicity in a 48 h MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay against HL-60 cells, and they all showed IC₅₀ values >10 µM.

Four rearranged diterpenoids, oxeatine (77, Figure 8) and oxeatamides H–J (78–80), were isolated from the sponge Darwinella cf. oxeata [97]. Oxeatine has a new heterocyclic skeleton, and oxeatamide J has an N-methyl urea group included in a γ-lactam moiety. The 4,8-dimethyl-5-(1,3,3-trimethylcyclohexyl)-octahydro-1H-2λ²-isoquinoline heterocyclic skeleton found in oxeatine, which features a δ-lactam with the nitrogen atom bridging C-6 and C-15 of a rearranged spongian carbon framework, was unknown in nature or from synthesis.

3.11. Dendrilla

A total of 11 diterpenes were obtained from Dendrilla sponges. Two norditerpenes, named 9,11-dihydrogracilin A (81, Figure 9) and 9,11-dihydrogracillinone A (82), were isolated from the Antarctic sponge Dendrilla antarctica [78].

Their antifouling ability was tested using soluble-matrix paints, and both compounds showed activity against a variety of colonizing organisms. Compound 82 demonstrated a more pronounced antifouling effect, with a smaller area covered by the solitary colonial ascidian (Botrylloides sp.) compared to compound 81.

Two diterpenes bearing one or more methyl acetal functionalities, membranoids B and D (83–84, Figure 9), were also obtained from the Dendrilla antarctica sponge [70]. They displayed low micromolar activity (IC₅₀ values of 0.8 and 1.4 µM, respectively) against Leishmani donovani, with no discernible cytotoxicity against uninfected J774A.1 cells. Membranoids B and D are considered to be artifacts and can be obtained by treating aplysulfurin with methanol. Dendrillins B–D (85–87, Figure 9) were also produced by the D. antarctica sponge [62]. Dendrillin B showed an IC₅₀ of 3.5 µM against the leishmaniasis parasite. Moreover, it achieved 90% eradication at 100 µg/mL in the MRSA biofilm assay.

A rearranged spongian diterpene, darwinolide (88, Figure 9), has been isolated from the Antarctic Dendroceratid sponge Dendrilla membranosa [63]. A broth dilution assay determined darwinolide’s MIC against MRSA to be 132.9 μM. It was also found that darwinolide was cytotoxic, rather than cytostatic, toward S. aureus. Further experiments revealed an IC₅₀ value of 33.2 µM against the biofilm formation of the same MRSA strain. Hence, the compound darwinolide displays 4-fold selectivity against the biofilm phase of MRSA compared to the planktonic phase.

Three spongian diterpenes, named aplyroseols 20–22 (89–91, Figure 9), were isolated from two specimens of the Australian marine sponge Dendrilla rosea [98]. The 3-hydroxybutyrate present in aplyroseol 22 was reported in the spongian diterpenes for the first time. The compounds were screened for activity against Staphylococcus aureus, but they were inactive at 64 µg/mL.

3.12. Diacarnus

The Diacarnus sponges yielded six diterpenes in total. These included five norditerpene endoperoxides, diacarperoxides H–L (92–96, Figure 10), together with a norditerpene diol, diacardiol B (97).

These were isolated from the South China Sea sponge Diacarnus megaspinorhabdosa [71]. Diacarperoxides H–J showed antimalarial activity against Plasmodium falciparum (W2 clones) in vitro, with IC₅₀ values of 12.9, 4.8, and 1.8 µM, respectively, while diacarperoxides H–I exhibited activity against P. falciparum (D6 clones), with IC₅₀ values of 7.9 and 1.6 µM, respectively. The IC₅₀ values of the control drug artemisinin were 0.14 µM (W2 clones) and 0.071 (D6 clones).

3.13. Dysidea

A total of 13 diterpenes were obtained from Dysidea sponges. Seven spongian-class diterpenes (98–104, Figure 11) were isolated from the sponge Dysidea cf. arenaria collected in Okinawa [42]. Compounds 99, 103, and 104 showed cytotoxicity against NBT-T2 rat bladder epithelial cells, with IC₅₀ values of 1.9, 1.8, and 4.2 µg/mL, respectively. Four diterpenes, compounds 105–108 (Figure 11), were isolated from a sample of the Dysidea cf. arenaria sponge [43]. They were found to have inhibitory effects on NBT-T2 cells, with IC₅₀ values of 3.1, 1.9, 8.4, and 3.1 µM, respectively. Chromodorolides D–E (109–110, Figure 11) were also generated by the Dysidea sp. sponge [99].

3.14. Fascaplysinopsis

Only one diterpene was reported to be produced by the Fascaplysinopsis sponge. The dolabellane diterpenoid, named clavirolide H (111, Figure 11), was isolated from the Xisha sponge Fascaplysinopsis reticulata [100]. Clavirolide H was evaluated for cytotoxic activities against human leukemia K562, HL-60, HeLa, HCT-116, A549, normal human hepatocytes L-02, and human hepatocellular carcinoma BEL-7402 cell lines, but no activity was observed.

3.15. Halichondria

A total of four diterpenes were obtained from Halichondria sponges. These four homoverrucosane-type diterpenes (112–115, Figure 11), common in land plants but rare in sponges, were isolated from a sample of the marine sponge Halichondria sp. [44]. This was the first report of homoverrucosanes isolated from the marine sponge Halichondria sp. Compounds 112–115 were evaluated for their activities against the RPMI-8266 cell line, and their IC₅₀ values were all greater than 10 µM.

3.16. Haliclona

Only one diterpene was reported from the Haliclona sponges. The marine sponge genus Haliclona contains over 600 species, but only a small number of them have been classified and chemically investigated [21]. The diterpenoid halioxepine (116, Figure 12) is a meroditerpene produced by Haliclona sp. [45]. It showed cytotoxicity against NBT-T2 cells (RIKEN), with an IC₅₀ value of 4.8 µg/mL. It also showed antioxidant activity against DPPH, with an IC₅₀ of 3.2 µg/mL.

3.17. Hamigera

The Hamigera sponges yielded 16 diterpenes in total. Hamigera sponges, belonging to the Hymedesmiidae family, are second only to the genus Phorbas in the same family in terms of the richness of obtained secondary metabolites [16].

The 16 hamigeran diterpenoids were isolated from the New Zealand marine sponge Hamigera tarangaensis (117–132, Figure 12) [46,101]. The compound hamigeran R (117) was the first benzonitrile-based marine natural product, while the compound hamigeran S (118) was the first dimeric structure in the series. The formation of hamigerans R and S is thought to occur via the reaction of hamigeran G with a nitrogen source, where the nitrile carbon of hamigeran R is derived from the terpenoid skeleton.

The compound hamigeran M (124) represents the first instance of a non-benzo-fused, oxazole-containing terpenoid isolated from the marine environment. Compounds 124–130 were tested for their cytotoxicity against the HL-60 cell line using the MTT method, and their IC₅₀ values were 6.9, 19.5, 14.1, 14.7, 21.3, 11.6, and 33.3 µM, respectively.

3.18. Hippospongia

Two diterpenes were produced by Hippospongia sponges. These two diterpenes, hipposponlachnins A and B (133–134, Figure 13), with antiallergic activity, were obtained from the South China Sea marine sponge Hippospongia lachne [73]. They possess an unprecedented tetracyclo [9.3.0.0^2,8.0^3,7] tetradecane ring system. Hipposponlachnins A and B did not cause significant cytotoxicity in rat basophilic leukemia (RBL-2H3) cells after 24 h of treatment. They showed inhibitory activity on the release of β-hexosaminidase in DNP-IgE-stimulated RBL-2H3 cells, with IC₅₀ values of 49.37 and 23.91 µM, respectively, higher than that of the market-available anti-asthmatic drug ketotifen fumarate (IC₅₀ = 63.88 µM). In addition, hipposponlachnins A and B also suppressed IL-4 production in a dose-dependent manner and significantly inhibited LTB4 release in activated RBL-2H3 cells compared with untreated controls. The results indicate that these are promising antiallergic lead compounds.

3.19. Hyattella

The Hyattella sponges yielded three diterpenes in total. These three diterpenes, named 2α-hydroxyspongia-13(16),14-diene-3-one (135, Figure 13), 3β-hydroxyspongia-13(16),14-diene-2-one (136), and 2α,3α-diacetoxy-17,19-dihydroxyspongia-13(16),14-diene (137), were extracted from the sponge Hyattella aff. intestinalis [47]. They were tested against adenovirus (AdV), and all showed IC₅₀ values > 20 µg/mL. Their cytotoxicity was also examined against NBT-T2 cells using the MTT assay, and compound 136 showed an IC₅₀ value of 24.1 µM.

3.20. Hymeniacidon

Only one diterpene was produced by Hymeniacidon sponges. The molecule monamphilectine A (138, Figure 13) is a diterpenoid β-lactam alkaloid generated by Hymeniacidon sp. [64]. When tested against a CQ-R Plasmodium falciparum W2 strain, it showed an IC₅₀ value of 0.60 µM. In vitro antituberculosis screening against Mycobacterium tuberculosis H₃₇Rv revealed an MIC value of 15.3 µg/mL. Preliminary KB assays against E. coli revealed that, at a concentration of 150 nM, monamphilectine A possesses 43% and 38% of the bactericidal strength of the β-lactam antibiotics carbenicillin and amphicillin, respectively.

3.21. Hymerhabdia

Similarly, only one diterpene was reported from the Hymerhabdia sponges. The unusual diterpene hymerhabdrin A (139, Figure 13) was isolated from an intertidal marine sponge Hymerhabdia sp. [79]. It possessed a novel 6/6/5 fused-ring skeleton. Hymerhabdrin A exhibited antifouling activity against Balanus amphitrite larvae, with an LC₅₀ (lethal concentration 50) value of 3.6 µg/mL.

3.22. Hyrtios

The Hyrtios sponges yielded three diterpenes in total. These three cyanthiwigin-type diterpenes, named erectcyanthins A–C (140–142, Figure 13), were isolated from the marine sponge Hyrtios erectus [74]. The compound erectcyanthin B not only exhibited anti-dyslipidemia activity but also possessed antioxidant and anti-inflammatory activities. In the anti-dyslipidemia experiment, erectcyanthin B exhibited activity against 3-hydroxy-3-methylglutaryl-coenzyme A reductase, with an IC₅₀ value of 0.07 mM, compared to 0.08 mM for the drug atorvastatin. The antioxidant activities of erectcyanthin B, assessed using the stable DPPH and ABTS⁺ scavenging tests, were indicated by IC₅₀ values of 0.45 and 0.40 mM, compared to 1.51 and 1.70 mM of the standard α-tocopherol, respectively. The anti-inflammatory activity of erectcyanthin B (IC₅₀ 0.88–1.09 mM, Table 1), assessed using 5-LOX and isoforms of COX-2/1, was superior to that of other erectcyanthin analogs.

3.23. Luffariella

Only one diterpene was generated by Luffariella sponges. The dolabellane diterpene was obtained from the South China Sea sponge Luffariella variabilis and was named 6,10,18-triacetoxy-2E,7E-dolabelladien (143, Figure 13) [48]. This is the first dolabellane-type diterpenoid from the genus Luffariella. Compound 143 showed cytotoxicity against the MDA-MB-231 cell line, with an IC₅₀ value of 11.57 µM.

3.24. Niphates

Similarly, only one diterpene was reported from the Niphates sponges. This compound, named niphateolide A (144, Figure 13), was isolated from the marine sponge Niphates olemda [83]. The inhibitory effect of compound 144 on the p53–Hdm2 interaction was examined using ELISA. It inhibited the interaction, with an IC₅₀ value of 16 µM. Genetic mutations within the p53 tumor suppressor pathway are a common occurrence in human tumors. Mdm2/Hdm2 functions as an E3 ubiquitin ligase for p53 within the ubiquitin–proteasome system. The activity of niphateolide A in inhibiting the p53–Hdm2 interaction enables it to serve as a substance for reactivating p53, thereby giving it potential for further research and development in the field of oncology.

3.25. Pseudoaxinella

Pseudoaxinella is another genus of sponge that has produced only one diterpene. The isonitrile diterpene (145, Figure 13), with anticancer activity, was isolated from the Caribbean sponge Pseudoaxinella flava [49]. Compound 145 showed growth-inhibitory activity against human PC3 prostate cancer cells, with an IC₅₀ value of 7 µM.

3.26. Raspailia

Raspailia sponges also produced one diterpene in total. The clerodane diterpene, named raspadiene (146, Figure 13), was isolated from the marine sponge Raspailia bouryesnaultae collected in South Brazil [84]. The evaluation of potential anti-herpes activity against herpes simplex virus type 1 (HSV-1) showed that the compound raspadiene at 100 µg/mL inhibited the replication of HSV-1 (KOS and 29R strains, sensitive and resistant to acyclovir, respectively) by 83% and 74%, respectively.

3.27. Spongia

The Spongia genus produced the highest number of diterpenoids among all sponge genera. A total of 62 diterpenoids have been derived from Spongia sponges, accounting for 27% of all sponge-derived diterpenoids reported from 2009 to 2022. Many of these molecules exhibit strong biological activity, highlighting the potential and significance of Spongia sponges as a valuable resource for marine drug development.

Three unreported furanoditerpenoids (147–149, Figure 14) were isolated from the marine sponge Spongia sp. [102]. Compound 147 is a spongian diterpene with a modified oxidation pattern, while compounds 148 and 149 represent two new ring-A-contracted spongians, displaying a novel and unprecedented norspongian carbon skeleton.

Three compounds, 18-nor-3,17-dihydroxyspongia-3,13(16),14-trien-2-one (150, Figure 14), 18-nor-3,5,17-trihydroxyspongia-3,13(16),14-trien-2-one (151), and spongiapyridine (152), were isolated from an Indonesian sponge of the genus Spongia [85]. Structurally, the D-ring possessed by compound 152 belongs to the pyridyl ring system, which is different from ordinary spongians possessing standard δ-lactone. In the in vitro biological activity experiment, compound 151 exhibited aromatase-inhibitory activity, with an IC₅₀ value of 34.4 µM, and it also induced quinone reductase 1 (QR1) activity in cultured Hepa 1c1c7 cells, with a CD value (the concentration needed to double the QR1 activity) of 11.2 µM. Aromatase is an essential cytochrome P450 enzyme that facilitates the conversion of androgens like testosterone and androstenedione into estrogens such as estradiol and estrone. Inhibiting aromatase reduces the available estrogen and demonstrates considerable effectiveness in preventing certain types of breast cancer. Quinone reductase 1 is a protective enzyme that helps prevent cancer by blocking intracellular semiquinone radicals and producing α-tocopherolhydroquinone, which acts as a chemopreventive agent. Compound 151 holds promise as a potential therapeutic agent for both breast cancer prevention and chemoprevention, due to its dual action as an aromatase inhibitor and an inducer of quinone reductase 1 activity.

Seven spongian diterpenes, ceylonamides A–F (153–158, Figure 14) and 15α,16-dimethoxyspongi-13-en-19-oic acid (159), were isolated from the Indonesian marine sponge Spongia ceylonensis [80]. Compounds 153–158 are nitrogenous spongian diterpenes. Ceylonamides A and B exhibited inhibitory effects on RANKL-induced osteoclastogenesis in RAW264 macrophages, with IC₅₀ values of 13 and 18 µM, respectively. In a follow-up study of the structure–activity relationship, the authors found that the carbonyl position of the γ-lactam ring and the volume of the substituent on the nitrogen atom had a great influence on the inhibitory effect.

Another nine spongian diterpene derivatives, ceylonins A–F (160–165, Figure 14) [81,103] and ceylonins G–I (166–168, Figure 15) [81,103], were also isolated from the Spongia ceylonensis sponge. Ceylonins A–F contain three additional carbons in ring D to supply an ether-bridged bicyclic ring system. Ceylonins A and D–F (50 µM) inhibited the RANKL-induced formation of multinuclear osteoclasts in RAW264 cells by 70%, 28%, 47%, and 31%, respectively. The inhibitory activity of ceylonins G–I against the cancer therapeutic drug target ubiquitin-specific protease 7 (USP7) was tested, but their IC₅₀ values were all over 50 µM.

3-Nor-spongiolide A (169, Figure 15), having the rare 3-nor-spongian carbon skeleton, and spongiolides A and B (170–171), possessing a γ-butenolide ring instead of the usual furan ring for ring D, were isolated from South China Sea sponge Spongia officinalis [104]. They were evaluated for their cytotoxic activity against HL-60 cells, but none of them exhibited potent cytotoxic activity.

Two furanoditerpenes, 3β-hydroxyspongia-13(16),14-dien-2-one (172, Figure 15) and 19-dehydroxy-spongian diterpene 17 (173), were isolated from the sponge Spongia tubulifera, collected in the Mexican Caribbean [50]. Compound 172 showed activity against the A549, A2058, HepG2, and MiaPaca-2 cell lines, with IC₅₀ values of 88.1, 71.4, 91.3, and 90.0 µM, respectively.

Spongiains A–G (174–180, Figure 15) were isolated from the marine sponge Spongia sp. [105]. Spongiains A–C were the first examples of spongian diterpenes bearing a pentacyclic skeleton composed of a fused 5/5/6/6/5 ring system through ring-A rearrangement. The cytotoxic activities of spongiains A–G were evaluated, and none of them exhibited antiproliferative effects on several cancer cell lines.

Twelve norspongian diterpenes, dinorspongians A–F (181–186, Figure 15) and epoxynorspongians A-F (187–192), were isolated from the marine sponge Spongia sp. [51]. Among them, dinorspongians A–F were the first examples of dinorspongian diterpenes bearing the unprecedented 3,4-seco-3,19-dinorspongian diterpene skeleton. Epoxynorspongian E exhibited inhibitory activity against the PC3 and PBL-2H3 cell lines, with IC₅₀ values of 24.8 and 27.2 µM, respectively.

Five diterpenes—including a 5,5,6,6,5-pentacyclic diterpene, sponalactone (193, Figure 16); two spongian diterpenes, 17-O-acetylepispongiatriol (194) and 17-O-acetylspongiatriol (195); and two spongian diterpene artifacts, 15α,16α-dimethoxy-15,16-dihydroepispongiatriol (196) and 15α-ethoxyepispongiatriol-16(15H)-one (197)—were isolated from the marine sponge Spongia officinalis collected from the South China Sea [75]. The in vitro anti-inflammatory activities of these compounds were tested by inhibition of LPS-induced NO production in RAW264.7 macrophages, with IC₅₀ values of 32, 15, 12, 22, and 12 µM, respectively.

A rare A-ring contracted diterpene, 17-dehydroxysponalactone (198, Figure 16), was isolated from the Red Sea marine sponge Spongia sp. [76]. The in vitro anti-inflammatory activity of the compound was tested. Compound 198 significantly reduced the superoxide anion generation and elastase release, with inhibition rates of 91% and 90%, respectively, at a concentration of 10 µM, and the IC₅₀ values were 3.37 and 4.07 µM, respectively.

A novel acetoxy diterpenoid, 2β,3α,19-triacetoxy-17-hydroxyspongia-13(16),14-diene (199, Figure 16), and 18-nor-2,17-hydroxyspongia-1,4,13(16),14-quaien-3-one (200), belonging to the rare 18-norspongian carbon skeleton, were isolated from the aquaculture Spongia officinalis Linnaeus, 1759 [52]. The in vitro biological activity evaluation showed that compound 199 had cytotoxic activity against the K562 cell line, with an IC₅₀ value of 7.3 µM. A bicyclic diterpene, jellynolide A (201), with a penta-substituted carbon skeleton, was also isolated from this sponge [106]. The compound jellynolide A biogenically implies an irregular non-head-to-tail linkage between GPP (geranyl diphosphate) and isoprene units, as well as a novel cyclization position.

Dinorspongiapyridine (202, Figure 16) is a dinorspongian diterpene produced by the marine sponge Spongia sp. [107]. It was the first instance of a 3,4-seco-3,19-dinorspongian diterpene bearing a rare pyridyl D-ring system.

Spongenolactones A–C (203–205, Figure 16) were obtained from a Red Sea sponge Spongia sp. [65]. They are all pentacyclic spongian diterpenes, featuring 5,5,6,6,5, 5,5,6,6,6, and 5,5,6,6,7 ring systems, respectively. They were found to exert inhibitory activity against superoxide anion generation in fMLF/CB-stimulated human neutrophils, with IC₅₀ values of 16.5, 13.1, and 17.4 µM, respectively. Furthermore, spongenolactone A showed higher inhibitory activity against the growth of S. aureus in comparison to B (Table 1).

Ceylonamides G–I (206–208, Figure 16) are diterpene alkaloids from an Indonesian marine sponge of Spongia sp. [53]. Ceylonamide G inhibited the growth of DU145 human prostate cancer cells in a two-dimensional monolayer culture, with an IC₅₀ of 6.9 µM. It was also effective (minimum effective concentration of 10 µM) on spheroids of a three-dimensional cell culture model, which was prepared from DU145 cells.

3.28. Spongionella

The Spongionella sponges yielded five diterpenes in total. Four diterpenes, gracilins J–L and 3′-norspongiolactone (209–212, Figure 16), were isolated from the extracts of the marine Spongionella sp. sponges [54]. Gracilins J–L belong to the rare classes trisnorditerpenes, bisnorditerpenes, and norditerpenes, respectively. The in vitro cytotoxicity of these compounds was determined using K562 and normal human peripheral blood mononuclear cells (PBMCs). Compounds 209–212 showed cytotoxic activity against the K562 cell line, with IC₅₀ values ranging from 2.65 to 15 µM (Table 1). They showed similar or slightly less toxicity against the normal PBMCs, with IC₅₀ values ranging from 3 to 30 µM (Table 1). The activity of gracilins J–L was also evaluated using an oxidative in vitro stress model [86]. The compound gracilin J presented neuroprotection effects at the mitochondrial function level. The neurons’ mitochondrial activity decreased by 28.6 ± 3.4% (p < 0.001) after treatment with 200 µM H₂O₂. Gracilin J at 0.1 µM reduced this effect, restoring the activity to control levels (98.9 ± 4.7%, p < 0.001).

A spongian diterpene, spongionellol A (213, Figure 16), was obtained from the marine sponge Spongionella sp. [55]. It exhibited activity and selectivity in a panel of seven human prostate cancer cells. The panel included AR-negative PC3 and DU145 cells, which are known to be resistant to various hormonal and standard chemotherapeutics, docetaxel-resistant PC3-DR and DU145-DR cells (derived from PC3 cells and DU145 cells, respectively), AR-FL- (androgen receptor full-length) and AR-V7-positive (androgen receptor splice variant V7) hormone-resistant 22Rv1 and VCaP cells, and AR-FL-positive hormone-sensitive LNCaP cells (Table 1).

3.29. Strongylophora

Only one diterpene was reported to be produced by the Strongylophora sponge. This meroditerpene, 26-O-ethylstrongylophorine-14 (214, Figure 16), was isolated from the Caribbean marine sponge Strongylophora strongilata [87]. It was found to inhibit PTP1B associated with type 2 diabetes, with an IC₅₀ value of 8.7 µM, compared with 0.7 µM for the positive control oleanolic acid. This is the first report of meroditerpenes inhibiting PTP1B activity.

3.30. Stylissa

The Stylissa sponges yielded two diterpenes in total. These two amphilectane-type diterpenes, 8-isocyanato-15-formamidoamphilect-11(20)-ene and 8-isothiocyanato-15-formamidoamphilect-11(20)-ene (215–216, Figure 17), were isolated from the sponge Stylissa cf. massa [108]. Their antimalarial activities were evaluated, and both compounds were inactive.

3.31. Svenzea

A total of four diterpenes were obtained from Svenzea sponges. Two isocyanide amphilectane-type diterpenes, named monamphilectines B and C (217–218, Figure 17), were isolated from the Caribbean sponge Svenzea flava [72]. Monamphilectines B and C exhibited activities against the human malaria parasite Plasmodium falciparum (the non-resistant (wild-type standard) 3D7 strain), with IC₅₀ values of 44.5 and 43.3 nM, respectively.

Two rare isoneoamphilectane-based diterpenes, 7-methylaminoisoneoamphilecta-1(14),15-diene and 7-formamidoisoneoamphilecta-1(14),15-diene (219–220, Figure 17), were also isolated from the Caribbean marine sponge Svenzea flava [67]. Their MIC values against the strain Mycobacterium tuberculosis H₃₇Rv were 15 and 32 µg/mL, respectively.

3.32. Tedania

Only one diterpene was reported from Tedania sponges. The molecule, tedanol (221, Figure 17), was a brominated and sulfated pimarane diterpene isolated from the Caribbean sponge Tedania ignis [77]. Tedanol, which showed good solubility in water, significantly reduced both the acute (4 h) and subchronic (48 h) phases of carrageenan-induced paw edema in mice, which was coupled with a strong inhibition of COX-2 expression, cellular infiltration measured as myeloperoxidase (MPO) levels, and iNOS expression.

3.33. Theonella

The Theonella sponges yielded two diterpenes in total. The two nitrogenous prenylbisabolane diterpenes, named amitorines A and B (222–223, Figure 17), were isolated from Theonella swinhoei [109]. No activity data have been reported for them.

3.34. Others

A total of five diterpenes were isolated from other sponges, specifically those whose genera have not been determined.

The Kingdom of Tonga is an archipelago in the central Indo-Pacific Ocean; many novel marine natural products with bioactivities have been reported from organisms collected within Tongan territorial waters [110]. Coincidentally, three labdane diterpenes, luakuliides A–C (224–226, Figure 17), were isolated from a Tongan dictyoceratid marine sponge [56]. They share a trans-fused [4.4.0]-bicyclodecane system with a hemi-acetal functional group bridging C-8 and C-10. In terms of activity, luakuliide A has inhibitory activity against HL-60 cells, with an IC₅₀ value of 21.7 µM.

Two diterpenes (227–228, Figure 17) were isolated from an Okinawan marine sponge [57]. Compound 227, named chromodorolide D, is an example of a diterpenoid with a highly rearranged chromodorane carbon skeleton, while compound 228 retains the open side chains. Compounds 227 and 228 showed cytotoxicity against NBT-T2 cells, with IC₅₀ values of 5.6 and 12 µg/mL, respectively.

4. Conclusions

This review summarizes the structures and bioactivities of 228 diterpenes reported in 73 research papers, originating from more than 33 different genera of sponges. Notably, the genera Spongia, Agelas, and Acanthella reported the highest number of diterpenes, with counts of 62, 33, and 17, respectively, accounting for 27%, 14%, and 7% of the total reported molecules, respectively. In contrast, in more than 26 genera of sponges, fewer than 10 diterpenoids have been reported per genus, with 12 of these genera producing just one diterpene each.

Most of the reported diterpenes have been evaluated for their bioactivity, with 110 molecules exhibiting one or more types of bioactivity. Among them, the highest numbers were seen in those with cytotoxic, antibacterial, and anti-inflammatory properties, amounting to 54, 22, and 13 molecules, respectively. These correspond to 24%, 10%, and 6% of the reported 228 molecules, respectively.

Some compounds exhibit cytotoxic activity against a variety of tumor cells. For example, the compounds axistatins 1–3 (20–22) have shown inhibitory activity against seven different tumor cell lines. Axistatins 1–2 have GI₅₀ values ≤ 5 µM against five and four cell lines, respectively. Axistatin 3 has GI₅₀ values ranging from 3.5 to 8.9 µM against seven cell lines. It is worth noting that, in addition to cytotoxic activity against tumor cells, the potential of some diterpenes as antitumor active molecules is reflected in their inhibitory activity against specific target proteins like Cbl-b, aromatase, etc. The production of cytotoxic metabolites by sponges may be beneficial for their self-protection, such as against predators and spatial competition [28].

Reports have documented the antibacterial, antifungal, antiviral, and antiparasitic activities of diterpenoids derived from various sources, such as sponges, fungi, and plants [111]. In our review of the literature on sponge-derived diterpenoids, we noticed that some molecules exhibit multiple activities. For instance, the compound (−)-agelamide D (43) exhibited cytotoxic activity against L5178Y mouse lymphoma cells and, in another activity evaluation model, demonstrated cytotoxic activity against Hep3B cells. It has also been proven to enhance the radiosensitivity of Hep3B cells. Furthermore, (−)-agelamide D also inhibits the biofilm formation of S. epidermidis. The compound iso-agelasine C (40) showed cytotoxicity against the HL-60, K562, and HCT-116 cell lines, exhibited antibacterial activity against Proteusbacillus vulgaris, and demonstrated antifungal activity against Candida albicans.

Some compounds have very low active concentrations. For example, monamphilectines B–C (217–218) exhibited antiparasitic activity against P. falciparum, with IC₅₀ values of 44.5 and 43.3 nM, respectively. Compound (−)-agelasine D (42) inhibited the growth of planktonic forms of the biofilm-forming bacterium Staphylococcus epidermidis, with an MIC < 0.0877 µM. The compound spongionellol A (213) showed cytotoxicity against seven cancer cell lines, with IC₅₀ values ranging from 0.94 to 2.64 µM. Kalihinols O–T (11–16) showed antifouling activity against Balanus amphitrite larvae, with EC₅₀ values ranging from 0.53 to 1.48 µM.

The diversity in chemical structure and biological activity exhibited by these sponge-derived diterpenoids demonstrates their great potential in the development of marine drugs. However, the variety of activity evaluation models, while providing opportunities to discover different activities of these molecules, makes it challenging to compare the activities among different diterpenoids, and the structure–activity relationships are difficult to define. Activity concentration units such as µM, mM, and µg/mL further complicate the comparison of different studies. Moreover, there is no unified standard for defining the presence and strength of activity. Balancing standardization with diversity is a challenge. Additionally, most activity evaluations only characterize inhibition rates or IC₅₀ values; further research to identify active targets and elucidate mechanisms of action will better facilitate the application and development of these molecules.