Bioactive Secondary Metabolites from the Marine Sponge Genus Agelas

Abstract

The marine sponge genus Agelas comprises a rich reservoir of species and natural products with diverse chemical structures and biological properties with potential application in new drug development. This review for the first time summarized secondary metabolites from Agelas sponges discovered in the past 47 years together with their bioactive effects.

Full text

marine drugs
Review
Bioactive Secondary Metabolites from the Marine
Sponge Genus Agelas
Huawei Zhang 1, *ID , Menglian Dong 1, Jianwei Chen 1, Hong Wang 1, Karen Tenney 2and
Phillip Crews 2ID
1Department of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China;
baixl2012@163.com (M.D.); cjw983617@zjut.edu.cn (J.C.); hongw@zjut.edu.cn (H.W.)
2
Department of Chemistry & Biochemistry, University of California Santa Cruz, Santa Cruz 95064, CA, USA;
ktenney@ucsc.edu (K.T.); pcrews@ucsc.edu (P.C.)
*Correspondence: hwzhang@zjut.edu.cn; Tel.: +86-571-8832-0613
Received: 19 September 2017; Accepted: 3 November 2017; Published: 8 November 2017
Abstract:
The marine sponge genus Agelas comprises a rich reservoir of species and natural products
with diverse chemical structures and biological properties with potential application in new drug
development. This review for the first time summarized secondary metabolites from Agelas sponges
discovered in the past 47 years together with their bioactive effects.
Keywords: marine sponge; Agelas; secondary metabolite; natural product; bioactivity
1. Introduction
The search for natural drug candidates from marine organisms is the eternal impetus to
pharmaceutical scientists. For the past six decades, marine sponges have been a prolific and chemically
diverse source of natural compounds with potential therapeutic application [
1
,
2
]. The marine sponge
Agelas (Porifera, Demospongiae, Agelasida, Agelasidae) is widely distributed in the marine eco-system
and includes at least 19 species (Figure 1): A. axifera,A. cerebrum,A. ceylonica,A. citrina,A. clathrodes,
A. conifera,A. dendromorpha,A. dispar,A. gracilis,A. linnaei,A. longissima,A. mauritiana,A. nakamurai,
A. nemoechinata,A. oroides,A. sceptrum,A. schmidtii,A. sventres, and A. wiedenmayeri. Since the beginning
of the 1970s, many research groups around the world have carried out chemical investigation on
Agelas spp., resulting in fruitful achievements. Their studies revealed that Agelas sponges harbor
many bioactive secondary metabolites, including alkaloids (especially bromopyrrole derivatives),
terpenoids, glycosphingolipids, carotenoids, fatty acids and meroterpenoids [
3
]. These natural
products are an attractive resource for drug candidates due to their rich chemodiversity and interesting
biological activities.
Mar. Drugs 2017,15, 351; doi:10.3390/md15110351 www.mdpi.com/journal/marinedrugs

Mar. Drugs 2017,15, 351 2 of 29
Mar. Drugs 2017, 15, 351 2 of 29
Agelas clathrodes Agelas conifera
Agelas dispar Agelas inequalis
Agelas mauritiana Agelas sceptrum
Agelas wiendermayeri Agelas sp.
Figure 1. Photos of Agelas sponges provided by professor Crews.
2. Natural Products from Agelas Genus
The chemical diversity of natural products is determined by the biological diversity of organisms.
To date, 291 secondary metabolites (1–291) have been isolated and characterized from the marine
sponge Agelas spp. (Table 1). These chemicals were introduced and assorted as follows according to
their biological sources.
Figure 1. Photos of Agelas sponges provided by professor Crews.
2. Natural Products from Agelas Genus
The chemical diversity of natural products is determined by the biological diversity of organisms.
To date, 291 secondary metabolites (
1
–
291
) have been isolated and characterized from the marine
sponge Agelas spp. (Table 1). These chemicals were introduced and assorted as follows according to
their biological sources.

Mar. Drugs 2017,15, 351 3 of 29
2.1. Agelas axifera
Three new alkaloids, named axistatins 1 (
1
), 2 (
2
), and 3 (
3
) (Figure 2), were isolated and
characterized from Agelas axifera collected in the Republic of Palau and found to exhibit inhibitory
effects on cancer cell lines, including P388, BXPC-3, MCF-7, SF-268, NCI-H460, KM20L2 and DU-145.
The exquisitely sensitive Gram-negative pathogen Neisseria gonorrheae and the opportunistic fungus
Cryptococcus neoformans were inhibited by
1
–
3
with MIC values of 1–8, 2–4, and 8
µ
g/mL, and
1–4, 2, and 8–16
µ
g/mL, respectively. Furthermore, these compounds had antimicrobial effect on
Gram-positive bacteria, including Staphylococcus aureus,Streptococcus pneumoniae,Enterococcus faecalis
and Micrococcus luteus [4].
Mar. Drugs 2017, 15, 351 3 of 29
2.1. Agelas axifera
Three new alkaloids, named axistatins 1 (1), 2 (2), and 3 (3) (Figure 2), were isolated and
characterized from Agelas axifera collected in the Republic of Palau and found to exhibit inhibitory
effects on cancer cell lines, including P388, BXPC-3, MCF-7, SF-268, NCI-H460, KM20L2 and DU-145.
The exquisitely sensitive Gram-negative pathogen Neisseria gonorrheae and the opportunistic fungus
Cryptococcus neoformans were inhibited by 1–3 with MIC values of 1–8, 2–4, and 8 μg/mL, and 1–4, 2,
and 8–16 μg/mL, respectively. Furthermore, these compounds had antimicrobial effect on Gram-
positive bacteria, including Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis and
Micrococcus luteus [4].
1 2 3
Figure 2. Chemical structures of compounds 1–3.
2.2. Agelas cerebrum
Marine sponge Agelas cerebrum was classified as a new species in 2001 [5]. Chemical investigation
of Caribbean specimen A. cerebrum led to the isolation of three brominated compounds, 5-bromopyrrole-
2-carboxylic acid (4), 4-bromopyrrole-2-carboxylic acid (5) and 3,4-bromopyrrole-2-carboxylic acid (6)
(Figure 3) [6]. Biological tests indicated that these isolates had strong cytotoxic activities in vitro against
human tumor cell lines at ≥1 mg/mL, including A549, HT29 and MDA-MB-231.
4: R1= H, R2=H, R3= Br
5: R1 = H, R2 = Br, R3 = H
6: R1 = Br, R2 = Br, R3 = H.
Figure 3. Chemical structures of compounds 4–6.
2.3. Agelas ceylonica
Only one case of chemical study on Agelas ceylonica has been reported [7]. The specimen of A.
ceylonica collected from India Mandapam coast was found to produce one methyl ester hanishin (7)
(Figure 4), which has been previously found in the marine sponge Homaxinella sp. [8].
7
Figure 4. Chemical structures of compounds 7.
2.4. Agelas citrina
The Caribbean specimen of Agelas citrina was firstly found to yield three new diterpene alkaloids,
(−)-agelasidine E (8), (−)-agelasidine F (9) and agelasine N (10) [9]. Latter chemical investigation
Figure 2. Chemical structures of compounds 1–3.
2.2. Agelas cerebrum
Marine sponge Agelas cerebrum was classified as a new species in 2001 [
5
]. Chemical investigation of
Caribbean specimen A. cerebrum led to the isolation of three brominated compounds, 5-bromopyrrole-2-
carboxylic acid (
4
), 4-bromopyrrole-2-carboxylic acid (
5
) and 3,4-bromopyrrole-2-carboxylic acid (
6
)
(Figure 3) [
6
]. Biological tests indicated that these isolates had strong cytotoxic activities
in vitro
against
human tumor cell lines at ≥1 mg/mL, including A549, HT29 and MDA-MB-231.
Mar. Drugs 2017, 15, 351 3 of 29
2.1. Agelas axifera
Three new alkaloids, named axistatins 1 (1), 2 (2), and 3 (3) (Figure 2), were isolated and
characterized from Agelas axifera collected in the Republic of Palau and found to exhibit inhibitory
effects on cancer cell lines, including P388, BXPC-3, MCF-7, SF-268, NCI-H460, KM20L2 and DU-145.
The exquisitely sensitive Gram-negative pathogen Neisseria gonorrheae and the opportunistic fungus
Cryptococcus neoformans were inhibited by 1–3 with MIC values of 1–8, 2–4, and 8 μg/mL, and 1–4, 2,
and 8–16 μg/mL, respectively. Furthermore, these compounds had antimicrobial effect on Gram-
positive bacteria, including Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis and
Micrococcus luteus [4].
1 2 3
Figure 2. Chemical structures of compounds 1–3.
2.2. Agelas cerebrum
Marine sponge Agelas cerebrum was classified as a new species in 2001 [5]. Chemical investigation
of Caribbean specimen A. cerebrum led to the isolation of three brominated compounds, 5-bromopyrrole-
2-carboxylic acid (4), 4-bromopyrrole-2-carboxylic acid (5) and 3,4-bromopyrrole-2-carboxylic acid (6)
(Figure 3) [6]. Biological tests indicated that these isolates had strong cytotoxic activities in vitro against
human tumor cell lines at ≥1 mg/mL, including A549, HT29 and MDA-MB-231.
4: R1= H, R2=H, R3= Br
5: R1 = H, R2 = Br, R3 = H
6: R1 = Br, R2 = Br, R3 = H.
Figure 3. Chemical structures of compounds 4–6.
2.3. Agelas ceylonica
Only one case of chemical study on Agelas ceylonica has been reported [7]. The specimen of A.
ceylonica collected from India Mandapam coast was found to produce one methyl ester hanishin (7)
(Figure 4), which has been previously found in the marine sponge Homaxinella sp. [8].
7
Figure 4. Chemical structures of compounds 7.
2.4. Agelas citrina
The Caribbean specimen of Agelas citrina was firstly found to yield three new diterpene alkaloids,
(−)-agelasidine E (8), (−)-agelasidine F (9) and agelasine N (10) [9]. Latter chemical investigation
Figure 3. Chemical structures of compounds 4–6.
2.3. Agelas ceylonica
Only one case of chemical study on Agelas ceylonica has been reported [
7
]. The specimen of
A. ceylonica collected from India Mandapam coast was found to produce one methyl ester hanishin (
7
)
(Figure 4), which has been previously found in the marine sponge Homaxinella sp. [8].
Mar. Drugs 2017, 15, 351 3 of 29
2.1. Agelas axifera
Three new alkaloids, named axistatins 1 (1), 2 (2), and 3 (3) (Figure 2), were isolated and
characterized from Agelas axifera collected in the Republic of Palau and found to exhibit inhibitory
effects on cancer cell lines, including P388, BXPC-3, MCF-7, SF-268, NCI-H460, KM20L2 and DU-145.
The exquisitely sensitive Gram-negative pathogen Neisseria gonorrheae and the opportunistic fungus
Cryptococcus neoformans were inhibited by 1–3 with MIC values of 1–8, 2–4, and 8 μg/mL, and 1–4, 2,
and 8–16 μg/mL, respectively. Furthermore, these compounds had antimicrobial effect on Gram-
positive bacteria, including Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis and
Micrococcus luteus [4].
1 2 3
Figure 2. Chemical structures of compounds 1–3.
2.2. Agelas cerebrum
Marine sponge Agelas cerebrum was classified as a new species in 2001 [5]. Chemical investigation
of Caribbean specimen A. cerebrum led to the isolation of three brominated compounds, 5-bromopyrrole-
2-carboxylic acid (4), 4-bromopyrrole-2-carboxylic acid (5) and 3,4-bromopyrrole-2-carboxylic acid (6)
(Figure 3) [6]. Biological tests indicated that these isolates had strong cytotoxic activities in vitro against
human tumor cell lines at ≥1 mg/mL, including A549, HT29 and MDA-MB-231.
4: R1= H, R2=H, R3= Br
5: R1 = H, R2 = Br, R3 = H
6: R1 = Br, R2 = Br, R3 = H.
Figure 3. Chemical structures of compounds 4–6.
2.3. Agelas ceylonica
Only one case of chemical study on Agelas ceylonica has been reported [7]. The specimen of A.
ceylonica collected from India Mandapam coast was found to produce one methyl ester hanishin (7)
(Figure 4), which has been previously found in the marine sponge Homaxinella sp. [8].
7
Figure 4. Chemical structures of compounds 7.
2.4. Agelas citrina
The Caribbean specimen of Agelas citrina was firstly found to yield three new diterpene alkaloids,
(−)-agelasidine E (8), (−)-agelasidine F (9) and agelasine N (10) [9]. Latter chemical investigation
Figure 4. Chemical structures of compounds 7.

Mar. Drugs 2017,15, 351 4 of 29
2.4. Agelas citrina
The Caribbean specimen of Agelas citrina was firstly found to yield three new diterpene alkaloids,
(
−
)-agelasidine E (
8
), (
−
)-agelasidine F (
9
) and agelasine N (
10
) [
9
]. Latter chemical investigation
showed that this sponge also produces four new pyrrole-imidazole alkaloids, citrinamines A–D
(
11
–
14
), and one bromopyrrole alkaloid N-methylagelongine (
15
) (Figure 5) [
10
]. Compounds
12
–
14
had antimicrobial activities whereas no inhibitory effect on cell proliferation of mouse fibroblasts was
found for 11–14.
Mar. Drugs 2017, 15, 351 4 of 29
showed that this sponge also produces four new pyrrole-imidazole alkaloids, citrinamines A–D (11–
14), and one bromopyrrole alkaloid N-methylagelongine (15) (Figure 5) [10]. Compounds 12–14 had
antimicrobial activities whereas no inhibitory effect on cell proliferation of mouse fibroblasts was
found for 11–14.
8: R = CH2OH
9: R = CHO 10
11 12
13 14
15
Figure 5. Chemical structures of compounds 8–15.
2.5. Agelas clathrodes
Marine sponge Agelas clathrodes was the excellent producer of secondary metabolites, including
glycosphingolipid derivatives (GSLs) and alkaloids. Clarhamnoside (16), containing an unusual L-
rhamnose unit in the sugar head, was the first rhamnosylated α-galactosylceramide from A. clathrodes
collected along the coast of Grand Bahamas Island (Sweetings Cay) [11]. The Caribbean sponge A.
clathrodes could metabolize clathrosides A–C (17–19) and isoclathrosides A–C (20–22), which,
respectively, belonged to two families of different glycolipids [12]. Compound 23 was also isolated from
the Caribbean specimen (Figure 6) [13]. It was noted that all the GSLs from A. clathrodes were actually
elucidated as mixtures of homologs, which play an important role in therapeutic immunomodulation.
16
Figure 5. Chemical structures of compounds 8–15.
2.5. Agelas clathrodes
Marine sponge Agelas clathrodes was the excellent producer of secondary metabolites, including
glycosphingolipid derivatives (GSLs) and alkaloids. Clarhamnoside (
16
), containing an unusual
L-rhamnose unit in the sugar head, was the first rhamnosylated
α
-galactosylceramide from A. clathrodes
collected along the coast of Grand Bahamas Island (Sweetings Cay) [
11
]. The Caribbean sponge
A. clathrodes could metabolize clathrosides A–C (
17
–
19
) and isoclathrosides A–C (
20
–
22
), which,
respectively, belonged to two families of different glycolipids [
12
]. Compound
23
was also isolated from
the Caribbean specimen (Figure 6) [
13
]. It was noted that all the GSLs from A. clathrodes were actually
elucidated as mixtures of homologs, which play an important role in therapeutic immunomodulation.
Six alkaloids, (
−
)-agelasidine A (
24
), (
−
)-agelasidine C (
25
), (
−
)-agelasidine D (
26
), clathramide
A (
27
), clathramide B (
28
) and clathrodin (
29
), were detected in the Caribbean sponge A. clathrodes
(Figure 7). Bioassay results suggested that compound
24
possessed inhibitory effect on Staphilococcus
aureus but no effect on fungi, while
25
and
26
were shown to have antimicrobial activities against
S. aureus,Klebsiella pneumoniae and Proteus vulgaris [
14
].
In vitro
cytotoxic test indicated that

Mar. Drugs 2017,15, 351 5 of 29
25
and
26
significantly inhibited the growth of CHO-K1 cells with the ED
50
values of 5.70 and
2.21
µ
g/mL, respectively. Compound
26
also possessed the inhibition against the growth of E. coli
and Hafnia alvei [15], while 27 and 28 had a moderate antifungal activity against Aspergillus niger [16].
Interestingly, compound
29
contained a nonbrominated pyrrole and a guanidine moiety [
17
]. One
specimen of A. clathrodes from the South China Sea was shown to produce an ionic compound (
30
),
which had weak cytotoxicity against cancer cell lines A549 and SGC7901 with IC
50
values of 26.5 and
22.7
µ
g/mL, respectively [
18
]. Four brominated compounds, dispacamides A–D (
31
–
34
) (Figure 7),
were detected not only in A. clathrodes, but also in A. conifera,A. dispar and A. longissima, and exhibited
antihistamine activity [19,20].
Mar. Drugs 2017, 15, 351 4 of 29
showed that this sponge also produces four new pyrrole-imidazole alkaloids, citrinamines A–D (11–
14), and one bromopyrrole alkaloid N-methylagelongine (15) (Figure 5) [10]. Compounds 12–14 had
antimicrobial activities whereas no inhibitory effect on cell proliferation of mouse fibroblasts was
found for 11–14.
8: R = CH2OH
9: R = CHO 10
11 12
13 14
15
Figure 5. Chemical structures of compounds 8–15.
2.5. Agelas clathrodes
Marine sponge Agelas clathrodes was the excellent producer of secondary metabolites, including
glycosphingolipid derivatives (GSLs) and alkaloids. Clarhamnoside (16), containing an unusual L-
rhamnose unit in the sugar head, was the first rhamnosylated α-galactosylceramide from A. clathrodes
collected along the coast of Grand Bahamas Island (Sweetings Cay) [11]. The Caribbean sponge A.
clathrodes could metabolize clathrosides A–C (17–19) and isoclathrosides A–C (20–22), which,
respectively, belonged to two families of different glycolipids [12]. Compound 23 was also isolated from
the Caribbean specimen (Figure 6) [13]. It was noted that all the GSLs from A. clathrodes were actually
elucidated as mixtures of homologs, which play an important role in therapeutic immunomodulation.
16
Mar. Drugs 2017, 15, 351 5 of 29
17: R = CH2CH2CH3
18: R = H(CH3)CH2CH3
19: R = CH2CH(CH3)2
20: R = CH2CH2CH3
21: R = CH(CH3)CH2CH3
22: R= CH2CH(CH3)2
23
Figure 6. Chemical structures of compounds 16–23.
Six alkaloids, (−)-agelasidine A (24), (−)-agelasidine C (25), (−)-agelasidine D (26), clathramide A
(27), clathramide B (28) and clathrodin (29), were detected in the Caribbean sponge A. clathrodes
(Figure 7). Bioassay results suggested that compound 24 possessed inhibitory effect on Staphilococcus
aureus but no effect on fungi, while 25 and 26 were shown to have antimicrobial activities against S.
aureus, Klebsiella pneumoniae and Proteus vulgaris [14]. In vitro cytotoxic test indicated that 25 and 26
significantly inhibited the growth of CHO-K1 cells with the ED50 values of 5.70 and 2.21 μg/mL,
respectively. Compound 26 also possessed the inhibition against the growth of E. coli and Hafnia alvei
[15], while 27 and 28 had a moderate antifungal activity against Aspergillus niger [16]. Interestingly,
compound 29 contained a nonbrominated pyrrole and a guanidine moiety [17]. One specimen of A.
clathrodes from the South China Sea was shown to produce an ionic compound (30), which had weak
cytotoxicity against cancer cell lines A549 and SGC7901 with IC50 values of 26.5 and 22.7 μg/mL,
respectively [18]. Four brominated compounds, dispacamides A–D (31–34) (Figure 7), were detected
not only in A. clathrodes, but also in A. conifera, A. dispar and A. longissima, and exhibited antihistamine
activity [19,20].
24 25: R = H
26: R = OH
27: R1= H, R2 = COOH
28: R1 = COOH, R2 = H
29 30
31: R = Br
32: R = H
33: R = Br
34: R = H
Figure 7. Chemical structures of compounds 24–34.
2.6. Agelas conifera
Chemical study of two specimens of Agelas conifera from the Florida Keys and Belize led to the
isolation of two new dimeric bromopyrrole alkaloids, bromosceptrin (35) and debromosceptrin (36),
respectively [21,22]. Seven new bromopyrrole metabolites (37–43) were firstly purified from the
Caribbean sponge A. conifera [23], but the detailed structure elucidation of ageliferin (41),
bromoageferin (42) and dibromoageliferin (43) were established by Kobayashi and his co-workers
[24]. Bioassay results indicated that compounds 37, 41, 42 and 43 possessed biological activities
Figure 6. Chemical structures of compounds 16–23.
Mar. Drugs 2017, 15, 351 5 of 29
17: R = CH2CH2CH3
18: R = H(CH3)CH2CH3
19: R = CH2CH(CH3)2
20: R = CH2CH2CH3
21: R = CH(CH3)CH2CH3
22: R= CH2CH(CH3)2
23
Figure 6. Chemical structures of compounds 16–23.
Six alkaloids, (−)-agelasidine A (24), (−)-agelasidine C (25), (−)-agelasidine D (26), clathramide A
(27), clathramide B (28) and clathrodin (29), were detected in the Caribbean sponge A. clathrodes
(Figure 7). Bioassay results suggested that compound 24 possessed inhibitory effect on Staphilococcus
aureus but no effect on fungi, while 25 and 26 were shown to have antimicrobial activities against S.
aureus, Klebsiella pneumoniae and Proteus vulgaris [14]. In vitro cytotoxic test indicated that 25 and 26
significantly inhibited the growth of CHO-K1 cells with the ED50 values of 5.70 and 2.21 μg/mL,
respectively. Compound 26 also possessed the inhibition against the growth of E. coli and Hafnia alvei
[15], while 27 and 28 had a moderate antifungal activity against Aspergillus niger [16]. Interestingly,
compound 29 contained a nonbrominated pyrrole and a guanidine moiety [17]. One specimen of A.
clathrodes from the South China Sea was shown to produce an ionic compound (30), which had weak
cytotoxicity against cancer cell lines A549 and SGC7901 with IC50 values of 26.5 and 22.7 μg/mL,
respectively [18]. Four brominated compounds, dispacamides A–D (31–34) (Figure 7), were detected
not only in A. clathrodes, but also in A. conifera, A. dispar and A. longissima, and exhibited antihistamine
activity [19,20].
24 25: R = H
26: R = OH
27: R1= H, R2 = COOH
28: R1 = COOH, R2 = H
29 30
31: R = Br
32: R = H
33: R = Br
34: R = H
Figure 7. Chemical structures of compounds 24–34.
2.6. Agelas conifera
Chemical study of two specimens of Agelas conifera from the Florida Keys and Belize led to the
isolation of two new dimeric bromopyrrole alkaloids, bromosceptrin (35) and debromosceptrin (36),
respectively [21,22]. Seven new bromopyrrole metabolites (37–43) were firstly purified from the
Caribbean sponge A. conifera [23], but the detailed structure elucidation of ageliferin (41),
bromoageferin (42) and dibromoageliferin (43) were established by Kobayashi and his co-workers
[24]. Bioassay results indicated that compounds 37, 41, 42 and 43 possessed biological activities
Figure 7. Chemical structures of compounds 24–34.

Mar. Drugs 2017,15, 351 6 of 29
2.6. Agelas conifera
Chemical study of two specimens of Agelas conifera from the Florida Keys and Belize led to
the isolation of two new dimeric bromopyrrole alkaloids, bromosceptrin (
35
) and debromosceptrin
(
36
), respectively [
21
,
22
]. Seven new bromopyrrole metabolites (
37
–
43
) were firstly purified from
the Caribbean sponge A. conifera [
23
], but the detailed structure elucidation of ageliferin (
41
),
bromoageferin (
42
) and dibromoageliferin (
43
) were established by Kobayashi and his co-workers [
24
].
Bioassay results indicated that compounds
37
,
41
,
42
and
43
possessed biological activities against
Bacillus subtilis at 10
µ
g/disk and
41
and
42
could inhibit the growth of E. coli at 10
µ
g/disk. Using
new protein-guided methods by its affinity to proteins within tumor cell proteomes, one unique
polyhydroxybutyrated
β
-GSL coniferoside (
44
), was detected in A. conifera derived from Puerto Rico
as well as another GSL derivative (45) (Figure 8) [25,26].
Mar. Drugs 2017, 15, 351 6 of 29
against Bacillus subtilis at 10 μg/disk and 41 and 42 could inhibit the growth of E. coli at 10 μg/disk.
Using new protein-guided methods by its affinity to proteins within tumor cell proteomes, one
unique polyhydroxybutyrated β-GSL coniferoside (44), was detected in A. conifera derived from
Puerto Rico as well as another GSL derivative (45) (Figure 8) [25,26].
35 36
R1 R2 R3 R4 R5
37: Br H H H A
38: Br Br Br Br A
39: H H H Br B
40: Br H H Br B
41: R1 = H, R2 = H
42: R1 = Br, R2 = H
43: R1 = Br, R2 = Br
44
45
Figure 8. Chemical structures of compounds 35–45.
2.7. Agelas dendromorpha
Natural product analysis of the marine sponge Agelas dendromorpha revealed three novel
agelastatins (46–48) with pyrrole-2-imidazole structure. Agelastatin A (46) was obtained from the
Axinellid specimen grown in the Coral Sea and had strong cytotoxicity [27]. Agelastatins E (47) and
F (48) (Figure 9) purified from the New Caledonian A. dendromorpha were shown to exhibit weak
cytotoxicity against the KB cell line at 30 μM [28].
46 47: R1= H, R2= CH3
,
R3 = CH3
48: R1 = Br, R2 = H, R3 = H
Figure 9. Chemical structures of compounds 46–48.
Figure 8. Chemical structures of compounds 35–45.
2.7. Agelas dendromorpha
Natural product analysis of the marine sponge Agelas dendromorpha revealed three novel
agelastatins (
46
–
48
) with pyrrole-2-imidazole structure. Agelastatin A (
46
) was obtained from the
Axinellid specimen grown in the Coral Sea and had strong cytotoxicity [
27
]. Agelastatins E (
47
) and
F (
48
) (Figure 9) purified from the New Caledonian A. dendromorpha were shown to exhibit weak
cytotoxicity against the KB cell line at 30 µM [28].

Mar. Drugs 2017,15, 351 7 of 29
Mar. Drugs 2017, 15, 351 6 of 29
against Bacillus subtilis at 10 μg/disk and 41 and 42 could inhibit the growth of E. coli at 10 μg/disk.
Using new protein-guided methods by its affinity to proteins within tumor cell proteomes, one
unique polyhydroxybutyrated β-GSL coniferoside (44), was detected in A. conifera derived from
Puerto Rico as well as another GSL derivative (45) (Figure 8) [25,26].
35 36
R1 R2 R3 R4 R5
37: Br H H H A
38: Br Br Br Br A
39: H H H Br B
40: Br H H Br B
41: R1 = H, R2 = H
42: R1 = Br, R2 = H
43: R1 = Br, R2 = Br
44
45
Figure 8. Chemical structures of compounds 35–45.
2.7. Agelas dendromorpha
Natural product analysis of the marine sponge Agelas dendromorpha revealed three novel
agelastatins (46–48) with pyrrole-2-imidazole structure. Agelastatin A (46) was obtained from the
Axinellid specimen grown in the Coral Sea and had strong cytotoxicity [27]. Agelastatins E (47) and
F (48) (Figure 9) purified from the New Caledonian A. dendromorpha were shown to exhibit weak
cytotoxicity against the KB cell line at 30 μM [28].
46 47: R1= H, R2= CH3
,
R3 = CH3
48: R1 = Br, R2 = H, R3 = H
Figure 9. Chemical structures of compounds 46–48.
Figure 9. Chemical structures of compounds 46–48.
2.8. Agelas dispar
It is notable that Caribbean Agelas dispar harbors a distinct biogeographical bromination trend.
Five compounds containing bromine, dispyrin (
49
), dibromoagelaspongin methyl ether (
50
), longamide
B (
51
), clathramides C (
52
) and D (
53
), have been found in the Caribbean sponge A. dispar [
29
,
30
].
Only compound
51
had moderate anti-bacterial activities against B. subtilis and S. aureus with MIC
values of about 50
µ
g/mL. The GSL derivative (
54
) and betaine alkaloids (
55
–
57
) were detected in the
Caribbean A. dispar [
31
,
32
]. Antibacterial tests indicated that compounds
55
and
56
had the inhibitory
activities against B. subtilis and S. aureus with MIC values ranging from 2.5 to 8.0
µ
g/mL [
32
]. The first
quaternary derivative of adenine in nature, agelasine (58) (Figure 10), was also found in A. dispar [33].
Mar. Drugs 2017, 15, 351 7 of 29
2.8. Agelas dispar
It is notable that Caribbean Agelas dispar harbors a distinct biogeographical bromination trend.
Five compounds containing bromine, dispyrin (49), dibromoagelaspongin methyl ether (50),
longamide B (51), clathramides C (52) and D (53), have been found in the Caribbean sponge A. dispar
[29,30]. Only compound 51 had moderate anti-bacterial activities against B. subtilis and S. aureus with
MIC values of about 50 μg/mL. The GSL derivative (54) and betaine alkaloids (55–57) were detected
in the Caribbean A. dispar [31,32]. Antibacterial tests indicated that compounds 55 and 56 had the
inhibitory activities against B. subtilis and S. aureus with MIC values ranging from 2.5 to 8.0 μg/mL
[32]. The first quaternary derivative of adenine in nature, agelasine (58) (Figure 10), was also found
in A. dispar [33].
49 50 51
52: R1 = H, R2=COOH
53: R1 = COOH, R2 = H
54 55 56
57 58
Figure 10. Chemical structures of compounds 49–58.
2.9. Agelas gracilis
Bioassay-guided fractionation of the crude extract of the deep-sea sponge Agelas gracilis collected
in southern Japan afforded three novel antiprotozoan compounds, gracilioethers A–C (59–61) (Figure
11) [34]. Antimalarial tests showed that these metabolites possessed inhibitory effects on Plasmodium
falciparum with IC50 values of 0.5–10 μg/mL.
59 60 61
Figure 11. Chemical structures of compounds 59–61.
2.10. Agelas linnaei
Eleven novel brominated pyrrole derivatives (62–72) (Figure 12) were purified from the
Indonesian sponge Agelas linnaei and compounds 66–69 had prominent activities against the murine
L1578Y mouse lymphoma cell line with IC50 values of 9.55, 9.25, 16.76 and 13.06 μM, respectively [35].
Figure 10. Chemical structures of compounds 49–58.
2.9. Agelas gracilis
Bioassay-guided fractionation of the crude extract of the deep-sea sponge Agelas gracilis collected
in southern Japan afforded three novel antiprotozoan compounds, gracilioethers A–C (
59
–
61
)
(Figure 11) [
34
]. Antimalarial tests showed that these metabolites possessed inhibitory effects on
Plasmodium falciparum with IC50 values of 0.5–10 µg/mL.
2.10. Agelas linnaei
Eleven novel brominated pyrrole derivatives (
62
–
72
) (Figure 12) were purified from the Indonesian
sponge Agelas linnaei and compounds
66
–
69
had prominent activities against the murine L1578Y mouse
lymphoma cell line with IC50 values of 9.55, 9.25, 16.76 and 13.06 µM, respectively [35].

Mar. Drugs 2017,15, 351 8 of 29
Mar. Drugs 2017, 15, 351 7 of 29
2.8. Agelas dispar
It is notable that Caribbean Agelas dispar harbors a distinct biogeographical bromination trend.
Five compounds containing bromine, dispyrin (49), dibromoagelaspongin methyl ether (50),
longamide B (51), clathramides C (52) and D (53), have been found in the Caribbean sponge A. dispar
[29,30]. Only compound 51 had moderate anti-bacterial activities against B. subtilis and S. aureus with
MIC values of about 50 μg/mL. The GSL derivative (54) and betaine alkaloids (55–57) were detected
in the Caribbean A. dispar [31,32]. Antibacterial tests indicated that compounds 55 and 56 had the
inhibitory activities against B. subtilis and S. aureus with MIC values ranging from 2.5 to 8.0 μg/mL
[32]. The first quaternary derivative of adenine in nature, agelasine (58) (Figure 10), was also found
in A. dispar [33].
49 50 51
52: R1 = H, R2=COOH
53: R1 = COOH, R2 = H
54 55 56
57 58
Figure 10. Chemical structures of compounds 49–58.
2.9. Agelas gracilis
Bioassay-guided fractionation of the crude extract of the deep-sea sponge Agelas gracilis collected
in southern Japan afforded three novel antiprotozoan compounds, gracilioethers A–C (59–61) (Figure
11) [34]. Antimalarial tests showed that these metabolites possessed inhibitory effects on Plasmodium
falciparum with IC50 values of 0.5–10 μg/mL.
59 60 61
Figure 11. Chemical structures of compounds 59–61.
2.10. Agelas linnaei
Eleven novel brominated pyrrole derivatives (62–72) (Figure 12) were purified from the
Indonesian sponge Agelas linnaei and compounds 66–69 had prominent activities against the murine
L1578Y mouse lymphoma cell line with IC50 values of 9.55, 9.25, 16.76 and 13.06 μM, respectively [35].
Figure 11. Chemical structures of compounds 59–61.
Mar. Drugs 2017, 15, 351 8 of 29
NN
NHN
Br
Br O
NH2
HO
62 63 64
65 72
66: R1 = H, R2 = Br
67: R1 = H, R2 = I
68: R1 = Br, R2 = Br
69: R1 = Br, R2 = I
70: R = H
71: R = CH2CH3
Figure 12. Chemical structures of compounds 62–72.
2.11. Agelas longissima
Five alkaloids (73–77) (Figure 13) have been isolated from Agelas longissima specimens, all of
which were collected from the Caribbean Sea. Agelongine (73) contained a pyridinium ring instead
of the commonly found imidazole nucleus in Agelas alkaloids and was shown to be specific to inhibit
the agonist 5-hydroxytryptamine (5-HT) [36]. Compound 75 was unique for its unusual
pyrrolopiperazine nucleus [37]. Two new GSL analogs (76 and 77) were also found in the Caribbean
A. longissima [38,39].
73 74
75 76
77
Figure 13. Chemical structures of compounds 73–77.
2.12. Agelas mauritiana
Agelas mauritiana is one of the most fruitful producers of secondary metabolites among all Agelas
species. Thirty-five compounds (78–112) have been isolated and identified from A. mauritiana,
Figure 12. Chemical structures of compounds 62–72.
2.11. Agelas longissima
Five alkaloids (
73
–
77
) (Figure 13) have been isolated from Agelas longissima specimens, all of
which were collected from the Caribbean Sea. Agelongine (
73
) contained a pyridinium ring instead of
the commonly found imidazole nucleus in Agelas alkaloids and was shown to be specific to inhibit the
agonist 5-hydroxytryptamine (5-HT) [
36
]. Compound
75
was unique for its unusual pyrrolopiperazine
nucleus [
37
]. Two new GSL analogs (
76
and
77
) were also found in the Caribbean A. longissima [
38
,
39
].
2.12. Agelas mauritiana
Agelas mauritiana is one of the most fruitful producers of secondary metabolites among all
Agelas species. Thirty-five compounds (
78
–
112
) have been isolated and identified from A. mauritiana,
including terpenoids, pyrrole derivatives, GSLs, carotenoids and other alkaloids. Specimens of
A. mauritiana collected from the South China Sea were found to metabolize eight terpenoids
(
78
–
85
) [
40
,
41
]. Compound
79
possessed inhibitory effects on S. aureus with MIC
90
value of 1–8
µ
g/mL
and activities against PC9, A549, HepG2, MCF-7, and U937 cell lines with IC
50
values of 4.49–14.41
µ
M.
Compound
84
possessed activities against C. neoformans,S. aureus, methicillin-resistant S. aureus and
Leishmania donovani with IC
50
/MIC values of 4.96/10.00, 7.21/10.00, 9.20/20.00 and 28.55/33.19
µ
g/mL,
respectively. Agelasimines A (
86
) and B (
87
) and an unusual purino-diterpene (
88
) were purified from
Eniwetak A. mauritiana and
86
and
87
had inhibitory effect on L1210 leukemia with ED
50
values of
2.1 and 3.9 nM, respectively. From Pohnpei-derived A. mauritiana, epi-agelasine C (
89
) was isolated
and shown to have no activity against S. aureus,Vibrio costicola,E. coli and B. subtilis [
42
–
44
]. Chemical
analysis of one specimen of A. auritiana collected from the Solomon Islands afforded agelasines
J (
90
), K (
91
) and L (
92
) (Figure 14), which exhibited moderate activities against P. falciparum and low
cytotoxicity on MCF-7 cells [45].

Mar. Drugs 2017,15, 351 9 of 29
Mar. Drugs 2017, 15, 351 8 of 29
NN
NHN
Br
Br O
NH2
HO
62 63 64
65 72
66: R1 = H, R2 = Br
67: R1 = H, R2 = I
68: R1 = Br, R2 = Br
69: R1 = Br, R2 = I
70: R = H
71: R = CH2CH3
Figure 12. Chemical structures of compounds 62–72.
2.11. Agelas longissima
Five alkaloids (73–77) (Figure 13) have been isolated from Agelas longissima specimens, all of
which were collected from the Caribbean Sea. Agelongine (73) contained a pyridinium ring instead
of the commonly found imidazole nucleus in Agelas alkaloids and was shown to be specific to inhibit
the agonist 5-hydroxytryptamine (5-HT) [36]. Compound 75 was unique for its unusual
pyrrolopiperazine nucleus [37]. Two new GSL analogs (76 and 77) were also found in the Caribbean
A. longissima [38,39].
73 74
75 76
77
Figure 13. Chemical structures of compounds 73–77.
2.12. Agelas mauritiana
Agelas mauritiana is one of the most fruitful producers of secondary metabolites among all Agelas
species. Thirty-five compounds (78–112) have been isolated and identified from A. mauritiana,
Figure 13. Chemical structures of compounds 73–77.
Mar. Drugs 2017, 15, 351 9 of 29
including terpenoids, pyrrole derivatives, GSLs, carotenoids and other alkaloids. Specimens of A.
mauritiana collected from the South China Sea were found to metabolize eight terpenoids (78–85)
[40,41]. Compound 79 possessed inhibitory effects on S. aureus with MIC90 value of 1–8 μg/mL and
activities against PC9, A549, HepG2, MCF-7, and U937 cell lines with IC50 values of 4.49–14.41 μM.
Compound 84 possessed activities against C. neoformans, S. aureus, methicillin-resistant S. aureus and
Leishmania donovani with IC50/MIC values of 4.96/10.00, 7.21/10.00, 9.20/20.00 and 28.55/33.19 μg/mL,
respectively. Agelasimines A (86) and B (87) and an unusual purino-diterpene (88) were purified from
Eniwetak A. mauritiana and 86 and 87 had inhibitory effect on L1210 leukemia with ED50 values of 2.1
and 3.9 nM, respectively. From Pohnpei-derived A. mauritiana, epi-agelasine C (89) was isolated and
shown to have no activity against S. aureus, Vibrio costicola, E. coli and B. subtilis [42–44]. Chemical
analysis of one specimen of A. auritiana collected from the Solomon Islands afforded agelasines J (90),
K (91) and L (92) (Figure 14), which exhibited moderate activities against P. falciparum and low
cytotoxicity on MCF-7 cells [45].
78 79 80
81 82
83 84 85
86 87
88 89
Figure 14. Cont.

Mar. Drugs 2017,15, 351 10 of 29
Mar. Drugs 2017, 15, 351 10 of 29
90 91 92
Figure 14. Chemical structures of compounds 78–92.
The same species of A. mauritiana grown in different places were found to produce different
pyrrole derivatives, such as debromodispacamides B (93) and D (94) from Solomon Island specimen
[46], 4-bromo-N-(butoxymethyl)-1H-pyrrole-2-carboxamide (95) from the South China Sea [41], 5-
debromomidpacamide (96) from Enewetak Atoll [47], mauritamide A (97) from Fiji [48] and mauritiamine
(98) from Hachijo-jima Island [49]. Compound 98 exhibited inhibitory effect on larval metamorphosis of
the barnacle Balanus amphitrite with ED50 value of 15 μg/mL and moderate antibacterial activity against
Flavobacterium marinotypicum with the inhibition zone of 10 mm at 10 μg/disk. Interestingly, the Pacific
sponge A. mauritiana was found to metabolize other pyrroles, including debromokeramadine (99),
benzosceptrin A (100), nagelamide S (101) and nagelamide T (102) (Figure 15) [50,51].
93:R = H
94:R = OH 95
96 97
98 99
100 101
102
Figure 15. Chemical structures of compounds 93–102.
Figure 14. Chemical structures of compounds 78–92.
The same species of A. mauritiana grown in different places were found to produce different
pyrrole derivatives, such as debromodispacamides B (
93
) and D (
94
) from Solomon Island
specimen [
46
], 4-bromo-N-(butoxymethyl)-1H-pyrrole-2-carboxamide (
95
) from the South China
Sea [
41
], 5-debromomidpacamide (
96
) from Enewetak Atoll [
47
], mauritamide A (
97
) from Fiji [
48
]
and mauritiamine (
98
) from Hachijo-jima Island [
49
]. Compound
98
exhibited inhibitory effect on
larval metamorphosis of the barnacle Balanus amphitrite with ED
50
value of 15
µ
g/mL and moderate
antibacterial activity against Flavobacterium marinotypicum with the inhibition zone of 10 mm at
10
µ
g/disk. Interestingly, the Pacific sponge A. mauritiana was found to metabolize other pyrroles,
including debromokeramadine (
99
), benzosceptrin A (
100
), nagelamide S (
101
) and nagelamide T (
102
)
(Figure 15) [50,51].
Mar. Drugs 2017, 15, 351 10 of 29
90 91 92
Figure 14. Chemical structures of compounds 78–92.
The same species of A. mauritiana grown in different places were found to produce different
pyrrole derivatives, such as debromodispacamides B (93) and D (94) from Solomon Island specimen
[46], 4-bromo-N-(butoxymethyl)-1H-pyrrole-2-carboxamide (95) from the South China Sea [41], 5-
debromomidpacamide (96) from Enewetak Atoll [47], mauritamide A (97) from Fiji [48] and mauritiamine
(98) from Hachijo-jima Island [49]. Compound 98 exhibited inhibitory effect on larval metamorphosis of
the barnacle Balanus amphitrite with ED50 value of 15 μg/mL and moderate antibacterial activity against
Flavobacterium marinotypicum with the inhibition zone of 10 mm at 10 μg/disk. Interestingly, the Pacific
sponge A. mauritiana was found to metabolize other pyrroles, including debromokeramadine (99),
benzosceptrin A (100), nagelamide S (101) and nagelamide T (102) (Figure 15) [50,51].
93:R = H
94:R = OH 95
96 97
98 99
100 101
102
Figure 15. Chemical structures of compounds 93–102.
Figure 15. Chemical structures of compounds 93–102.

Mar. Drugs 2017,15, 351 11 of 29
Agelasphins (
103
–
110
) from the Okinawan A. mauritiana were the first example of
galactosylceramides containing an
α
-galactosyl linkage [
52
,
53
]. These compounds exhibited high
activity with the relative tumor proliferation rate (T/C) ranging from 160% to 190% and 200–400%
relative
3
H-TdR incorporation at <l
µ
g/mL. But no activity was observed against B16 melanoma cells
at 20
µ
g/mL. Two natural carotenoids, isotedanin (
111
) and isoclathriaxanthin (
112
) (Figure 16), were
also detected in the specimen of A. mauritiana from Kagoshima [54].
Mar. Drugs 2017, 15, 351 11 of 29
Agelasphins (103–110) from the Okinawan A. mauritiana were the first example of
galactosylceramides containing an α-galactosyl linkage [52,53]. These compounds exhibited high
activity with the relative tumor proliferation rate (T/C) ranging from 160% to 190% and 200–400%
relative 3H-TdR incorporation at <l μg/mL. But no activity was observed against B16 melanoma cells
at 20 μg/mL. Two natural carotenoids, isotedanin (111) and isoclathriaxanthin (112) (Figure 16), were
also detected in the specimen of A. mauritiana from Kagoshima [54].
103: R = CH3
104: R = CH2CH3
105: R = CH(CH3)2
106: R = CH(CH3)C2H5
107: n = 21, R =
108: n = 22, R =
109: n = 13, R =
110: n = 20, Y = 10 and/or Z = 11;
n = 21, Y = 9 and/or Z = 10
111 112
Figure 16. Chemical structures of compounds 103–112.
2.13. Agelas nakamurai
Thirty-three chemicals have been characterized from Agelas nakamurai, including 16 terpenoids
and 17 pyrrole alkaloids. The Okinawan A. nakamurai seems to occupy the majority of terpenoid
compounds, including agelasidines B (113) and C (114) [55], nakamurols A–D (115–118) [56], 2-
oxoagelasiines A (119) and F (120), 10-hydro-9-hydroxyagelasine F (121) [57], agelasines E (122) and
F (123) [58]. Compounds 113 and 114 were found to have inhibitory effects on the growth of S. aureus
at 3.3 μg/mL and on contractile responses of smooth muscles. Compounds 119 and 120 showed
markedly reduced activity against Mycobacterium smegmatis. The Indonesian A. nakamurai was found
to yield two novel diterpenes, (−)-agelasine D (124) and (−)-ageloxime D (125). Antibacterial assay
revealed 124 could inhibit the growth of Staphylococcus epidermidis with a MIC value < 0.0877 μM [35].
Isoagelasine C (126) and isoagelasidine B (127) were isolated from specimen of the South China Sea
and possessed weak cytotoxicities against HL-60, K562 and HCT-116 cell lines with IC50 values
ranging from 18.4 to 39.2 μM [59]. A new diterpene (128) (Figure 17) with a 9-methyladenum moiety
produced by the Papua New Guinean A. nakamurai Hoshino was shown to be inactive against HIV-
1 integrase, E. coli and Pseudomonas aeruginosa at 12.5 μg/mL [60].
113 114
OH
115 116 117
Figure 16. Chemical structures of compounds 103–112.
2.13. Agelas nakamurai
Thirty-three chemicals have been characterized from Agelas nakamurai, including 16 terpenoids
and 17 pyrrole alkaloids. The Okinawan A. nakamurai seems to occupy the majority of terpenoid
compounds, including agelasidines B (
113
) and C (
114
) [
55
], nakamurols A–D (
115
–
118
) [
56
],
2-oxoagelasiines A (
119
) and F (
120
), 10-hydro-9-hydroxyagelasine F (
121
) [
57
], agelasines E (
122
)
and F (
123
) [
58
]. Compounds
113
and
114
were found to have inhibitory effects on the growth of S.
aureus at 3.3
µ
g/mL and on contractile responses of smooth muscles. Compounds
119
and
120
showed
markedly reduced activity against Mycobacterium smegmatis. The Indonesian A. nakamurai was found
to yield two novel diterpenes, (
−
)-agelasine D (
124
) and (
−
)-ageloxime D (
125
). Antibacterial assay
revealed
124
could inhibit the growth of Staphylococcus epidermidis with a MIC value < 0.0877
µ
M [
35
].
Isoagelasine C (
126
) and isoagelasidine B (
127
) were isolated from specimen of the South China Sea
and possessed weak cytotoxicities against HL-60, K562 and HCT-116 cell lines with IC
50
values ranging
from 18.4 to 39.2
µ
M [
59
]. A new diterpene (
128
) (Figure 17) with a 9-methyladenum moiety produced
by the Papua New Guinean A. nakamurai Hoshino was shown to be inactive against HIV-1 integrase,
E. coli and Pseudomonas aeruginosa at 12.5 µg/mL [60].
Mar. Drugs 2017, 15, 351 11 of 29
Agelasphins (103–110) from the Okinawan A. mauritiana were the first example of
galactosylceramides containing an α-galactosyl linkage [52,53]. These compounds exhibited high
activity with the relative tumor proliferation rate (T/C) ranging from 160% to 190% and 200–400%
relative 3H-TdR incorporation at <l μg/mL. But no activity was observed against B16 melanoma cells
at 20 μg/mL. Two natural carotenoids, isotedanin (111) and isoclathriaxanthin (112) (Figure 16), were
also detected in the specimen of A. mauritiana from Kagoshima [54].
103: R = CH3
104: R = CH2CH3
105: R = CH(CH3)2
106: R = CH(CH3)C2H5
107: n = 21, R =
108: n = 22, R =
109: n = 13, R =
110: n = 20, Y = 10 and/or Z = 11;
n = 21, Y = 9 and/or Z = 10
111 112
Figure 16. Chemical structures of compounds 103–112.
2.13. Agelas nakamurai
Thirty-three chemicals have been characterized from Agelas nakamurai, including 16 terpenoids
and 17 pyrrole alkaloids. The Okinawan A. nakamurai seems to occupy the majority of terpenoid
compounds, including agelasidines B (113) and C (114) [55], nakamurols A–D (115–118) [56], 2-
oxoagelasiines A (119) and F (120), 10-hydro-9-hydroxyagelasine F (121) [57], agelasines E (122) and
F (123) [58]. Compounds 113 and 114 were found to have inhibitory effects on the growth of S. aureus
at 3.3 μg/mL and on contractile responses of smooth muscles. Compounds 119 and 120 showed
markedly reduced activity against Mycobacterium smegmatis. The Indonesian A. nakamurai was found
to yield two novel diterpenes, (−)-agelasine D (124) and (−)-ageloxime D (125). Antibacterial assay
revealed 124 could inhibit the growth of Staphylococcus epidermidis with a MIC value < 0.0877 μM [35].
Isoagelasine C (126) and isoagelasidine B (127) were isolated from specimen of the South China Sea
and possessed weak cytotoxicities against HL-60, K562 and HCT-116 cell lines with IC50 values
ranging from 18.4 to 39.2 μM [59]. A new diterpene (128) (Figure 17) with a 9-methyladenum moiety
produced by the Papua New Guinean A. nakamurai Hoshino was shown to be inactive against HIV-
1 integrase, E. coli and Pseudomonas aeruginosa at 12.5 μg/mL [60].
113 114
OH
115 116 117
Figure 17. Cont.

Mar. Drugs 2017,15, 351 12 of 29
Mar. Drugs 2017, 15, 351 12 of 29
XN
N
N
N
H2N
O
118 119 120
121 122 123
124 125 126
127 128
Figure 17. Chemical structures of compounds 113–128.
Five non-brominated pyrrole derivatives, nakamurines A–E (129–133), were purified from the
South China Sea A. nakamurai [59,61]. Bioassay results showed that compound 130 had weak
inhibition against Candida albicans with a MIC value of 60 μg/mL [61]. Bromopyrrole alkaloid was
one of the most common secondary metabolites from marine sponges [62]. Two bromopyrrole
alkaloids (134 and 135) were firstly isolated from the Papua New Guinean A. nakamurai in 1998 [60].
Ageladine A (136) containing 2-aminoimidazolopyridine was shown to have inhibitory effects on
Matrix metalloproteinases-1, -2, -8, -9, -12 and -13 with IC50 values of 1.2, 2.0, 0.39, 0.79, 0.33, and 0.47
μg/mL, respectively [63]. Chemical investigation of the Indonesia A. nakamurai afforded longamide
C (137) [35]. Nakamuric acid (138) and its methyl ester (139) were characterized from the Indopacific
specimen and shown to be active against B. subtilis [64]. The Okinawan A. nakamurai was found to
produce six brominated pyrrole derivatives, slagenins A–C (140–142) and mukanadins A–C (143–145)
(Figure 18), of which 141 and 142 showed inhibitory effect on murine leukemia L1210 cells in vitro
with IC50 values of 7.5 and 7.0 μg/mL, respectively [65,66].
Figure 17. Chemical structures of compounds 113–128.
Five non-brominated pyrrole derivatives, nakamurines A–E (
129
–
133
), were purified from the
South China Sea A. nakamurai [
59
,
61
]. Bioassay results showed that compound
130
had weak inhibition
against Candida albicans with a MIC value of 60
µ
g/mL [
61
]. Bromopyrrole alkaloid was one of
the most common secondary metabolites from marine sponges [
62
]. Two bromopyrrole alkaloids
(
134
and
135
) were firstly isolated from the Papua New Guinean A. nakamurai in 1998 [
60
]. Ageladine
A (
136
) containing 2-aminoimidazolopyridine was shown to have inhibitory effects on Matrix
metalloproteinases-1, -2, -8, -9, -12 and -13 with IC
50
values of 1.2, 2.0, 0.39, 0.79, 0.33, and 0.47
µ
g/mL,
respectively [
63
]. Chemical investigation of the Indonesia A. nakamurai afforded longamide C (
137
) [
35
].
Nakamuric acid (
138
) and its methyl ester (
139
) were characterized from the Indopacific specimen
and shown to be active against B. subtilis [
64
]. The Okinawan A. nakamurai was found to produce six
brominated pyrrole derivatives, slagenins A–C (
140
–
142
) and mukanadins A–C (
143
–
145
) (Figure 18),
of which
141
and
142
showed inhibitory effect on murine leukemia L1210 cells
in vitro
with IC
50
values
of 7.5 and 7.0 µg/mL, respectively [65,66].

Mar. Drugs 2017,15, 351 13 of 29
Mar. Drugs 2017, 15, 351 13 of 29
129 130 131 (+)-132
(−)-132 (+)-133 (−)-133 134
135 136 137 138: R = H
139: R = CH3
140: R = H
141: R = CH3 142 143
144 145
Figure 18. Chemical structures of compounds 129–145.
2.14. Agelas nemoechinata
Nemoechines A–D (146–149) and nemoechioxide A (150) were obtained from the sponge Agelas
aff. nemoechinata collected from the South China Sea. Compounds 146–148 had enantiomeric
configurations and 146 had an unusual cyclopentene-fused imidazole ring system. Bioassay results
suggested that only 149 had cytotoxicity against HL-60 cell lines with an IC50 value of 9.9 μM [67].
Two new nemoechine members, nemoechines F (151) and G (152) possessing N-methyladenine, were
purified from the South China Sea-derived A. nemoechinata. Compound 152 had weak toxicity against
Jurkat cell line with an IC50 value of 17.1 μM [68]. Oxysceptrin (153) (Figure 19) derived from the
Okinawan A. nemoechinata was a potent actomyosin ATPase activator [69].
(+)-146
(−)-146
(+)-147
(−)-147
(+)-148
(−)-148 149
150 151 152 153
Figure 19. Chemical structures of compounds 146–153.
Figure 18. Chemical structures of compounds 129–145.
2.14. Agelas nemoechinata
Nemoechines A–D (
146
–
149
) and nemoechioxide A (
150
) were obtained from the sponge Agelas aff.
nemoechinata collected from the South China Sea. Compounds
146
–
148
had enantiomeric configurations
and
146
had an unusual cyclopentene-fused imidazole ring system. Bioassay results suggested that
only
149
had cytotoxicity against HL-60 cell lines with an IC
50
value of 9.9
µ
M [
67
]. Two new
nemoechine members, nemoechines F (
151
) and G (
152
) possessing N-methyladenine, were purified
from the South China Sea-derived A. nemoechinata. Compound
152
had weak toxicity against Jurkat
cell line with an IC
50
value of 17.1
µ
M [
68
]. Oxysceptrin (
153
) (Figure 19) derived from the Okinawan
A. nemoechinata was a potent actomyosin ATPase activator [69].
Mar. Drugs 2017, 15, 351 13 of 29
129 130 131 (+)-132
(−)-132 (+)-133 (−)-133 134
135 136 137 138: R = H
139: R = CH3
140: R = H
141: R = CH3 142 143
144 145
Figure 18. Chemical structures of compounds 129–145.
2.14. Agelas nemoechinata
Nemoechines A–D (146–149) and nemoechioxide A (150) were obtained from the sponge Agelas
aff. nemoechinata collected from the South China Sea. Compounds 146–148 had enantiomeric
configurations and 146 had an unusual cyclopentene-fused imidazole ring system. Bioassay results
suggested that only 149 had cytotoxicity against HL-60 cell lines with an IC50 value of 9.9 μM [67].
Two new nemoechine members, nemoechines F (151) and G (152) possessing N-methyladenine, were
purified from the South China Sea-derived A. nemoechinata. Compound 152 had weak toxicity against
Jurkat cell line with an IC50 value of 17.1 μM [68]. Oxysceptrin (153) (Figure 19) derived from the
Okinawan A. nemoechinata was a potent actomyosin ATPase activator [69].
(+)-146
(−)-146
(+)-147
(−)-147
(+)-148
(−)-148 149
150 151 152 153
Figure 19. Chemical structures of compounds 146–153.
Figure 19. Chemical structures of compounds 146–153.

Mar. Drugs 2017,15, 351 14 of 29
2.15. Agelas oroides
Thirty-six secondary metabolites (
154
–
189
) (Figure 20) have been isolated from the marine sponge
Agelas oroides, including pyrrole derivatives, sterols and fatty acids. Chemical investigation of A. oroides
from the Great Barrier Reef afforded three fistularin-3 derivatives, agelorin A (
154
), agelorin B (
155
)
and 11-epi-fistularin-3 (
156
). These metabolites exhibited antimicrobial activities against B. subtilis
and M. luteus and
156
had moderate cytotoxicity against breast cancer cells [
70
]. Later on, two new
naturally occurring pyrrole derivatives (
157
and
158
) and 2,4,6,6-tetramethyl-3(6H)-pyridone (
159
)
were obtained from the same specimen [
71
,
72
]. Mediterranean A. oroides was shown to produce
four novel compounds, cyclooroidin (
160
), taurodispacamide A (
161
), monobromoagelaspongin (
162
)
and (
−
)-equinobetaine B (
163
), of which
161
displayed strong antihistaminic activity [
73
,
74
]. Five
bromopyrrole alkaloids (
164
–
168
) and fifteen sterols (
169
–
183
) were detected in the sponge A. oroides
collected in the Bay of Naples [
75
,
76
]. Interestingly, one imidazole compound (
184
), taurine (
185
) and
some fatty acids (186–189) were also found in the Northern Aegean Sea-derived specimen [77].
Mar. Drugs 2017, 15, 351 14 of 29
2.15. Agelas oroides
Thirty-six secondary metabolites (154–189) (Figure 20) have been isolated from the marine
sponge Agelas oroides, including pyrrole derivatives, sterols and fatty acids. Chemical investigation
of A. oroides from the Great Barrier Reef afforded three fistularin-3 derivatives, agelorin A (154),
agelorin B (155) and 11-epi-fistularin-3 (156). These metabolites exhibited antimicrobial activities
against B. subtilis and M. luteus and 156 had moderate cytotoxicity against breast cancer cells [70].
Later on, two new naturally occurring pyrrole derivatives (157 and 158) and 2,4,6,6-tetramethyl-
3(6H)-pyridone (159) were obtained from the same specimen [71,72]. Mediterranean A. oroides was
shown to produce four novel compounds, cyclooroidin (160), taurodispacamide A (161),
monobromoagelaspongin (162) and (−)-equinobetaine B (163), of which 161 displayed strong
antihistaminic activity [73,74]. Five bromopyrrole alkaloids (164–168) and fifteen sterols (169–183)
were detected in the sponge A. oroides collected in the Bay of Naples [75,76]. Interestingly, one
imidazole compound (184), taurine (185) and some fatty acids (186–189) were also found in the
Northern Aegean Sea-derived specimen [77].
154 155
156 157 158 159
160 161 162 163
164: R = OCH3
165: R = NH2
166: R = OH
167 168
183 184
185
186: n = 11
187: n = 12
188: n = 13
189: n = 14
Figure 20. Chemical structures of compounds 154–189.
Figure 20. Chemical structures of compounds 154–189.

Mar. Drugs 2017,15, 351 15 of 29
2.16. Agelas sceptrum
One novel C
29
sterol containing the typical nucleus of ergosterol, 26-nor-25-isopropyl-ergosta-
5,7,22E-trien-3
β
-ol (
190
), was purified from the Jamaican A. sceptrum [
78
]. Sceptrin (
191
) was obtained
from A. sceptrum collected at Glover Reef and found to have a broad spectrum of antimicrobial
activities against S. aureus,B. subtilis,C. albicans,Pseudomonas aeruginosa,Alternaria sp. and Cladosporium
cucumerinum [
79
]. Chemical study of the sponge from Bahamas afforded two hybrid pyrrole-imidazole
alkaloids: 150-oxoadenosceptrin (192) and decarboxyagelamadin C (193) (Figure 21) [80].
Mar. Drugs 2017, 15, 351 15 of 29
2.16. Agelas sceptrum
One novel C29 sterol containing the typical nucleus of ergosterol, 26-nor-25-isopropyl-ergosta-
5,7,22E-trien-3β-ol (190), was purified from the Jamaican A. sceptrum [78]. Sceptrin (191) was obtained
from A. sceptrum collected at Glover Reef and found to have a broad spectrum of antimicrobial activities
against S. aureus, B. subtilis, C. albicans, Pseudomonas aeruginosa, Alternaria sp. and Cladosporium
cucumerinum [79]. Chemical study of the sponge from Bahamas afforded two hybrid pyrrole-imidazole
alkaloids: 15′-oxoadenosceptrin (192) and decarboxyagelamadin C (193) (Figure 21) [80].
190 191
192 193
Figure 21. Chemical structures of compounds 190–193.
2.17. Agelas schmidtii
Three monohydroxyl sterols (194–196) were isolated from the Caribbean Agelas schmidtii [81].
Additionally, four carotenoids named α-carotene (197), isorenieratene (198), trikentriorhodin (199)
and zeaxanthin (200) (Figure 22) were also derived from this sponge collected from West Indies [82].
194
195: Δ7 196 197
198 199
200
Figure 22 Chemical structures of compounds 194–200.
Figure 21. Chemical structures of compounds 190–193.
2.17. Agelas schmidtii
Three monohydroxyl sterols (
194
–
196
) were isolated from the Caribbean Agelas schmidtii [
81
].
Additionally, four carotenoids named
α
-carotene (
197
), isorenieratene (
198
), trikentriorhodin (
199
) and
zeaxanthin (200) (Figure 22) were also derived from this sponge collected from West Indies [82].
Mar. Drugs 2017, 15, 351 15 of 29
2.16. Agelas sceptrum
One novel C29 sterol containing the typical nucleus of ergosterol, 26-nor-25-isopropyl-ergosta-
5,7,22E-trien-3β-ol (190), was purified from the Jamaican A. sceptrum [78]. Sceptrin (191) was obtained
from A. sceptrum collected at Glover Reef and found to have a broad spectrum of antimicrobial activities
against S. aureus, B. subtilis, C. albicans, Pseudomonas aeruginosa, Alternaria sp. and Cladosporium
cucumerinum [79]. Chemical study of the sponge from Bahamas afforded two hybrid pyrrole-imidazole
alkaloids: 15′-oxoadenosceptrin (192) and decarboxyagelamadin C (193) (Figure 21) [80].
190 191
192 193
Figure 21. Chemical structures of compounds 190–193.
2.17. Agelas schmidtii
Three monohydroxyl sterols (194–196) were isolated from the Caribbean Agelas schmidtii [81].
Additionally, four carotenoids named α-carotene (197), isorenieratene (198), trikentriorhodin (199)
and zeaxanthin (200) (Figure 22) were also derived from this sponge collected from West Indies [82].
194
195: Δ7 196 197
198 199
200
Figure 22 Chemical structures of compounds 194–200.
Figure 22. Chemical structures of compounds 194–200.

Mar. Drugs 2017,15, 351 16 of 29
2.18. Agelas sventres
Only one new bromopyrrole alkaloid, sventrin (
201
) (Figure 23), has been purified from the
Caribbean sponge Agelas sventres. Biological assay showed that this chemical has feeding deterrent
activity against omnivorous reef fish [83].
Mar. Drugs 2017, 15, 351 16 of 29
2.18. Agelas sventres
Only one new bromopyrrole alkaloid, sventrin (201) (Figure 23), has been purified from the
Caribbean sponge Agelas sventres. Biological assay showed that this chemical has feeding deterrent
activity against omnivorous reef fish [83].
201
Figure 23. Chemical structure of compounds 201.
2.19. Agelas wiedenmayeri
Chemical investigation of Agelas wiedenmayeri from Florida Keys afforded one new pyrrole
derivative, 4-bromopyrrole-2-carboxyhomoarginine (202) (Figure 24), which might be alternatively a
biosynthetic precursor of hymenidin/oroidin-related alkaloids [84].
202
Figure 24. Chemical structure of compounds 202.
2.20. Other Agelas spp.
Eighty-nine secondary metabolites (203–291) were isolated and chemically identified from
unclassified Agelas species and assorted into two classes, ionic and non-ionic compounds as below.
2.20.1. Ionic Compounds
As described above, ionic compounds are the major secondary metabolites of Agelas sponge,
which can be grouped in bromine-containing and non-bromine-containing compounds. It is eminent
that all ionic brominated metabolites were produced by the Okinawan Agelas spp. besides
dibromoagelaspongin hydrochloride (203) [85]. Agelamadins A (204) and B (205), possessing an
agelastatin-like tetracyclic moiety and an oroidin-like linear moiety, were shown to have
antimicrobial activity against B. subtilis, M. luteus and C. neoformans [86]. The same specimen was also
found to metabolize agelamadins C–F (206–209) and tauroacidin E (210) (Figure 25), of which 209 was
the first occurrence bromopyrrole alkaloid for containing aminoimidazole and pyridinium moieties
simultaneously [87,88].
O
HN N
H
H
N
HN
HOOC
O
O
NH
Br
Br
NH2
NH3
2CF3COO
203 204: R=OCH3
205: R=OH 206 207
Figure 23. Chemical structure of compounds 201.
2.19. Agelas wiedenmayeri
Chemical investigation of Agelas wiedenmayeri from Florida Keys afforded one new pyrrole
derivative, 4-bromopyrrole-2-carboxyhomoarginine (
202
) (Figure 24), which might be alternatively
a biosynthetic precursor of hymenidin/oroidin-related alkaloids [84].
Mar. Drugs 2017, 15, 351 16 of 29
2.18. Agelas sventres
Only one new bromopyrrole alkaloid, sventrin (201) (Figure 23), has been purified from the
Caribbean sponge Agelas sventres. Biological assay showed that this chemical has feeding deterrent
activity against omnivorous reef fish [83].
201
Figure 23. Chemical structure of compounds 201.
2.19. Agelas wiedenmayeri
Chemical investigation of Agelas wiedenmayeri from Florida Keys afforded one new pyrrole
derivative, 4-bromopyrrole-2-carboxyhomoarginine (202) (Figure 24), which might be alternatively a
biosynthetic precursor of hymenidin/oroidin-related alkaloids [84].
202
Figure 24. Chemical structure of compounds 202.
2.20. Other Agelas spp.
Eighty-nine secondary metabolites (203–291) were isolated and chemically identified from
unclassified Agelas species and assorted into two classes, ionic and non-ionic compounds as below.
2.20.1. Ionic Compounds
As described above, ionic compounds are the major secondary metabolites of Agelas sponge,
which can be grouped in bromine-containing and non-bromine-containing compounds. It is eminent
that all ionic brominated metabolites were produced by the Okinawan Agelas spp. besides
dibromoagelaspongin hydrochloride (203) [85]. Agelamadins A (204) and B (205), possessing an
agelastatin-like tetracyclic moiety and an oroidin-like linear moiety, were shown to have
antimicrobial activity against B. subtilis, M. luteus and C. neoformans [86]. The same specimen was also
found to metabolize agelamadins C–F (206–209) and tauroacidin E (210) (Figure 25), of which 209 was
the first occurrence bromopyrrole alkaloid for containing aminoimidazole and pyridinium moieties
simultaneously [87,88].
O
HN N
H
H
N
HN
HOOC
O
O
NH
Br
Br
NH2
NH3
2CF3COO
203 204: R=OCH3
205: R=OH 206 207
Figure 24. Chemical structure of compounds 202.
2.20. Other Agelas spp.
Eighty-nine secondary metabolites (
203
–
291
) were isolated and chemically identified from
unclassified Agelas species and assorted into two classes, ionic and non-ionic compounds as below.
2.20.1. Ionic Compounds
As described above, ionic compounds are the major secondary metabolites of Agelas sponge, which
can be grouped in bromine-containing and non-bromine-containing compounds. It is eminent that all
ionic brominated metabolites were produced by the Okinawan Agelas spp. besides dibromoagelaspongin
hydrochloride (
203
) [
85
]. Agelamadins A (
204
) and B (
205
), possessing an agelastatin-like tetracyclic
moiety and an oroidin-like linear moiety, were shown to have antimicrobial activity against B. subtilis,
M. luteus and C. neoformans [
86
]. The same specimen was also found to metabolize agelamadins C–F
(
206
–
209
) and tauroacidin E (
210
) (Figure 25), of which
209
was the first occurrence bromopyrrole alkaloid
for containing aminoimidazole and pyridinium moieties simultaneously [87,88].
Mar. Drugs 2017, 15, 351 16 of 29
2.18. Agelas sventres
Only one new bromopyrrole alkaloid, sventrin (201) (Figure 23), has been purified from the
Caribbean sponge Agelas sventres. Biological assay showed that this chemical has feeding deterrent
activity against omnivorous reef fish [83].
201
Figure 23. Chemical structure of compounds 201.
2.19. Agelas wiedenmayeri
Chemical investigation of Agelas wiedenmayeri from Florida Keys afforded one new pyrrole
derivative, 4-bromopyrrole-2-carboxyhomoarginine (202) (Figure 24), which might be alternatively a
biosynthetic precursor of hymenidin/oroidin-related alkaloids [84].
202
Figure 24. Chemical structure of compounds 202.
2.20. Other Agelas spp.
Eighty-nine secondary metabolites (203–291) were isolated and chemically identified from
unclassified Agelas species and assorted into two classes, ionic and non-ionic compounds as below.
2.20.1. Ionic Compounds
As described above, ionic compounds are the major secondary metabolites of Agelas sponge,
which can be grouped in bromine-containing and non-bromine-containing compounds. It is eminent
that all ionic brominated metabolites were produced by the Okinawan Agelas spp. besides
dibromoagelaspongin hydrochloride (203) [85]. Agelamadins A (204) and B (205), possessing an
agelastatin-like tetracyclic moiety and an oroidin-like linear moiety, were shown to have
antimicrobial activity against B. subtilis, M. luteus and C. neoformans [86]. The same specimen was also
found to metabolize agelamadins C–F (206–209) and tauroacidin E (210) (Figure 25), of which 209 was
the first occurrence bromopyrrole alkaloid for containing aminoimidazole and pyridinium moieties
simultaneously [87,88].
O
HN N
H
H
N
HN
HOOC
O
O
NH
Br
Br
NH2
NH3
2CF3COO
203 204: R=OCH3
205: R=OH 206 207
Figure 25. Cont.

Mar. Drugs 2017,15, 351 17 of 29
Mar. Drugs 2017, 15, 351 17 of 29
208 209 210
Figure 25. Chemical structures of compounds 203–210.
Twenty-one nagelamides (211–231) (Figure 26) have been characterized from the Okinawan
Agelas spp. Nagelamides A–H (211–218) and O (219) were shown to possess antimicrobial activities
against M. luteus, B. subtilis and E. coli. Compounds 211, 217 and 218 were shown to inhibit the growth
of protein phosphatase type 2A with IC50 values of 48, 13 and 46 μM, respectively [89,90].
Nagelamides K (220) and L (221) had inhibitory effect on M. luteus with a MIC value of 16.7 μg/mL
[91]. Bioactivity test uncovered that nagelamides M (222) and N (223) exhibited inhibition against A.
niger with the same MIC value of 33.3 μg/mL [92]. Nagelamides Q (224) and R (225), of which
compound 225 possessed an oxazoline ring for the first time, showed antimicrobial activity against
B. subtilis, Trichophyton mentagrophytes, C. neoformans, C. albicans and A. niger [93]. Nagelamides U (226)
and V (227) were the first occurence for a bromopyrrole alkaloid containing a γ-lactam ring with an
N-ethanesulfonic acid and guanidino moieties, while nagelamide W (228) was the first monomeric
bromopyrrole alkaloid with two aminoimidazole moieties in the molecule. Compounds 226 and 228
could inhibit against C. albicans with the same IC50 value of 4 μg/mL [94]. Nagelamides X (229) and Y
(230) were unique for their novel tricyclic skeleton consisting of spiro-bonded
tetrahydrobenzaminoimidazole and aminoimidazolidine moieties. In addition, nagelamide Z (231)
was the first example for dimeric bromopyrrole alkaloid involving the C-8 position in dimerization
and displayed strong antimicrobial activity against C. albicans with an IC50 value of 0.25 μg/mL [95].
2X
N
H
H
N
HN
NH
N
H
H
N
Br
Br
NH2
O
NH2
HN
O
NH
Br
Br
211: R = H
212: R = OH
213: Δ9(10),9′(10′)
214: 9,9',10,10'-tetrahydro
215: R1 = R2 =H
216: R1 = Br, R2 = H
217: R1 = R2 = Br
218 219 220
221 222 223
Figure 25. Chemical structures of compounds 203–210.
Twenty-one nagelamides (
211
–
231
) (Figure 26) have been characterized from the Okinawan
Agelas spp. Nagelamides A–H (
211
–
218
) and O (
219
) were shown to possess antimicrobial activities
against M. luteus,B. subtilis and E. coli. Compounds
211
,
217
and
218
were shown to inhibit the growth
of protein phosphatase type 2A with IC
50
values of 48, 13 and 46
µ
M, respectively [
89
,
90
]. Nagelamides
K (
220
) and L (
221
) had inhibitory effect on M. luteus with a MIC value of 16.7
µ
g/mL [
91
]. Bioactivity
test uncovered that nagelamides M (
222
) and N (
223
) exhibited inhibition against A. niger with the same
MIC value of 33.3
µ
g/mL [
92
]. Nagelamides Q (
224
) and R (
225
), of which compound
225
possessed
an oxazoline ring for the first time, showed antimicrobial activity against B. subtilis,Trichophyton
mentagrophytes,C. neoformans,C. albicans and A. niger [
93
]. Nagelamides U (
226
) and V (
227
) were
the first occurence for a bromopyrrole alkaloid containing a
γ
-lactam ring with an N-ethanesulfonic
acid and guanidino moieties, while nagelamide W (
228
) was the first monomeric bromopyrrole
alkaloid with two aminoimidazole moieties in the molecule. Compounds
226
and
228
could inhibit
against C. albicans with the same IC
50
value of 4
µ
g/mL [
94
]. Nagelamides X (
229
) and Y (
230
) were
unique for their novel tricyclic skeleton consisting of spiro-bonded tetrahydrobenzaminoimidazole
and aminoimidazolidine moieties. In addition, nagelamide Z (
231
) was the first example for dimeric
bromopyrrole alkaloid involving the C-8 position in dimerization and displayed strong antimicrobial
activity against C. albicans with an IC50 value of 0.25 µg/mL [95].
Mar. Drugs 2017, 15, 351 17 of 29
208 209 210
Figure 25. Chemical structures of compounds 203–210.
Twenty-one nagelamides (211–231) (Figure 26) have been characterized from the Okinawan
Agelas spp. Nagelamides A–H (211–218) and O (219) were shown to possess antimicrobial activities
against M. luteus, B. subtilis and E. coli. Compounds 211, 217 and 218 were shown to inhibit the growth
of protein phosphatase type 2A with IC50 values of 48, 13 and 46 μM, respectively [89,90].
Nagelamides K (220) and L (221) had inhibitory effect on M. luteus with a MIC value of 16.7 μg/mL
[91]. Bioactivity test uncovered that nagelamides M (222) and N (223) exhibited inhibition against A.
niger with the same MIC value of 33.3 μg/mL [92]. Nagelamides Q (224) and R (225), of which
compound 225 possessed an oxazoline ring for the first time, showed antimicrobial activity against
B. subtilis, Trichophyton mentagrophytes, C. neoformans, C. albicans and A. niger [93]. Nagelamides U (226)
and V (227) were the first occurence for a bromopyrrole alkaloid containing a γ-lactam ring with an
N-ethanesulfonic acid and guanidino moieties, while nagelamide W (228) was the first monomeric
bromopyrrole alkaloid with two aminoimidazole moieties in the molecule. Compounds 226 and 228
could inhibit against C. albicans with the same IC50 value of 4 μg/mL [94]. Nagelamides X (229) and Y
(230) were unique for their novel tricyclic skeleton consisting of spiro-bonded
tetrahydrobenzaminoimidazole and aminoimidazolidine moieties. In addition, nagelamide Z (231)
was the first example for dimeric bromopyrrole alkaloid involving the C-8 position in dimerization
and displayed strong antimicrobial activity against C. albicans with an IC50 value of 0.25 μg/mL [95].
2X
N
H
H
N
HN
NH
N
H
H
N
Br
Br
NH2
O
NH2
HN
O
NH
Br
Br
211: R = H
212: R = OH
213: Δ9(10),9′(10′)
214: 9,9',10,10'-tetrahydro
215: R1 = R2 =H
216: R1 = Br, R2 = H
217: R1 = R2 = Br
218 219 220
221 222 223
Figure 26. Cont.

Mar. Drugs 2017,15, 351 18 of 29
Mar. Drugs 2017, 15, 351 18 of 29
224 225 226: β-H
227: α-H
228 229: R = OH
230: R = H 231
Figure 26. Chemical structures of compounds 211–231.
Eight new bromopyrrole alkaloids, 2-bromokeramadine (232), 2-bromo-9,10-dihydrokeramadine
(233), tauroacidins C (234) and D (235), mukanadin G (236), 2-debromonagelamides U (237) and G (238),
2-debromonagelamide P (239), keramadine (240) and agelasine G (241) (Figure 27) were detected in the
Okinawan Agelas spp. [96–99] Antimicrobial tests suggested that compound 236 exhibited inhibitory
effects on C. albicans and C. neoformans with IC50 values of 16 and 8 μg/mL, respectively [96].
Compounds 237 and 239 could inhibit the growth of T. mentagrophytes with IC50 values of 16 and 32
μg/mL, respectively. Cytotoxicity assay revealed that 241 showed toxicity against murine lymphoma
L1210 cells in vitro with an IC50 value of 3.1 μg/mL [97,99].
232 233 234
235 236 237
N
H
Br
H
N
O
NH
NNH2
X
238 239 240
Figure 26. Chemical structures of compounds 211–231.
Eight new bromopyrrole alkaloids, 2-bromokeramadine (
232
), 2-bromo-9,10-dihydrokeramadine
(
233
), tauroacidins C (
234
) and D (
235
), mukanadin G (
236
), 2-debromonagelamides U (
237
) and
G (
238
), 2-debromonagelamide P (
239
), keramadine (
240
) and agelasine G (
241
) (Figure 27) were
detected in the Okinawan Agelas spp. [
96
–
99
] Antimicrobial tests suggested that compound
236
exhibited inhibitory effects on C. albicans and C. neoformans with IC
50
values of 16 and 8
µ
g/mL,
respectively [
96
]. Compounds
237
and
239
could inhibit the growth of T. mentagrophytes with IC
50
values of 16 and 32
µ
g/mL, respectively. Cytotoxicity assay revealed that
241
showed toxicity against
murine lymphoma L1210 cells in vitro with an IC50 value of 3.1 µg/mL [97,99].
Mar. Drugs 2017, 15, 351 18 of 29
224 225 226: β-H
227: α-H
228 229: R = OH
230: R = H 231
Figure 26. Chemical structures of compounds 211–231.
Eight new bromopyrrole alkaloids, 2-bromokeramadine (232), 2-bromo-9,10-dihydrokeramadine
(233), tauroacidins C (234) and D (235), mukanadin G (236), 2-debromonagelamides U (237) and G (238),
2-debromonagelamide P (239), keramadine (240) and agelasine G (241) (Figure 27) were detected in the
Okinawan Agelas spp. [96–99] Antimicrobial tests suggested that compound 236 exhibited inhibitory
effects on C. albicans and C. neoformans with IC50 values of 16 and 8 μg/mL, respectively [96].
Compounds 237 and 239 could inhibit the growth of T. mentagrophytes with IC50 values of 16 and 32
μg/mL, respectively. Cytotoxicity assay revealed that 241 showed toxicity against murine lymphoma
L1210 cells in vitro with an IC50 value of 3.1 μg/mL [97,99].
232 233 234
235 236 237
N
H
Br
H
N
O
NH
NNH2
X
238 239 240
Figure 27. Cont.

Mar. Drugs 2017,15, 351 19 of 29
Mar. Drugs 2017, 15, 351 19 of 29
241
Figure 27. Chemical structures of compounds 232–241.
Nineteen non-bromine-containing ionic compounds have been isolated from unclassified Agelas
spp., including eleven agalasines (242–252) from Okinawa [100,101], two agelasines (253 and 254)
from Yap Island [102], four higher unsaturated 9-N-methyladeninium bicyclic diterpenoids (255–258)
from Papua New Guinea [103] and two quarternary 9-methyladenine salts of diterpenes agelines (259
and 260) from Argulpelu Reef [104]. Compounds 242–245 displayed strong inhibitory effects on Na,
K-ATPase and antimicrobial activities [100]. Agelasine M (255) exhibited potent activity against
Trypanosoma brucei [103], while agelines A (259) and B (260) (Figure 28) showed mild ichthyotoxins
and antimicrobial activities [104].
242 243 244
245 246 247
X
N
N
N
N
H
N
O
O
B
r
NH2
248 249 250
251 252 253 254
Figure 27. Chemical structures of compounds 232–241.
Nineteen non-bromine-containing ionic compounds have been isolated from unclassified
Agelas spp., including eleven agalasines (
242
–
252
) from Okinawa [
100
,
101
], two agelasines (
253
and
254
)
from Yap Island [
102
], four higher unsaturated 9-N-methyladeninium bicyclic diterpenoids (
255
–
258
)
from Papua New Guinea [
103
] and two quarternary 9-methyladenine salts of diterpenes agelines
(
259
and
260
) from Argulpelu Reef [
104
]. Compounds
242
–
245
displayed strong inhibitory effects on
Na, K-ATPase and antimicrobial activities [
100
]. Agelasine M (
255
) exhibited potent activity against
Trypanosoma brucei [
103
], while agelines A (
259
) and B (
260
) (Figure 28) showed mild ichthyotoxins and
antimicrobial activities [104].
Mar. Drugs 2017, 15, 351 19 of 29
241
Figure 27. Chemical structures of compounds 232–241.
Nineteen non-bromine-containing ionic compounds have been isolated from unclassified Agelas
spp., including eleven agalasines (242–252) from Okinawa [100,101], two agelasines (253 and 254)
from Yap Island [102], four higher unsaturated 9-N-methyladeninium bicyclic diterpenoids (255–258)
from Papua New Guinea [103] and two quarternary 9-methyladenine salts of diterpenes agelines (259
and 260) from Argulpelu Reef [104]. Compounds 242–245 displayed strong inhibitory effects on Na,
K-ATPase and antimicrobial activities [100]. Agelasine M (255) exhibited potent activity against
Trypanosoma brucei [103], while agelines A (259) and B (260) (Figure 28) showed mild ichthyotoxins
and antimicrobial activities [104].
242 243 244
245 246 247
X
N
N
N
N
H
N
O
O
B
r
NH2
248 249 250
251 252 253 254
Figure 28. Cont.

Mar. Drugs 2017,15, 351 20 of 29
Mar. Drugs 2017, 15, 351 20 of 29
255 256 257 258
259 260
Figure 28. Chemical structures of compounds 242–260.
2.20.2. Non-Ionic Compounds
Since 1983, 29 non-ionic brominated metabolites (261–289) have been found in some unclassified
Agelas spp. collected from the Okinawan Sea, the South China Sea, the Caribbean Sea, Papua New
Guinea and the Indian Ocean. Agesamides A (261) and B (262) [105], benzosceptrin C (263) [106],
nagelamide J (264) [107], nagelamide P (265), mukanadin E (266), mukanadin F (267) [92], nagelamide
I (268) and 2,2’-didebromonagelamide B (269) [108] were obtained from the Okinawan specimen.
Compound 264 had a cyclopentane ring fused to an amino imidazole ring and exhibited inhibitory
effect on S. aureus and C. neoformans with MIC values of 8.35 and 16.7 μg/mL, respectively.
Compounds 268 and 269 were inactive against murine lymphoma L1210 and human epidermoid
carcinoma KB cells in vitro. Chemical study of an unidentified Agelas spp. from the South China Sea
afforded ten new non-ionic bromopyrrole derivatives, longamides D–F (270–272), 3-oxethyl-4-[1-(4,5-
dibromopyrrole-2-yl)-formamido]-butanoic acid methyl ester (273), 2-oxethyl-3-[1-(4,5-
dibromopyrrole-2-yl)-formamido]-methyl propionate (274), 9-oxethyl-mukanadin F (275) [109],
hexazosceptrin (276), agelestes A (277) and B (278) and (9S, 10R, 9’S, 10’R)-nakamuric acid (279) [110].
Inspiringly, bioassay results revealed that (+)-270, (−)-271 and (+)-272 had significant antimicrobial
activity against C. albicans with MIC values of 80, 20 and 140 μM, respectively.
Monobromoisophakellin (280) was isolated from the Caribbean Agelas sp. and shown to possess
antifeedant activity against Thalassoma bifasciatum [111]. Chemical investigation of Agelas sponges
from Wewak and Indonesian sea respectively led to the isolation of two phakellin alkaloids (281,282)
and 5-bromophakelline (283) [112,113]. In addition, 2,3-dibromopyrrole (284) and 2,3-dibromo-5-
methoxymethylpyrrole (285) belonging to non-ionic bromopyrrole alkaloid were purified from the
marine sponge Agelas sp. [114]. Apart from alkaloids, four new brominated phospholipid fatty acids
(286–289) (Figure 29) were also detected in the Caribbean Agelas spp. [115].
261 262 263 264
Figure 28. Chemical structures of compounds 242–260.
2.20.2. Non-Ionic Compounds
Since 1983, 29 non-ionic brominated metabolites (
261
–
289
) have been found in some unclassified
Agelas spp. collected from the Okinawan Sea, the South China Sea, the Caribbean Sea, Papua
New Guinea and the Indian Ocean. Agesamides A (
261
) and B (
262
) [
105
], benzosceptrin C
(
263
) [
106
], nagelamide J (
264
) [
107
], nagelamide P (
265
), mukanadin E (
266
), mukanadin F
(
267
) [
92
], nagelamide I (
268
) and 2,2’-didebromonagelamide B (
269
) [
108
] were obtained from
the Okinawan specimen. Compound
264
had a cyclopentane ring fused to an amino imidazole
ring and exhibited inhibitory effect on S. aureus and C. neoformans with MIC values of 8.35 and
16.7
µ
g/mL, respectively. Compounds
268
and
269
were inactive against murine lymphoma L1210
and human epidermoid carcinoma KB cells
in vitro
. Chemical study of an unidentified Agelas spp.
from the South China Sea afforded ten new non-ionic bromopyrrole derivatives, longamides D–F
(
270
–
272
), 3-oxethyl-4-[1-(4,5-dibromopyrrole-2-yl)-formamido]-butanoic acid methyl ester (
273
),
2-oxethyl-3-[1-(4,5-dibromopyrrole-2-yl)-formamido]-methyl propionate (
274
), 9-oxethyl-mukanadin
F (
275
) [
109
], hexazosceptrin (
276
), agelestes A (
277
) and B (
278
) and (9S, 10R, 9’S, 10’R)-nakamuric
acid (
279
) [
110
]. Inspiringly, bioassay results revealed that (+)-
270
, (
−
)-
271
and (+)-
272
had
significant antimicrobial activity against C. albicans with MIC values of 80, 20 and 140
µ
M,
respectively. Monobromoisophakellin (
280
) was isolated from the Caribbean Agelas sp. and shown
to possess antifeedant activity against Thalassoma bifasciatum [
111
]. Chemical investigation of
Agelas sponges from Wewak and Indonesian sea respectively led to the isolation of two phakellin
alkaloids (
281
,
282
) and 5-bromophakelline (
283
) [
112
,
113
]. In addition, 2,3-dibromopyrrole (
284
)
and 2,3-dibromo-5-methoxymethylpyrrole (
285
) belonging to non-ionic bromopyrrole alkaloid were
purified from the marine sponge Agelas sp. [
114
]. Apart from alkaloids, four new brominated
phospholipid fatty acids (286–289) (Figure 29) were also detected in the Caribbean Agelas spp. [115].
Mar. Drugs 2017, 15, 351 20 of 29
255 256 257 258
259 260
Figure 28. Chemical structures of compounds 242–260.
2.20.2. Non-Ionic Compounds
Since 1983, 29 non-ionic brominated metabolites (261–289) have been found in some unclassified
Agelas spp. collected from the Okinawan Sea, the South China Sea, the Caribbean Sea, Papua New
Guinea and the Indian Ocean. Agesamides A (261) and B (262) [105], benzosceptrin C (263) [106],
nagelamide J (264) [107], nagelamide P (265), mukanadin E (266), mukanadin F (267) [92], nagelamide
I (268) and 2,2’-didebromonagelamide B (269) [108] were obtained from the Okinawan specimen.
Compound 264 had a cyclopentane ring fused to an amino imidazole ring and exhibited inhibitory
effect on S. aureus and C. neoformans with MIC values of 8.35 and 16.7 μg/mL, respectively.
Compounds 268 and 269 were inactive against murine lymphoma L1210 and human epidermoid
carcinoma KB cells in vitro. Chemical study of an unidentified Agelas spp. from the South China Sea
afforded ten new non-ionic bromopyrrole derivatives, longamides D–F (270–272), 3-oxethyl-4-[1-(4,5-
dibromopyrrole-2-yl)-formamido]-butanoic acid methyl ester (273), 2-oxethyl-3-[1-(4,5-
dibromopyrrole-2-yl)-formamido]-methyl propionate (274), 9-oxethyl-mukanadin F (275) [109],
hexazosceptrin (276), agelestes A (277) and B (278) and (9S, 10R, 9’S, 10’R)-nakamuric acid (279) [110].
Inspiringly, bioassay results revealed that (+)-270, (−)-271 and (+)-272 had significant antimicrobial
activity against C. albicans with MIC values of 80, 20 and 140 μM, respectively.
Monobromoisophakellin (280) was isolated from the Caribbean Agelas sp. and shown to possess
antifeedant activity against Thalassoma bifasciatum [111]. Chemical investigation of Agelas sponges
from Wewak and Indonesian sea respectively led to the isolation of two phakellin alkaloids (281,282)
and 5-bromophakelline (283) [112,113]. In addition, 2,3-dibromopyrrole (284) and 2,3-dibromo-5-
methoxymethylpyrrole (285) belonging to non-ionic bromopyrrole alkaloid were purified from the
marine sponge Agelas sp. [114]. Apart from alkaloids, four new brominated phospholipid fatty acids
(286–289) (Figure 29) were also detected in the Caribbean Agelas spp. [115].
261 262 263 264
Figure 29. Cont.

Mar. Drugs 2017,15, 351 21 of 29
Mar. Drugs 2017, 15, 351 21 of 29
H
N
N
H
N
H
N
O
Br
Br
O
NH2
N
NH
H
N
O
N
H
Br
NH2
265 266 267
268 269 (+)-270 (−)-270
(+)-271 (−)-271 (+)-272 (−)-272 (±)-273
(±)-274 275 276 277: R = H
278: R = CH3
279 280 281: R = Br
282: R = H 283
284 285
286: n= 13
287: n = 14
288: n = 12
289: n = 13
Figure 29. Chemical structures of compounds 261–289.
Only two non-ionic metabolites without bromine, agelasidine A (290) and agelagalastatin (291)
(Figure 30), have been detected in two unclassified specimens of Agelas sp. Compound 290 was the
first marine natural substance possessing sulfone and guanidine units purified from the Okinawan
sample and showed antispasmodic activity [116]. It was notable that compound 24 from the
Caribbean A. clathrodes is the optimal isomer of 290. Compound 291 was a new GSL derived from
Agelas sp. collected in Papua New Guinea and found to exhibit significant in vitro activity against
human cancer cell lines with lung NCI-H460 GI50 0.77 μg/mL to ovary OVCAR-3 GI50 2.8 μg/mL [117].
290 291: n= 21 or 20, m= 10 or 11
Figure 30. Chemical structures of compounds 290 and 291.
Figure 29. Chemical structures of compounds 261–289.
Only two non-ionic metabolites without bromine, agelasidine A (
290
) and agelagalastatin (
291
)
(Figure 30), have been detected in two unclassified specimens of Agelas sp. Compound
290
was the
first marine natural substance possessing sulfone and guanidine units purified from the Okinawan
sample and showed antispasmodic activity [
116
]. It was notable that compound
24
from the Caribbean
A. clathrodes is the optimal isomer of
290
. Compound
291
was a new GSL derived from Agelas sp.
collected in Papua New Guinea and found to exhibit significant
in vitro
activity against human cancer
cell lines with lung NCI-H460 GI50 0.77 µg/mL to ovary OVCAR-3 GI50 2.8 µg/mL [117].
Mar. Drugs 2017, 15, 351 21 of 29
H
N
N
H
N
H
N
O
Br
Br
O
NH2
N
NH
H
N
O
N
H
Br
NH2
265 266 267
268 269 (+)-270 (−)-270
(+)-271 (−)-271 (+)-272 (−)-272 (±)-273
(±)-274 275 276 277: R = H
278: R = CH3
279 280 281: R = Br
282: R = H 283
284 285
286: n= 13
287: n = 14
288: n = 12
289: n = 13
Figure 29. Chemical structures of compounds 261–289.
Only two non-ionic metabolites without bromine, agelasidine A (290) and agelagalastatin (291)
(Figure 30), have been detected in two unclassified specimens of Agelas sp. Compound 290 was the
first marine natural substance possessing sulfone and guanidine units purified from the Okinawan
sample and showed antispasmodic activity [116]. It was notable that compound 24 from the
Caribbean A. clathrodes is the optimal isomer of 290. Compound 291 was a new GSL derived from
Agelas sp. collected in Papua New Guinea and found to exhibit significant in vitro activity against
human cancer cell lines with lung NCI-H460 GI50 0.77 μg/mL to ovary OVCAR-3 GI50 2.8 μg/mL [117].
290 291: n= 21 or 20, m= 10 or 11
Figure 30. Chemical structures of compounds 290 and 291.
Figure 30. Chemical structures of compounds 290 and 291.

Mar. Drugs 2017,15, 351 22 of 29
Table 1. Agelas-derived secondary metabolites.
Organism Locality Secondary Metabolite References
Agelas axifera the Republic of Palau axistatins 1 (1), 2 (2), 3 (3) [4]
A. cerebrum Caribbean 5-bromopyrrole-2-carboxylic acid (4), 4-bromopyrrole-2-carboxylic acid (5), 3,4-bromopyrrole-2-carboxylic acid (6) [6]
A. ceylonica the Mandapam coast hanishin (7) [7]
A. citrina Caribbean (−)-agelasidine E (8), (−)-agelasidine F (9), agelasine N (10), citrinamines A–D (11–14), N-methylagelongine (15) [9,10]
A. clathrodes
Grand Bahamas Island clarhamnoside (16) [11]
Caribbean clathrosides A–C (17–19), isoclathrosides A–C (20–22), glycosphingolipid (23), (−)-agelasidine A (24), (−)-agelasidine C (25),
(−)-agelasidine D (26), clathramides A (27) and B (28), clathrodin (29), dispacamides A–D (31–34)[12–17,19,20]
South China Sea 3,3-bis(uracil-l-yl)-propan-1-aminium (30) [18]
A. conifera
Florida Keys bromosceptrin (35) [21]
Belize debromosceptrin (36) [22]
Caribbean bromopyrroles (37–43), glycosphingolipid (45) [23,24,26]
Puerto Rico coniferoside (44) [25]
A. dendromorpha
the Coral Sea agelastatin A (46) [27]
the New Caledonia agelastatins E (47) and F (48) [28]
A. dispar
Caribbean dispyrin (49), dibromoagelaspongin methyl ether (50), longamide B (51), clathramides C (52) and D (53),
aminozooanemonin (55), pyridinebetaines A (56) and B (57)[29,30,32]
San Salvador Island triglycosylceramide (54) [31]
agelasine (58) [33]
A. gracilis South Japan gracilioethers A–C (59–61) [34]
A. linnaei Indonesia brominated pyrrole derivatives (62–72) [35]
A. longissima Caribbean agelongine (73), 3,7-dimethylisoguanine (74), longamide (75), glycosphingolipids (76 and 77) [36–39]
A. mauritiana
South China Sea
(−)-80-oxo-agelasine B (78), (+)-agelasine B (79), (+)-8’-oxo-agelasine C (80), agelasine V (81), (+)-8’-oxo-agelasine E (82),
8’-oxo-agelasine D (83), ageloxime B (84), (+)-2-oxo-agelasidine C (85), 4-bromo-N-(butoxymethyl)-1H-pyrrole-
2-carboxamide (95)
[40,41]
Enewetak agelasimine A (86), agelasimine B (87), purino-diterpene (88), 5-debromomidpacamide (96) [42,43,47]
Pohnpei epi-agelasine C (89) [44]
Solomon Islands agelasines J (90), K (91) and L (92), debromodispacamides B (93) and D (94) [45,46]
Fiji mauritamide A (97) [48]
Hachijo-jima Island mauritiamine (98) [49]
the Pacific sea ebromokeramadine (99), benzosceptrin A (100), nagelamides S (101) and T (102) [50,51]
Okinawa agelasphins (103–110) [52,53]
Kagoshima isotedanin (111), isoclathriaxanthin (112) [54]

Mar. Drugs 2017,15, 351 23 of 29
Table 1. Cont.
Organism Locality Secondary Metabolite References
A. nakamurai
Okinawa agelasidines B (113) and C (114), nakamurols A–D (115–118), 2-oxoagelasiines A (119) and F (120),
10-hydro-9-hydroxyagelasine F (121), agelasines E (122) and F (123), slagenins A–C (140–142), mukanadins A–C (143–145)[55–58,65,66]
Indonesia (−)-agelasine D (124), (−)-ageloxime D (125) [35]
South China Sea isoagelasine C (126), isoagelasidine B (127) [59]
Papua New Guinea diterpene (128), bromopyrrole alkaloids (134 and 135) [60]
South China Sea nakamurines A–E (129–133) [59,61]
Japan ageladine A (136) [63]
Indonesia longamide C (137) [35]
Indopacific nakamuric acid (138) and its methyl ester (139) [64]
A. nemoechinata
South China Sea nemoechines A–D (146–149), nemoechioxide A (150), nemoechines F (151) and G (152) [67,68]
Okinawa oxysceptrin (153) [69]
A. oroides
the Great Barrier Reef
agelorin A (
154
), agelorin B (
155
), 11-epi-fistularin-3 (
156
), pyrrole-2-carboxamide (
157
), N-formyl-pymole-2-carboxamid (
158
),
2,4,6,6-tetramethyl-3(6H)-pyridone (159)[70–72]
Mediterranea Sea cyclooroidin (160) and taurodispacamide A (161), monobromoagelaspongin (162), (−)-equinobetaine B (163) [73,74]
Naples bromopyrroles (164–168), sterols (169–183) [75,76]
the Northern Aegean Sea
3-amino-1-(2-aminoimidazoyl)-prop-1-ene (184), taurine (185), fatty acid mixtures (186–189) [77]
A. sceptrum
Jamaica 26-nor-25-isopropyl-ergosta-5,7,22 E-trien-3β-ol (190) [78]
Belize sceptrin (191) [79]
Bahamas 150-oxoadenosceptrin (192), decarboxyagelamadin C (193) [80]
A. schmidtii Caribbean monohydroxyl sterols (194–196) [81]
West Indies α-carotene (197), isorenieratene (198), trikentriorhodin (199) and zeaxanthin (200) [82]
A. sventres Caribbean sventrin (201) [83]
A. wiedenmayeri
Florida Keys 4-bromopyrrole-2-carboxyhomoarginine (202) [84]
Unclassified
Agelas sp.
No record dibromoagelaspongin hydrochloride (203) [85]
Okinawa
agelamadins A (204) and B (205), agelamadins C–F (206–209), tauroacidin E (210), nagelamides A–H (211–218), nagelamides
K–O (219–223), nagelamides Q (224) and R (225), nagelamides U–Z (226–231), 2-bromokeramadine (232),
2-bromo-9,10-dihydrokeramadine (
233
), tauroacidins C (
234
) and D (
235
), mukanadin G (
236
), 2-debromonagelamides U (
237
)
and G (238), 2-debromonagelamide P (239), keramadine (240), agelasine G (241), agelasines A–D (242–245), agelasines
O–U (246–252), agesamides A (261) and B (262), benzosceptrin C (263), nagelamides J (264) and P (265), mukanadins E (266)
and F (267), nagelamide I (268), 2,2’-didebromonagelamide B (269), agelasidine A (290)
[86–101,105–108,116]
Yap Island agelasines H (253) and I (254) [102]
Papua New Guinea agelasine M (255), 2-oxo-agelasine B (256), gelasines A (257) and B (258), (−)-7-N-methyldibromophakellin (281),
(−)-7-N-methylmonobromophakellin (282), agelagalastatin (291)[103,112,117]
Palau Island agelines A (259) and B (260) [104]
South China Sea
longamides D–F (270–272), 3-oxethyl-4-[1-(4,5-dibromopyrrole-2-yl)-formamido]-butanoic acid methyl ester (273),
2-oxethyl-3-[1-(4,5-dibromopyrrole-2-yl)-formamido]-methyl propionate (274), 9-oxethyl-mukanadin F (275),
hexazosceptrin (276), agelestes A (277) and B (278) and (9S,10R,9’S,10’R)-nakamuric acid (279)
[109,110]
Caribbean Sea monobromoisophakellin (280), brominated phospholipid fatty acids (286–289) [111,115]
Indonesia 5-bromophakelline (283) [113]
No record 2,3-dibromopyrrole (284) and 2,3-dibromo-5-methoxymethylpyrrole (285) [114]

Mar. Drugs 2017,15, 351 24 of 29
3. Conclusions
Many efforts have been devoted to implement chemical investigation of Agelas sponges during
the past 47 years, from 1971 to 2017. Meanwhile, great achievements have been made on chemical
diversity of their secondary metabolites. Agelas sponges are widely distributed in the ocean, especially
in the Okinawa Sea, the Caribbean Sea and the South China Sea. Deep ocean technologies for specimen
collecting should be used to search more unknown species of Agelas sponges, such as manned and
remotely operated underwater vehicles. Advanced separation methodologies should be deployed
to explore more bioactive secondary metabolites of these sponges, such as UPLC-MS, metabolomics
approach [
74
]. Furthermore, special attention should be paid to symbiotic microorganisms of
Agelas sponges owing to the fact that a great number of therapeutic agents of marine sponges are
biosynthesized by their symbiotic microbes [
118
]. By a combination of gene engineering, pathway
reconstructing, enzyme engineering and metabolic networks, these microbes can be modified to
produce more novel chemicals containing enhanced structural features or a large quantity of known
valuable compounds for pharmaceutical production.
Acknowledgments:
Financial support from the National Natural Science Foundation of China (Nos. 41776139
and 81773628), the Zhejiang Provincial Natural Science Foundation of China (LY16H300007 and LY16H300008)
and the US National Cancer Institute grants (R01 CA 047135) are gratefully acknowledged.
Author Contributions:
H.Z. conceived and wrote the paper; M.D. and J.C. searched and collected all references;
and H.W., K.T. and P.C. made suggestive revision and provided eight photos of Agelas sponges.
Conflicts of Interest: The authors declare no conflict of interest.
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