Marine Fungal Indole Alkaloids
Prenylated Indole Alkaloids
Prenylated indole alkaloids are hybrid natural products with indole rings and isoprenoid
fragments derived from tryptophan and prenyl diphosphates or their precursors, displaying
a high structural diversity, especially the prenylated tryptophan diketopiperazine
skeleton (as shown in [Figs. 2 ], [3 ], [4 ], [5 ], [6 ], [7 ], [8 ], [9 ], [10 ]).[17 ] These alkaloids are widely discovered from terrestrial and marine fungi, mainly
focusing on the spectra of Aspergillus and Penicillium , with a wide spectrum of biological and pharmacological activities such as insecticidal,
antiparasitic, cytotoxic, and antimicrobial effects.[17 ]
[18 ]
[19 ]
Fig. 2 Chemical structures of prenylated indole alkaloids 1 –29 and 46 –49 .
Fig. 3 Chemical structures of prenylated indole alkaloids 30 –45 and 50 .
Fig. 4 Chemical structures of prenylated indole alkaloids 51–70 .
Fig. 5 Chemical structures of prenylated indole alkaloids 71–89 .
Fig. 6 Chemical structures of prenylated indole alkaloids 90–105 .
Fig. 7 Chemical structures of prenylated indole alkaloids 110–135 .
Fig. 8 Chemical structures of prenylated indole alkaloids 136–161 .
Fig. 9 Chemical structures of prenylated indole alkaloids 162–183 .
Fig. 10 Chemical structures of prenylated indole alkaloids 184–195 .
Notoamide/stephacidin-type alkaloids with a pyranoindole ring are one of the most
typical indole alkaloids. Notoamides A–D (1 –4 ) are four new doubly prenylated indole alkaloids, first isolated from the marine
fungus Aspergillus sp., which was derived from the common mussel Mytilus edulis ([Fig. 2 ]). Notoamides A–C (1 –3 ) with a dihydroxypyrano-2-oxindole ring system exhibited moderate cytotoxic effect
toward HeLa and L1210 cells.[20 ]
Notoamide E (5 ) ([Fig. 2 ]) was found in a marine-derived fungus Aspergillus sp., being considered as a key precursor of prenylated alkaloids in the biosynthesis
process.[21 ]
[22 ]
One new notoamide/stephacidin-type alkaloid, 21-hydroxystephacidin (6 ) ([Fig. 2 ]), was harbored from the culture of a marine fungus Aspergillus ostianus .[23 ] Notoamides F–K (7 –12 ) ([Fig. 2 ]) were harbored from a marine-derived fungus strain Aspergillus sp. Notoamide I (10 ) exhibited weak cytotoxic effect toward HeLa cells (IC50 = 21 μg/mL).[24 ]
[25 ]
Four notoamide/stephacidin type analogues, named antipodal (−)-versicolamide B (13 ) and notoamides L–N (14 –16 ) ([Fig. 2 ]), were produced by a marine-derived Aspergillus sp. Compound 14 is the first prenylated indole alkaloid presenting 25 carbons. Compound 15 is probably the precursor in the biosynthesis of the bicyclo[2.2.2]diazaoctane ring
system.[26 ]
Notoamides O–Q (17 –19 ) ([Fig. 2 ]) were isolated from a culture medium of marine-derived Aspergillus sp. Compound 17 contained a unique hemiacetal/hemiaminal ether moiety, which was unpresented in these
groups of prenylated indole alkaloids.[27 ]
[28 ]
17-Epi -notoamides Q (20 ) and M (21 ) ([Fig. 2 ]) were two new prenylated indole alkaloids, which were obtained from a marine-derived
fungus Aspergillus sp.[29 ]
[30 ]
Four new notoamide-type alkaloids, notoamides W–Z (22 –25 ), as well as seven known analogues, notoamide F (7 ), notoamide G (8 ), 19-epi -notoamide R (26 ), notoamide I (10 ), stephacidin A (27 ), avrainvillamide (28 ), and a dimer of notoamide-type alkaloid stephacidin B (29 ), were discovered from a coral-associated fungus Aspergillus ochraceus LZDX-32–15 ([Fig. 2 ]). Compounds 8 , 25 , and 26 exhibited potent inhibitory activity toward a panel of HCC (hepatocellular carcinoma)
cell lines with IC50 values in the range of 0.42 to 3.39 μmol/L. Notoamide G (8 ) inhibited the viability of HepG2 and Huh-7 cells via apoptosis and autophagy way
through a P38/JNK signaling pathway.[31 ]
Six new prenylated indole alkaloids with diketopiperazine ring, asperthrins A–F (30 –35 ), were obtained from marine fungi Aspergillus sp. YJ191021 ([Fig. 3 ]). Asperthrin A (30 ) showed moderate inhibitory activities against three agricultural pathogenic microorganisms
and significant antiinflammatory effect with IC50 value of 1.46 ± 0.21 μmol/L in the model of human monocyte cell line (THP-1) induced
by Propionibacterium acnes .[32 ]
Paraherquamide J (36 ) ([Fig. 3 ]) is a new prenylated indole alkaloid, obtained from the fungus Penicillium janthinellum HK1–6, which was derived from mangrove rhizosphere soil. This alkaloid showed inactive
effect in the assay of topoisomerase I (topo I) inhibitory, antibacterial, and lethality
against brine shrimp Artemia salina .[33 ]
Three new prenylated indole alkaloids waikikiamides A–C (37 –39 ) ([Fig. 3 ]) with a complex diketopiperazine moiety were produced by the marine fungus Aspergillus sp. FM242. Compounds 37 and 38 contain an unprecedented indole alkaloid skeleton featuring with a hendecacyclic[34 ] ring system. Compound 39 is the first unique heterodimer of two notoamide derivatives joined by an N − O − C
bridge. Compounds 37 and 39 showed significant antiproliferative activity against four cancer cell lines, HT1080,
PC3, Jurkat, and A2780, with IC50 values in the range of 0.56 to 1.86 μmol/L.[34 ]
Di -6-hydroxydeoxybrevianamide E (40 ) and dinotoamide J (41 ) ([Fig. 3 ]), two new homodimers, represent new examples of prenylated indole alkaloid, and
were discovered from Aspergillus austroafricanus Y32–2. They exhibited proangiogenic effect in a zebrafish model of vascular injury
induced by PTK787.[35 ]
Three new alkaloids, spirotryprostatin G (42 ), and cyclotryprostatins F and G (43 and 44 ) ([Fig. 3 ]), were isolated from the marine-derived fungal strain Penicillium brasilianum HBU-136. Compound 42 exhibited potent cytotoxic effect against the HL-60 cell line (IC50 = 6.0 μmol/L). Compounds 43 and 44 showed cytotoxicity toward the MCF-7 cell line with IC50 values of 7.6 and 10.8 μmol/L, respectively.[36 ]
17-Hydroxynotoamide D (45 ), 17-O -ethylnotoamide M (46 ), 10-O -acetylsclerotiamide (47 ), 10-O -ethylsclerotiamide (48 ), and 10-O -ethylnotoamide R (49 ) ([Figs. 1 ] and [3 ]) are five new prenylated indole alkaloids, being obtained from two marine-derived
fungi Aspergillus sulphureus KMM 4640 and Isaria felina KMM 4639 by co-culture method. Compound 46 showed inhibitory effect against the human prostate cancer cells 22Rv1 at a concentration
of 10 μmol/L.[37 ]
Asperversiamides A–H (50 –57 ) ([Figs. 3 ] and [4 ]), eight new linearly fused prenylated indole alkaloids with a rare pyrano[3,2-f ]indole moiety, were found from the marine-derived fungus Aspergillus versicolor . Compound 56 showed potent inhibitory activity toward iNOS with an IC50 value of 5.39 μmol/L in the antiinflammatory test.[38 ]
Three new indole diketopiperazine alkaloids, asperochramides A–C (58 –60 ) ([Fig. 4 ]), were obtained from a marine fungus A. ochraceus . Compound 58 exhibited significant antiinflammatory effects against the lipopolysaccharide (LPS)-stimulated
RAW 264.7 cells.[39 ]
Three new prenylated diketopiperazine indole alkaloids eurotiumins A–C (61 –63 ) and one new prenylated indole alkaloid eurotiumin D (64 ) ([Fig. 4 ]) were produced by the marine-derived fungus Eurotium sp. SCSIO F452. Compounds 61 and 62 are a pair of diastereomers both with a hexahydropyrrolo[2,3-b ]indole skeleton. Compound 63 exhibited significant radical scavenging effects toward DPPH with IC50 values of 13 μmol/L.[40 ]
Taichunamide H (65 ) ([Fig. 4 ]), a new indole alkaloid with a fused-imine-containing pyrrole ring, was isolated
from the fungus A. versicolor . The resonance at 190.4 ppm was assigned as the imine carbon in the molecule by using
X-ray diffraction, and the structure of taichunamide A was also revised. However,
compound 65 showed no antifungal and cytotoxic activity.[41 ]
Mangrovamides D–G (66 –69 ) ([Fig. 4 ]) are four new prenylated indole alkaloids from the mangrove sediment-derived fungus
Penicillium sp. SCSIO041218 with no antiallergic effect in vitro assay.[42 ]
SF5280–415 (70 ) ([Fig. 4 ]), a new bispyrrolidinoindoline diketopiperazine alkaloid, and a known analogue SF5280–451
(71 ) ([Fig. 5 ]) were obtained from the marine-derived fungus Aspergillus sp. SF-5280. Compounds 70 and 71 displayed potent inhibitory effect toward PTP1B with IC50 values of 14.2 ± 0.7 and 12.9 ± 0.7 μmol/L, respectively.[43 ]
Two new prenylated indole derivatives brevicompanine B (72 ) and verrucofortine (73 ) ([Fig. 5 ]) were found from a marine fungus Penicillium sp. NH-SL, and compound 73 showed potent cytotoxicity toward Hepa 1c1c7 cells.[44 ]
Four new indole diketopiperazine alkaloids, N -(40-hydroxyprenyl)-cyclo(alanyltryptophyl) (74 ), isovariecolorin I (75 ), 30-hydroxyechinulin (76 ), and 29-hydroxyechinulin (77 ) ([Fig. 5 ]), were obtained from the marine-derived fungus Eurotium cristatum EN-220. Compound 75 exhibited lethal effect against brine shrimp with the LD50 value of 19.4 μg/mL.[45 ]
Two new prenylated indole derivatives, named penicimutamides D and E (78 and 79 ) ([Fig. 5 ]), were produced by the mutant fungus strain of Penicillium purpurogenum G59 derived from marine through the stimulation of diethyl sulfate. These two derivatives
displayed weak suppressive effect toward cancer cell lines.[46 ]
4,3-Hydroxysperadine A (80 ) ([Fig. 5 ]), a new cyclopiazonic acid congener, was isolated from a marine sponge-associated
fungus Aspergillus oryzae HMP-F28 by a bioassay-guided separation.[47 ]
A known alkaloid, meleagrin (81 ) ([Fig. 5 ]), was rediscovered from a marine-derived fungus Emericella dentata Nq45. Its absolute structure was determined by the single-crystal X-ray diffraction
method. This compound exhibited potent cytotoxic activity toward KB-3–1 cell line
(the human cervix carcinoma) and KB-V1, a multidrug resistant sub-clone of KB-3–1,
with the IC50 values of 3.07 and 6.07 μmol/L, respectively. It also showed potent antibacterial
effect against Staphylococcus aureus (minimum inhibitory concentration [MIC] = 0.25 mg/mL).[48 ]
Misszrtine A (82 ) ([Fig. 5 ]) is a novel prenylated indole alkaloid possessing a N -isopentenyl fragment, which was the first example of tryptophan methyl ester in this
kind of alkaloids. This molecule, obtained from a marine sponge-derived fungus Aspergillus sp. SCSIO XWS03F03, displayed a significant antagonistic effect against HL60 and
LNCaP cell lines, with the IC50 values of 3.1 and 4.9 μmol/L, respectively.[49 ]
Cycloexpansamines A (83 ) and B (84 ) ([Fig. 5 ]), two novel prenylated alkaloids with a spiroindolinone moiety, were produced by
a marine fungus strain Penicillium sp. SF-5292.[50 ]
Penioxamide A (85 ) ([Fig. 5 ]), a new prenylated indole congener with a piperidine moiety and a unique antirelative
configuration of the bicyclo[2.2.2]diazaoctane ring system, was afforded from the
culture medium of fungus Penicillium oxalicum EN-201. Compound 85 exhibited pronounced lethality effect against brine shrimp (LD50 = 5.6 μmol/L).[51 ]
Two diketopiperazine indole alkaloids, named fumitremorgin C (86 ) and 12,13-dihydroxy-fumitremorgin C (87 ) ([Fig. 5 ]), were obtained from the culture of a fungus Aspergillus sp. BRF 030, displaying cytotoxic activity toward the HCT-116 cell line (IC50 = 15.17 and 4.53 μmol/L, respectively).[52 ]
A new diketopiperazine indole derivative, amauromine (88 ) ([Fig. 5 ]), was isolated from the marine fungus Auxarthron reticulatum derived from marine sponge. This compound was considered to be a remarkable lead
molecule for the research of selective antagonists of GPR18, for its potent suppressive
effect toward GPR18 with the IC50 value of 3.74 μmol/L.[53 ]
Spirotryprostatin K (89 ) ([Fig. 5 ]) is a new diketopiperazine alkaloid, obtained from an extract of the marine fungus
Aspergillus fumigatus .[54 ]
A new prenylated natural alkaloid takakiamide (90 ) ([Fig. 6 ]) was obtained from the culture medium of the algicolous-derived fungus Neosartorya takakii KUFC 7898. However, this compound showed no antibacterial effect and no quorum sensing
inhibitory activity.[55 ]
Rubrumazines A–C (91 –93 ) ([Fig. 6 ]) are three new isoechinulin-type indole diketopiperazine alkaloids bearing an oxygenated
prenyl ether segment and produced by a mangrove-derived fungus Eurotium rubrum MA-150. Compounds 92 exhibited remarkable lethality toward brine shrimp with the LD50 values of 2.43 μmol/L.[56 ]
Rubrumlines A–O (94 − 108 ) as well as its known analogue neoechinulin B (109 ) are a series of indole diketopiperazine alkaloids obtained from the extract of the
culture of the marine fungus E. rubrum ([Fig. 6 ]). Neoechinulin B (109 ) showed significant inhibitory activity toward H1N1 virus in MDCK cells, and a class
of influenza virus strains comprising amantadine- and oseltamivir-resistant ones,
which were isolated from clinical samples.[57 ]
Dihydrocarneamide A (110 ) and iso-notoamide B (111 ) ([Fig. 7 ]), two new prenylated indole analogues with the rare fused dimethyldihydropyran ring
in the indole moiety by C-5 prenylation, are produced by the culture of the marine
fungus Paecilomyces variotii EN-291. However, these two alkaloids represent weak cytotoxic effect toward the NCI-H460
cell line.[58 ]
Cladosporin A (112) and cladosporin B (113 ) ([Fig. 7 ]), two new sulfur-containing diketopiperazine indole derivatives, are harbored from
a culture of fungus Cladosporium sp. derived from marine. These two compounds show moderate cytotoxicity against HepG2
cell line (IC50 = 21 and 48 μg/mL).[59 ]
Penipalines A and B (114 and 115 ), two new β -carbolines, and penipaline C (116 ), one new indole carbaldehyde congener, were afforded from the culture of the deep-sea-sediment
fungus Penicillium paneum SD-44 ([Fig. 7 ]). Compounds 115 and 116 exhibited significant cytotoxicity on A-549 and HCT-116 cell lines.[60 ]
One new diketomorpholine derivative shornephine A (117 ) and a new prenylated indole 15b-β -methoxy-5-N -acetyladreemin (118 ) were yielded from a marine sediment-derived Aspergillus sp. CMB-M081F ([Fig. 7 ]). Compound 117 exhibited significant inhibitory activity against drug efflux mediated by P-glycoprotein
in human multidrug-resistant colon cancer cells at the concentration of 20 μmol/L.[61 ]
Versicamides A–H (119 –126 ) ([Fig. 7 ]), eight new prenylated alkaloids, were produced by the marine fungus A. versicolor HDN08–60. Compound 126 presented moderate suppressive effect on HL-60 cells (IC50 = 8.7 μmol/L), and it showed selective inhibitory function to PTK by further research
of target screening.[62 ]
Speradine F (127 ), a new alkaloid with a rare hexacyclic oxindole ring system, and two new alkaloids
bearing a tetracyclic oxindole moiety, speradines G (128 ) and H (129 ), were obtained from a strain of the marine fungus A. oryzae ([Fig. 7 ]). Unfortunately, these compounds displayed weak cytotoxic function toward the HeLa,
HL-60, and K562 cell lines.[63 ]
Three new indole diketopiperazine peroxides, 24-hydroxyverruculogen (130 ), 26-hydroxyverruculogen (131 ), and 13-O -prenyl-26-hydroxyverruculogen (132 ), were produced by the fungus Penicillium brefeldianum SD-273 isolated from marine sediment ([Fig. 7 ]). Compound 132 exhibited remarkable brine shrimp lethal effect toward A. salina (LD50 = 9.44 μmol/L).[64 ]
A prenylated indole, fumigaclavine C (133 ) ([Fig. 7 ]), was obtained from a marine-derived fungus A. fumigatus . This compound induced apoptosis in MCF-7 cells via PI3/Akt and NF-κB signaling,
resulting in activating the mitochondrial cell death pathway.[65 ]
Neoechinulins A (134 ) and B (135 ) ([Fig. 7 ]) are two diketopiperazine indole alkaloids which were discovered and identified
from the marine fungus Eurotium sp. SF-5989. Compounds 134 exhibited antiinflammatory activity by inhibiting the NF-κB and p38 MAPK pathways
in LPS-stimulated RAW264.7 macrophages.[66 ]
Brocaeloid C (136 ) ([Fig. 8 ]), a new indole alkaloid possessing a C-2 reversed prenylated segment, was harbored
from the cultures of Penicillium brocae MA-192, a marine fungus isolated from the fresh leaves of the mangrove Avicennia marina .[67 ]
6-Epi -stephacidin A (137 ), N -hydroxy-6-epi -stephacidin A (138 ), and 6-epi -avrainvillamide (139 ) ([Fig. 8 ]), prenylated alkaloids bearing a unique anti-bi cyclo-[2.2.2]diazaoctane core structure,
were obtained from the cultures of marine fungus Aspergillus taichungensis . (+)-Versicolamides B and C (140 and 141 ) with a spiro-center, as well as six derivatives (142 − 147 ), were harbored as conversion products of compound 138 through a photo-induced reaction ([Fig. 8 ]). Compounds 138 and 139 displayed remarkable cytotoxic effect toward two cell lines, with IC50 values of 3.02 and 1.92 μmol/L against A549 cells, 4.45 and 1.88 μmol/L against HL-60
cells, respectively.[68 ]
An indole alkaloid, named neoechinulin A (148 ) ([Fig. 8 ]), which was produced by a marine fungus Microsporum sp., exhibited inhibitory effect toward the microglia activation induced by amyloid-β
oligomer, and the protection of inflammation-mediated toxicity in PC-12 cells, suggesting
its potential to be developed as a protective agent for neuroinflammation associated
with Alzheimer's disease. Compound 148 also showed an effect of inducing apoptosis in HeLa cells in another biotest.[69 ]
[70 ]
Carneamides A–C (149 –151 ) ([Fig. 8 ]) are three prenylated indole alkaloids that are afforded from the fungus Aspergillus carneus KMM 4638 derived from marine environment. However, these compounds showed no in vitro antimicrobial and cytotoxic effects.[71 ]
Cristatumins A–D (152 –155 ) ([Fig. 8 ]), four new indole analogues, were obtained and identified from the culture of the
marine alga endophytic fungus E. cristatum EN-220. Compound 152 produced antibacterial effect both toward Escherichia coli and S. aureus .[72 ]
Waikialoid A (156 ) ([Fig. 8 ]), a new dimer of prenylated indole derivative, is produced by a strain of marine
fungus Aspergillus sp. This molecule exhibits potent inhibitory activity against the biofilm formation
of Candida albicans (IC50 = 1.4 μmol/L). And waikialoid A (156 ) displayed the potential to be developed as a promising lead for the biofilm inhibitors
in combination with antibiotics for this metabolite, and showed no cytotoxicity toward
fungi or human cells (200 μmol/L).[73 ]
Cyclotryprostatin E (157 ) ([Fig. 8 ]), a new indole diketopiperazine alkaloid, was discovered from the strain of marine
fungus Aspergillus sydowii SCSIO 00305, which was separated from a healthy tissue of gorgonian coral Verrucella umbraculum .[74 ]
Tryptoquivalines P and Q (158 and 159 ) ([Fig. 8 ]) are two new indole alkaloids which were produced by a marine-derived fungal strain
Neosartorya sp. HN-M-3.[75 ]
Two new prenylated indole alkaloids, identified as 2-(3,3-dimethylprop-1-ene)-costaclavine
(160 ) and 2-(3,3-dimethylprop-1-ene)-epicostaclavine (161 ) ([Fig. 8 ]), had been obtained from the culture of marine fungal strain A. fumigatus . Compounds 160 and 161 exhibited weak cytotoxicity against P388 cell lines.[76 ]
Two novel chlorinated prenylated indole alkaloids, (−)-spiromalbramide (162 ) and (+)-isomalbrancheamide B (163 ), and two new brominated derivatives, (+)-malbrancheamide C (164 ) and (+)-isomalbrancheamide C (165 ) ([Fig. 9 ]), were discovered from an invertebrate-derived fungal strain Malbranchea graminicola assisted by a direct analysis in real time mass spectrometry technique.[77 ]
A prenylated indole alkaloid, neoechinulin A (166 ) ([Fig. 9 ]), was produced by a marine fungus, and exhibited a protected effect toward PC12
cells against the cytotoxicity of 1-methyl-4-phenylpyridinium (MPP+ ) and rotenone, two neurotoxins inducing Parkinsonian.[78 ]
7-O -Methylvariecolortide A (167 ) ([Fig. 9 ]), a new alkaloid with spirocyclic diketopiperazine ring, was produced by the cultures
of fungal strain E. rubrum derived from the stems of mangrove Hibiscus tiliaceus .[79 ]
Compound (168 ), spirotryprostatins C–E (169 –171 ), fumitremorgin B derivatives 172 and 173 , and 13-oxoverruculogen (174 ) ([Fig. 9 ]) were seven new prenylated indole diketopiperazine alkaloids, which were obtained
and identified from the marine fungus A. fumigatus isolated from holothurian. Compounds 171 –173 exhibited better selectivity toward MOLT-4, HL-60, and A549 than toward other compounds.[80 ]
Three new prenylated indole alkaloids with an oxaspiro[4.4]lactam core ring system,
6-methoxyspirotryprostatin B (175 ), 18-oxotryprostatin A (176 ), and 14-hydroxyterezine D (177 ), were discovered from the cultures of a marine-derived fungus A. sydowii PFW1–13 ([Fig. 9 ]). Compounds 175 –177 showed significant cytotoxic effect toward the A549 cell line (IC50 = 8.29, 1.28, and 7.31 μmol/L, respectively). Compound 175 also exhibited weak inhibitory function to HL-60 cells (IC50 = 9.71 μmol/L). Compounds 176 and 177 produced potent antimicrobial effect toward Bacillus subtilis , E. coli , and Micrococcus lysodeikticus (MICs = 14.97, 3.74, and 7.49 μmol/L for 176 ; MICs = 5.33, 10.65, and 10.65 μmol/L for 177 ).[81 ]
Shearinines D − F (178 –180 ) ([Fig. 9 ]), three new prenylated indole alkaloids, were yielded from the culture of marine
fungal strain P. janthinellum Biourge. Compounds 178 and 179 could induce apoptosis in HL-60 cells, and 179 also exhibited inhibitory activity against EGF-induced malignant transformation in
JB6 P+ Cl 41 cells.[82 ]
Two new pentacyclic indolinone alkaloids, named citrinadins A and B (181 and 182 ), as well as 181 's known derivative compound 183 ([Fig. 9 ]), were obtained from the marine red alga-derived fungal strain of Penicillium citrinum . Compound 181 exhibited growth-inhibitory effect against L1210 and KB cells (IC50 = 6.2 and 10 μg/mL); compound 182 displayed modest cytotoxic activity toward L1210 cells (IC50 =10 μg/mL).[83 ]
[84 ] Lep F (184 ) and Lep C (185 ) ([Fig. 10 ]), two prenylated bisindole alkaloids produced by marine fungal strain of Leptoshaeria species, exhibited potent growth suppressive effect toward RPMI8402 and 293 tumor
cell lines. And these two compounds also induced apoptosis through suppressing the
survival pathway by inactivation of Akt/protein kinase B. What's more, they were remarkable
topoisomerase catalytic inhibitors. Compound 185 targets topo I both in vitro and in vivo and 184 targets both topo I and II in vitro .[85 ]
[86 ]
A class of isoechinulin-type indole alkaloids, dihydroxyisoechinulin A (186 ), golmaenone (187 ), neoechinulin A (188 ), L -alanyl-
L
-tryptophan anhydride (189 ), and echinulin (190 ) ([Fig. 10 ]), bearing isoprenic chains in the indole ring, were obtained from the cultures of
marine fungal strain Aspergillus sp. Compounds 186 and 188 displayed potent radical scavenging effect toward 1,1-diphenyl-2-picrylhydrazyl (DPPH)
(IC50 = 20, 20, and 24 μmol/L, respectively), similar to ascorbic acid (positive control,
IC50 = 20 μmol/L). They also displayed significant ultraviolet (UA)-A protective activity
(ED50 = 130, 90, and 170 μmol/L, respectively), more potent than oxybenzone (a currently
used sunscreen agent, ED50 = 350 μmol/L).[87 ]
[88 ]
A new chiral dipyrrolobenzoquinone alkaloid, terreusinone (191 ), was found from the marine algicolous fungus Aspergillus terreus . Another new analogue terreusinol (192 ) was produced by biotransformation of terreusinone (191 ) in the co-culture of terreusinone and Streptomyces sp. ([Fig. 10 ]). These two compounds showed potent UV-A protecting activity (ED50 = 70 μg/mL for 191 , and 150 μmol/L for 192 ), which were more active than positive control oxybenzone (ED50 = 350 μmol/L).[89 ]
[90 ]
Indolyl alkaloids with a prenylated chain, oxaline (193 ) ([Fig. 10 ]), was isolated from the extract of the culture of an unidentified fungal strain
derived from the marine red alga Gracilaria verrucosa .[91 ]
Tryprostatins A and B (194 and 195 ) ([Fig. 10 ]), two new prenylated indole alkaloids, were isolated from a marine fungal strain
A. fumigatus BM939, which was collected from a sea sediment sample. These two metabolites showed
mammalian cell-cycle inhibitory activity.[92 ]
Diketopiperazine Indole Alkaloids
The diketopiperazine indole alkaloids without a prenylated fragment were included
in this section ([Fig. 11 ]). The 2,5-diketopiperazine ring is usually a cyclodipeptide that is condensed by
two amino acids. In the diketopiperazine indoles, the condensed six-membered ring
is formed by tryptophan and another amino acid.[18 ]
Fig. 11 Chemical structures of diketopiperazine indole alkaloids 196–210 .
Haenamindole (196 ) ([Fig. 11 ]) is a diketopiperazine alkaloid with benzyl-hydroxypiperazindione and phenyl-pyrimidoindole
fragments, discovered from the marine-derived fungus Penicillium sp. KCB12F005. However, this compound displayed no significant cytotoxic and antimicrobial
activity.[93 ]
Three pairs of enantiomers (±)-acrozines A–C ((±)-197 to (±)-199 ) ([Fig. 11 ]) with a novel N -methoxy diketopiperazine ring system, were afforded from the marine green alga-derived
fungus Acrostalagmus luteoalbus TK-43. (+)-Acrozines A ((+)-197 ) displayed better inhibitory activity toward acetylcholinesterase (IC50 = 2.3 μmol/L) than that of (−)-acrozines A ((−)-197 ) and (±)-197 .[94 ]
A new indole diketopiperazine alkaloid, raistrickindole A (200 ) ([Fig. 11 ]), bearing a unique pyrazino[1′,2′:2,3]-[1,2]oxazino[6,5-b]indole tetraheterocyclic
core ring, was produced by the marine fungal strain of Penicillium raistrickii IMB17–034. Compound 200 exhibited inhibitory effects toward the hepatitis C virus.[95 ]
Dichotomocej D (201 ), a new aliphatic amide, and dichocerazines A and B (202 and 203 ) ([Fig. 11 ]), two diketopiperazines, were isolated from the culture of a marine fungal strain
of Dichotomomyces cejpii F31–1.[96 ]
A new indole diketopiperazine alkaloid, asperochramide D (204 ) ([Fig. 11 ]), was afforded from the culture extract of marine-derived fungus A. ochraceus . Compound 204 represents a rare example of indole diketopiperazines possessing a 3-hydroxyl-2-indolone
ring system.[39 ]
A pair of bridged irregularly epimonothiodiketopiperazine diastereomers, pseudellones
A and B (205 and 206 ) ([Fig. 11 ]), containing a unique 3-indolylglycine and alanine segments, and a new alkaloid
pseudellone C (207 ), bearing an unusual nucleus, were obtained from the culture medium of marine fungus
Pseudallescheria ellipsoidea F42–3.[97 ]
An indole diketopiperazine alkaloid, gliotoxin (208 ) ([Fig. 11 ]), discovered from the marine-derived fungus Aspergillus sp., produced apoptosis via the mitochondrial pathway in HeLa and SW1353 cells, resulting
in an apoptotic type of cell death.[98 ]
Luteoalbusins A and B (209 and 210 ) ([Fig. 11 ]), two new indole diketopiperazine alkaloids, were yielded from the deep-sea sediment-derived
fungus A. luteoalbus SCSIO F457. Compounds 209 and 210 exhibited potent cytotoxic activity toward SF-268, MCF-7, NCI-H460, and HepG-2 cell
lines.[99 ]
Quinazoline-Containing Indole Alkaloids
Aspertoryadins A–G (211 –217 ) are seven new quinazoline-containing indole alkaloids ([Fig. 12 ]), produced by the mollusk-derived marine fungus Aspergillus sp. HNMF114. Aspertoryadin A (211 ) bears a unique aminosulfonyl group in the molecule, an exceedingly rare moiety in
nature. Aspertoryadins F and G (216 and 217 ) were found to have quorum-sensing inhibitory effect to Chromobacterium violaceum CV026, both with MIC values of 32 μg/well.[100 ]
Fig. 12 Chemical structures of quinazoline-containing indole alkaloids 211–222 .
Chaetominine (CHA) (218 ) ([Fig. 12 ]), a quinazolinone alkaloid produced by marine crab-derived fungus A. fumigatus CY018, showed potent growth-inhibitory activity toward K562 and SW1116 cell lines.[101 ]
Neofiscalin A (219 ) and fiscalin C (220 ) ([Fig. 12 ]) were two quinazolinone alkaloids obtained from Neosartorya siamensis KUFA 0017, a marine sponge-associated fungus. They exhibited potential for the development
as new leads of anti-Gram-positive bacterial infectious agents especially in multidrug-resistant
strains.[102 ]
Tryptoquivalines R and S (221 and 222 ) ([Fig. 12 ]) are two new indole quinazolinone alkaloids harbored from the organic extract of
a marine fungal strain Neosartorya sp. HN-M-3.[103 ]
Bisindoles
Two new bisindole alkaloids, fusariumindoles A and B (223 and 224 ) ([Fig. 13 ]), were yielded from the marine fungus Fusarium sp. L1 stimulated by
L
-tryptophan supplementation.[104 ]
Fig. 13 Chemical structures of bisindole alkaloids 223–234 .
Asterriquinone F (225 ) ([Fig. 13 ]), a new bisindole quinone alkaloid, was obtained from the culture of A. terreus LM.1.5.[105 ]
(±)-Fusaspoid A (226a /226b ) ([Fig. 13 ]), obtained as a pair of new bisindole alkaloid enantiomers, were produced by the
marine fungal strain of Fusarium sp. XBB-9. Compounds 226a /226b were inactive in the cytotoxic assay in HCT-15 and RKO cell lines.[106 ]
Chaetoindolone A (227 ) and chaetoindolone C (228 ) ([Fig. 13 ]), two new indole alkaloids, were produced by the strain of Chaetomium globosum 1C51 through biotransformation, a fungus collected from a marine fish sample. Compound
227 was confirmed to suppress the growth of the rice-pathogenic bacteria Xanthomonas oryzae pv. oryzae (xoo) .[107 ]
2,2-Bis(6-bromo-3-indolyl)ethylamine (229 ) ([Fig. 13 ]), a bisindole alkaloid derived from a strain of marine fungus, was confirmed to
have the potential to be developed as an antibiofilm lead compound for its greatest
antimicrobial and biofilm formation inhibitory activity.[108 ]
A new bisindole alkaloid indolepyrazine A (230 ) ([Fig. 13 ]) containing an unpresented indole–pyrazine–oxindole skeleton was obtained from the
marine fungal strain of Acinetobacter sp. ZZ1275. Compound 230 exhibited significant antimicrobial effects toward methicillin-resistant strains
E. coli , S. aureus , and C. albicans (MIC values, 10, 12, and 12 μg/mL, respectively).[109 ]
Pseudboindoles A and B (231 and 232 ) ([Fig. 13 ]), two new bisindole alkaloids, were yielded from the cultures of marine fungus Pseudallescheria boydii F44–1 through adding amino acids to the culture medium.[110 ]
Varioloids C and D (233 and 234 ) ([Fig. 13 ]), two indolyl-6,10b -dihydro-5aH -[1]benzofuro[2,3-b ]indole alkaloids, were isolated from the strain of P. variotii EN-291, a marine alga-derived fungus. Both compounds 233 and 234 displayed cytotoxic activity toward HepG2, HCT116, and A549 cell lines (IC50 = 2.6–8.2 μg/mL).[111 ]
[112 ]
Indoloditerpenes
Indoloditerpenes are a series of structurally diverse meroterpenoids featuring with
an indole ring connected with a cyclic diterpene backbone, distributed widely both
in terrestrial and marine fungi, exhibiting great potential of drug research as lead
compounds for their potent insecticidal, antivirus, cytotoxic, and antimicrobial effects.[17 ]
[104 ]
[113 ]
Fusaindoterpenes A and B (235 and 236 ) ([Fig. 14 ]), two new indoloditerpenes or their derivatives, were afforded from a marine-derived
fungal strain of Fusarium sp. L1 by adding L -tryptophan in culture supplementation. Compound 235 possesses a unique 6/9/6/6/5 heterocyclic ring system. And compound 236 exhibited significant effect toward Zika virus (EC50 = 7.5 μmol/L).[104 ]
Fig. 14 Chemical structures of indoloditerpenes 235–249 .
Compound 237 ([Fig. 14 ]), a new indoloditerpene, was obtained from a culture of marine fungal strain of
A. versicolor ZZ761. This compound displayed antimicrobial effects against E. coli and C. albicans (MIC = 20.6 and 22.8 μmol/L, respectively).[113 ]
Anthcolorin G and H (238 and 239 ) ([Fig. 14 ]), two new oxoindoloditerpene epimers, were yielded from the cultures of A. versicolor , a mangrove endophytic fungus. Compound 239 produced weak cytotoxicity toward HeLa cells.[114 ]
Penicindopene A (240 ) ([Fig. 14 ]), a new indoloditerpene possessing a rare 3-hydroxyl-2-indolone fragment, was obtained
from the strain of Penicillium sp. YPCMAC1, a deep-sea-derived fungus. Compound 240 showed moderate cytotoxic activity against A549 and HeLa cell lines (IC50 = 15.2 and 20.5 μmol/L).[115 ]
Emindole SB β-mannoside (241 ) and 27-O -methylasporyzin C (242 ) ([Fig. 14 ]), two new indoloditerpenes, were produced by a marine-derived strain of D. cejpii . Compound 241 was confirmed to be a CB2 antagonist, and compound 242 was found to be the first indole derivative possessing selective GPR18 inhibitory
activity. These two indole derivatives may be investigated as lead molecules for the
research of GPR18- and CB receptor-blocking drugs.[116 ]
Asporyzins A–C (243 –245 ) ([Fig. 14 ]), three new indoloditerpene derivatives, were found from the cultures of A. oryzae , an endophytic fungus derived from the marine red alga Heterosiphonia japonica . Compound 245 showed potent inhibitory effect toward E. coli .[117 ]
Epipaxilline (246 ) and penerpene J (247 ) ([Fig. 14 ]), two new indoloditerpenes, were obtained from the organic extract of the cultures
of marine fungus Penicillium sp. KFD28. They displayed inhibitory effects toward PTP1B (IC50 = 31.5 and 9.5 μmol/L) and compound 247 also presented suppressive effects against TCPTP (IC50 = 14.7 μmol/L).[118 ]
Penerpenes A–D (248 –251 ) ([Figs. 14 ] and [15 ]), four unique indoleterpenoids, were obtained and identified from the marine fungal
strain of Penicillium sp. KFD28. Compounds 248 and 249 exhibited significant inhibitory effect against protein tyrosine phosphatases (PTP1B
and TCPTP).[119 ]
Fig. 15 Chemical structures of indoloditerpenes 250–272 .
Penerpenes E–I (252 –256 ) ([Fig. 15 ]), five new indoleterpenoids, were obtained from Penicillium sp. KFD28, a marine fungus isolated from a bivalve mollusk Meretrix lusoria . Compound 252 possesses a rare 6/5/5/6/6/5/5 heptacyclic moiety. Compound 253 is a new carbon skeleton of indolediterpenoid derived from paxilline. Compound 254 contains a unique 6/5/5/6/6/7 hexacyclic skeleton bearing a 1,3-dioxepane ring. Compounds
252 , 253 , and 256 displayed inhibitory effects toward protein tyrosine phosphatase 1B (PTP1B) (IC50 = 14, 27, and 23 μmol/L, respectively).[120 ]
Penijanthines C and D (257 and 258 ) ([Fig. 15 ]), two new indolediterpenoid derivatives, were obtained from the cultures of a marine-derived
fungal strain P. janthinellum . These two compounds exhibited potent antivibrio effect toward three pathogenic Vibrio spp. (MIC = 3.1–50.0 μmol/L).[121 ]
Asperindoles A–D (259 –262 ) ([Fig. 15 ]), four new indolediterpene alkaloids, were produced by the cultures of a marine
ascidian-derived fungal strain Aspergillus sp. Asperindoles C and D (261 and 262 ) bear an unusual 2-hydroxyisobutyric acid (2-HIBA) moiety, which is very rare in
natural products. Compound 259 showed cytotoxic effect toward PC-3 and 22Rv1 cells that are resistant to hormone
therapy, as well as human prostate cancer cells that are sensitive to hormone therapy,
and apoptosis-induced activity in the above-mentioned cells.[122 ]
Rhizovarins A–F (263 –268 ) ([Fig. 15 ]), six new indolediterpenes, were discovered by a genome-mining method from the strain
of Mucor irregularis QEN-189, a marine fungus derived from the mangrove plant Rhizophora stylosa . Among these molecules, compounds 263 –265 contain the most complex and unique structure of the indolediterpenes, with a rare
acetal linked to a hemiketal or a ketal forming a novel 4,6,6,8,5,6,6,6,6-fused indole–diterpene
skeleton. Compounds 263 and 264 displayed inhibitory effect toward A-549 and HL-60 cancer cell lines.[123 ]
19-Hydroxypenitrem A (269 ) and 19-hydroxypenitrem E (270 ) ([Fig. 15 ]), two new chlorinated indole-diterpenoids, were yielded from the marine strain of
Aspergillus nidulans EN-330, which was isolated from red alga Polysiphonia scopulorum var. villum . Compounds 269 and 270 showed cytotoxicity toward brine shrimp (LD50 = 3.2 and 4.6 μmol/L). In addition, compound 269 displayed moderate antimicrobial function against four pathogens Edwardsiella tarda , Vibrio anguillarum , E. coli , and S. aureus .[124 ]
Compounds 271 and 272 ([Fig. 15 ]), two new indole-diterpenoids, were harbored from the cultures of the marine-derived
fungal strain of Aspergillus flavus OUCMDZ-2205. Compound 271 presented antibacterial effect toward S. aureus (MIC = 20.5 μmol/L). And both compounds could arrest the cell cycle in the S phase
at 10 μmol/L in A549 cell lines. Compound 271 exhibited PKC-β inhibitory activity (IC50 = 15.6 μmol/L).[125 ]
Cytochalasans
Chaetoglobosin-510 (273 ), -540 (274 ), and -542 (275 ), three cytochalasin-type alkaloids ([Fig. 16 ]), were obtained from the cultures of the marine fungal strain of Phomopsis asparagi . Chaetoglobosin-542 (275 ) produced antimicrofilament effect and cytotoxic activity against leukemia cancer
and murine colon cell lines.[126 ]
Fig. 16 Chemical structures of cytochalasans 273 –287 .
Cytoglobosins A–G (276 –282 ) ([Fig. 16 ]), seven new cytochalasin-type alkaloids, were obtained from the cultures of marine
green alga-derived fungus C. globosum QEN-14. Compounds 278 and 279 exhibited cytotoxicity toward the A549 tumor cell line.[127 ]
A new cytochalasans derivative, 6-O -methyl-chaetoglobosin Q (283 ), along with several known analogues, was produced by a coral-associated fungus C. globosum C2F17. The known congeners chaetoglobosins E (284 ) and Fex (285 ) ([Fig. 16 ]), exhibited significant antiproliferative activity toward a series of cancer cell
lines (IC50 = 1.4–9.2 μmol/L).[128 ]
Cytoglobosins H and I (286 and 287 ) ([Fig. 16 ]), two new cytochalasans derivatives, as well as several known congeners, were obtained
from a deep-sea sediment-derived marine fungal strain of C. globosum . The known compound chaetoglobosin E (284 ) displayed potent growth-inhibitory effect against LNCaP and B16F10 cell lines (IC50 = 0.62 and 2.78 μmol/L, respectively). Besides, compound 284 suppressed the growth of LNCaP cells via inducing apoptosis.[129 ]
Other Indole Alkaloids
Plectosphaeroic acids A–C (288 –290 ) ([Fig. 17 ]), three new plectosphaeroic acid derivatives, were obtained from the laboratory
cultures of the fungus Plectosphaerella cucumerina collected from marine sediments. They were evaluated and presented significant inhibitory
activity against indoleamine-2,3-dioxygenase (IDO), with IC50 values of 2 μmol/L.[130 ]
Fig. 17 Chemical structures of other indole alkaloids 288 –306 .
Chaetoindolone B (291 ), chaetoindolone D (292 ), 19-O -demethylchaetogline A (293 ), 20-O -demethylchaetogline F (294 ), and chaetogline A (295 ) ([Fig. 17 ]) are five new indole alkaloids obtained from the marine fungus C. globosum 1C51, through biotransformation induced by 1-methyl-L -tryptophan (1-MT) supplemented in the culture medium. Chaetogline A (295 ) showed fungicidal effect toward a pathogenic fungus Sclerotinia sclerotiorum , the cause of rape sclerotinia rot, indicating the potential agrochemical significance
of indole alkaloids.[107 ]
Two new indole alkaloids, Fusariumindoles C (296 ) and (±)-isoalternatine A (297 ) ([Fig. 17 ]), were produced by the marine fungus Fusarium sp. L1, induced by the L -tryptophan added in the culture condition. However, they exhibited no significant
effect against Zika virus.[104 ]
A known marine indole alkaloid derivative isolated from a fungal strain of Neosartorya pseudofischeri , isochaetominine C (298 ) ([Fig. 17 ]), displayed potent cytotoxic activity toward the Sf9 cells.[52 ]
5,6-Dihydroxyindole-2-carboxylic acid (DHICA) (299 ) was yielded from the cultures of marine fungus A. nidulans ([Fig. 17 ]). The simple indole alkaloid 299 showed remarkable UV-B protecting effect both in vivo and in vitro assays, presenting the potential as a sun-protective agent added to sunscreen cream.[131 ]
Two simple indole alkaloids, tryptamine (300 ) and indole-3-carbaldehyde (301 ) ([Fig. 17 ]), were expressed by the marine-derived fungus Penicillium species. Compound 301 showed modest antimicrobial activity.[132 ]
1-(4-Hydroxybenzoyl)indole-3-carbaldehyde (302 ) ([Fig. 17 ]), a new indole alkaloid with an aldehyde group, was isolated from a strain of marine
fungus Engyodontium album IVB1b. It was inactive both in cytotoxic and antimicrobial tests.[133 ]
Indolepyrazine B (303 ) ([Fig. 17 ]), a new indole alkaloid, was harbored from the culture medium of marine-derived
fungus Acinetobacter sp. ZZ1275. It displayed antimicrobial effect against E. coli , S. aureus , and C. albicans , three methicillin-resistant pathogenic strains, with MIC values of 8, 12, and 14
μg/mL, respectively.[109 ]
A new indole carboxylic acid, nigrospin A (304 ) ([Fig. 17 ]), was obtained from the cultures of the marine fungal strain Nigrospora oryzae SCSGAF 0111.[134 ]
Compound 305 ([Fig. 17 ]) was a new tryptoquivaline derivative isolated from the marine alga-derived fungus
N. takakii KUFC 7898. In the antimicrobial biotests, it exhibited no significant activity.[55 ]
Fumiquinazoline K (306 ) ([Fig. 17 ]), a new indole alkaloid, had been obtained from a strain of marine fungus A. fumigatus KMM 4631, which was derived from the soft coral Sinularia sp.[135 ]
