Marine-Derived Fungal Metabolites 32.3 Marine Organic Compounds 769
Part F | 32.3
Sinularia sp. [32.89]. Fumiquinazoline K revealed neither cytotoxic nor antibacterial activity [32.89].
Farinomaleins C–E (41–43), three new dioxopyrrole derivatives, together with one new indole metabolite were isolated from an unidentified endophytic
fungus derived from the mangrove plant Avicennia
marina [32.90]. All isolated farinomaleins were investigated for their cytotoxic and antimicrobial activities;
however, none exhibited significant activities [32.90].
Aspergillamides A (44) and B (45), two new
pyrrolidine alkaloids, were isolated together with the
known compound aurantiamine from the marine fungus Aspergillus ustus derived from the Mediterranean
sponge Suberties domuncula collected from the Adriatic Sea [32.91]. In the cytotoxicity assay against the
murine lymphoma (L5178Y) cell line, neither 44 nor
45 exhibited more than 1020% activity compared to
controls [32.91].
32.3.2 Diketopiperazines
Amauromine (46), an indole diketopiperazine alkaloid,
was isolated from the fungus Auxanthron reticulatum derived from the marine sponge Ircinia variablis [32.92]. Amauromine (46) was identified as the
first fungal metabolite that revealed high and selective
affinity for the human cannabinoid receptor CB 1 recombinantly expressed in Chinese hamster ovary (CHO)
cells (K i D 178 nm) [32.92]. Based on the selective antagonistic potency, 46 may be a potential candidate
for further development as a lead structure for drug
development.
Four further indole alkaloids, cristatumins A–D
(47–50), were isolated together with six known derivatives from the endophytic fungus Eurotium cristatum
EN-220, obtained from the marine alga Sargassum
thunbergii [32.93]. In the antimicrobial activity assay, cristatumin A (47) displayed moderate activity
against Escherichia coli and Staphylococcus aureus,
while cristatumin B (48) provoked modest lethality in
brine shrimp Artemia salina [32.93].
From the ethyl acetate (EtOAc) extract of the solid
rice culture of the marine-derived endophytic fungus Eurotium rubrum, a new dioxopiperazine alkaloid,
namely 12-demethyl-12-oxo-eurotechinulin B (51) was
isolated together with one new anthraquinone derivative
and ten other known compounds [32.94]. In the cytotoxicity assay against seven human tumor cell lines, 51
revealed only moderate activity against SMMC-7721
cells with IC 50 of 65:5 M, while in the antimicrobial
activity assay it showed no activity [32.94].
Bioassay-guided fractionation of the mycelial extract of the marine fungal strain Aspergillus sydowii
(SCSIO00305), obtained from the gorgonian coral
Verrucella umbraculum, led to the isolation of two
new natural products, [4-(2-methoxyphenyl)-1-piperazinyl][(1-methyl-1H-indol-3-yl)]-methanone (52) and
cyclotryprostatin (53) together with eight known natural products [32.95]. Both 52 and 53 were subjected to a cytotoxicity (microculture tetrazolium assay,
MTT), but only 52 revealed significant cytotoxic activity against human melanoma (A375) cell line with IC 50
of 5:7 M [32.95].
Two new oxepin-type alkaloids, protuboxepins
A and B (54 and 55) and two diketopiperazine alkaloids, protubonines A and B (56 and 57), were reported
from the EtOAc extract of the marine sediment-derived
fungus Aspergillus sp. SF-5044 [32.96]. Compounds
(54, 56, and 57) were subjected to a cytotoxic activity assay against five different cancer cell lines. Results revealed that only protuboxepin A (54) showed
weak antiproliferative activity against five tested cancer
cell lines, namely HL-60 (leukemia), MDA-MB-231
(breast), Hep3B (liver), 3Y1 (fibroblast), and K562
(chronic myeloid leukemia, CML) with IC 50 values of
75, 130, 150, 180, and 250 M, respectively [32.96].
Two new gliotoxin-related metabolites, 58 and 59,
were isolated together with other five known derivatives from the fungus Penicillium sp. (JMF034) obtained from deep sea sediment collected off Suruga Bay (Japan) [32.97]. The absolute configuration of the new compounds was established based
on the modified Mosher’s method. All isolated compounds showed significant cytotoxic activity when
tested against murine leukemia cells (P388), except
for bis(dethio)-10a-methylthio-3a-deoxy-3,3a-didehydrogliotoxin (58) which exhibited only marginal activity [32.97]. However, compounds with disulfide
or tetrasulfide bonds exhibited potent inhibitory activity against histone methyltransferases (HMT) G9a
and HMT Set7/9 (lysine-specific histone methyltransferases). 6-Deoxy-5a,6-didehydrogliotoxin (59) containing a disulfide bond showed only weak activity,
which suggested that the C-6 hydroxy group interfered
with the G9a inhibitory activity based on the significant activity of other metabolites lacking this hydroxyl
group [32.97].
A new diketopiperazine alkaloid, pre-aurantiamine
(60) was isolated together with two new itaconic acid
derivatives from the culture broth of the fungus Aspergillus aculeatus CRI322-03, which was obtained
from the marine sponge Stylissa flabelliformis collected
Part F | 32.3
Sinularia sp. [32.89]. Fumiquinazoline K revealed neither cytotoxic nor antibacterial activity [32.89].
Farinomaleins C–E (41–43), three new dioxopyrrole derivatives, together with one new indole metabolite were isolated from an unidentified endophytic
fungus derived from the mangrove plant Avicennia
marina [32.90]. All isolated farinomaleins were investigated for their cytotoxic and antimicrobial activities;
however, none exhibited significant activities [32.90].
Aspergillamides A (44) and B (45), two new
pyrrolidine alkaloids, were isolated together with the
known compound aurantiamine from the marine fungus Aspergillus ustus derived from the Mediterranean
sponge Suberties domuncula collected from the Adriatic Sea [32.91]. In the cytotoxicity assay against the
murine lymphoma (L5178Y) cell line, neither 44 nor
45 exhibited more than 1020% activity compared to
controls [32.91].
32.3.2 Diketopiperazines
Amauromine (46), an indole diketopiperazine alkaloid,
was isolated from the fungus Auxanthron reticulatum derived from the marine sponge Ircinia variablis [32.92]. Amauromine (46) was identified as the
first fungal metabolite that revealed high and selective
affinity for the human cannabinoid receptor CB 1 recombinantly expressed in Chinese hamster ovary (CHO)
cells (K i D 178 nm) [32.92]. Based on the selective antagonistic potency, 46 may be a potential candidate
for further development as a lead structure for drug
development.
Four further indole alkaloids, cristatumins A–D
(47–50), were isolated together with six known derivatives from the endophytic fungus Eurotium cristatum
EN-220, obtained from the marine alga Sargassum
thunbergii [32.93]. In the antimicrobial activity assay, cristatumin A (47) displayed moderate activity
against Escherichia coli and Staphylococcus aureus,
while cristatumin B (48) provoked modest lethality in
brine shrimp Artemia salina [32.93].
From the ethyl acetate (EtOAc) extract of the solid
rice culture of the marine-derived endophytic fungus Eurotium rubrum, a new dioxopiperazine alkaloid,
namely 12-demethyl-12-oxo-eurotechinulin B (51) was
isolated together with one new anthraquinone derivative
and ten other known compounds [32.94]. In the cytotoxicity assay against seven human tumor cell lines, 51
revealed only moderate activity against SMMC-7721
cells with IC 50 of 65:5 M, while in the antimicrobial
activity assay it showed no activity [32.94].
Bioassay-guided fractionation of the mycelial extract of the marine fungal strain Aspergillus sydowii
(SCSIO00305), obtained from the gorgonian coral
Verrucella umbraculum, led to the isolation of two
new natural products, [4-(2-methoxyphenyl)-1-piperazinyl][(1-methyl-1H-indol-3-yl)]-methanone (52) and
cyclotryprostatin (53) together with eight known natural products [32.95]. Both 52 and 53 were subjected to a cytotoxicity (microculture tetrazolium assay,
MTT), but only 52 revealed significant cytotoxic activity against human melanoma (A375) cell line with IC 50
of 5:7 M [32.95].
Two new oxepin-type alkaloids, protuboxepins
A and B (54 and 55) and two diketopiperazine alkaloids, protubonines A and B (56 and 57), were reported
from the EtOAc extract of the marine sediment-derived
fungus Aspergillus sp. SF-5044 [32.96]. Compounds
(54, 56, and 57) were subjected to a cytotoxic activity assay against five different cancer cell lines. Results revealed that only protuboxepin A (54) showed
weak antiproliferative activity against five tested cancer
cell lines, namely HL-60 (leukemia), MDA-MB-231
(breast), Hep3B (liver), 3Y1 (fibroblast), and K562
(chronic myeloid leukemia, CML) with IC 50 values of
75, 130, 150, 180, and 250 M, respectively [32.96].
Two new gliotoxin-related metabolites, 58 and 59,
were isolated together with other five known derivatives from the fungus Penicillium sp. (JMF034) obtained from deep sea sediment collected off Suruga Bay (Japan) [32.97]. The absolute configuration of the new compounds was established based
on the modified Mosher’s method. All isolated compounds showed significant cytotoxic activity when
tested against murine leukemia cells (P388), except
for bis(dethio)-10a-methylthio-3a-deoxy-3,3a-didehydrogliotoxin (58) which exhibited only marginal activity [32.97]. However, compounds with disulfide
or tetrasulfide bonds exhibited potent inhibitory activity against histone methyltransferases (HMT) G9a
and HMT Set7/9 (lysine-specific histone methyltransferases). 6-Deoxy-5a,6-didehydrogliotoxin (59) containing a disulfide bond showed only weak activity,
which suggested that the C-6 hydroxy group interfered
with the G9a inhibitory activity based on the significant activity of other metabolites lacking this hydroxyl
group [32.97].
A new diketopiperazine alkaloid, pre-aurantiamine
(60) was isolated together with two new itaconic acid
derivatives from the culture broth of the fungus Aspergillus aculeatus CRI322-03, which was obtained
from the marine sponge Stylissa flabelliformis collected