Psammocindoles A-C: Isolation, Synthesis, and Bioactivity of Indole-γ-lactams from the Sponge Psammocinia vermis

Article abstract of DOI:10.1021/acs.orglett.1c01410

Psammocindoles A-C (1-3), a new class of indole alkaloids, were isolated from a Psammocinia vermis sponge. By combined spectroscopic analyses, the structures of these compounds were determined to be the indole-γ-lactams derived from three amino acid residues. In addition, an enantiomer psammocindole D (4), and the N-lactam isomers isopsammocindoles A-D (5-8) were also synthesized. These natural products and synthetic analogues were found to significantly stimulate adiponectin secretion in human bone marrow mesenchymal stem cells.

Full text of DOI:10.1021/acs.orglett.1c01410

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Letter
Psammocindoles A−C: Isolation, Synthesis, and Bioactivity of
Indole-γ-lactams from the Sponge Psammocinia vermis
Oh-Seok Kwon,† Sungjin Ahn,† Ju-eun Jeon, In Guk Park, Tae Hyung Won, Chung J. Sim,
Hyeung-geun Park, Dong-Chan Oh, Ki-Bong Oh, Minsoo Noh,* and Jongheon Shin*
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ABSTRACT: Psammocindoles A−C (1−3), a new class of indole alkaloids,
were isolated from a Psammocinia vermis sponge. By combined spectroscopic
analyses, the structures of these compounds were determined to be the
indole-γ-lactams derived from three amino acid residues. In addition, an
enantiomer psammocindole D (4), and the N-lactam isomers isopsammo-
cindoles A−D (5−8) were also synthesized. These natural products and
synthetic analogues were found to significantly stimulate adiponectin
secretion in human bone marrow mesenchymal stem cells.
ndole alkaloids are recognized as excellent platforms for
Ipharmaceutical development, because their diverse structural
motifs and potent bioactivities render them attractive candidates
for medicinal research.1,2 A number of these compounds have
been found in diverse marine organisms, and their chemical
syntheses have received growing attention to permit advanced
medicinal studies.3,4 Sponges, the most prolific sources of
biologically active and structurally unique compounds among
marine organisms, produce numerous small indole alkaloids.5,6
The most notable examples may include the indole-creatinines,
aplysinopsins,7 bisindole-imidazoles, topsentins,8 and trypt-
amines.9 Thus, comprehensive chemical investigations, includ-
ing a synthetic approach, in conjunction with bioactivity
evaluation, into new sponge-derived indole alkaloids could be
a relevant approach for natural-product-based medicinal
research.
During the search for novel compounds from marine
invertebrates, we encountered the black clustering Psammocinia
vermis (order Dictyoceratida, family Irciniidae) sponge from
Chuja-do, Korea.10 Liquid chromatography/electrospray ion-
ization−mass spectrometry (LC/ESI−MS) analysis of the
organic extract from this specimen revealed the presence of
unusual constituents in moderate polarity, while common linear
sesterterpenes were detected in the less polar region.11
Figure 1. Chemical structures of isolated new compounds (1−3) and
synthetic analogues (4−8).
Thus, we herein report three indole alkaloids, namely,
psammocindoles A−C (1−3), indole-γ-lactams of a new
structural class (Figure 1). The isolation of these compounds
was afforded by large-scale extraction followed by solvent-
partitioning and chromatographic separations. In our biological
evaluation, psammocindoles A and B (1 and 2) significantly
increased adiponectin biosynthesis. To identify their absolute
Received: April 24, 2021
Published: June 1, 2021
https://doi.org/10.1021/acs.orglett.1c01410
© 2021 American Chemical Society
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Table 1. 13C and 1H NMR Assignments for Compounds 1−3
1
2
3
position
C (ppm, type)
H [δ, mult, (J in Hz)]
C (ppm, type)
H [δ, mult, (J in Hz)]
C (ppm, type)
H [δ, mult, (J in Hz)]
1
2
128.1, CH
111.5, C
7.64, s
128.0, CH
111.6, C
7.64, s
128.0, CH
111.5, C
7.59, s
3
127.5, C
127.5, C
127.4, C
4
5
6
7
121.8, CH
122.3, CH
124.1, CH
113.8, CH
138.9, C
7.68, dd (8.0, 0.9)
7.14, td (7.5, 0.9)
7.19, td (8.0, 0.9)
7.44, dd (8.0, 0.9)
121.8, CH
122.3, CH
124.1, CH
113.8, CH
138.9, C
7.69, dd (8.0, 0.9)
7.14, td (7.5, 0.9)
7.19, td (8.0, 0.9)
7.44, dd (8.0, 0.9)
121.7, CH
122.2, CH
124.1, CH
113.7, CH
138.9, C
7.51, dd (8.0, 0.9)
7.10, td (7.5, 0.9)
7.17, td (8.0, 0.9)
7.42, dd (8.0, 0.9)
8
9
176.4, C
176.0, C
176.0, C
10
11
12
13
1′
124.7, C
146.8, C
55.9, CH2
12.2, CH3
50.4, CH2
124.8, C
146.8, C
55.2, CH2
12.1, CH3
42.6, CH2
124.6, C
147.0, C
55.9, CH2
12.0, CH3
46.1, CH2
4.52, br q (1.5)
2.05, br t (1.5)
3.44, dd (13.7, 7.1)
3.38, dd (13.8, 7.9)
1.88, m
4.52, br q (1.4)
2.04, br t (1.5)
3.59, t (7.5)
4.32, br q (1.4)
2.03, br t (1.5)
3.80, t (7.3)
2′
3′
36.3, CH
28.9, CH2
39.3, CH2
27.9, CH
1.57, m
1.62, m
36.8, CH2
141.3, C
2.98, t (7.3)
1.46, m
1.20, m
4′
5′
6′
7′
8′
12.3, CH3
18.1, CH3
0.96, t (7.5)
0.92, d (6.7)
23.7, CH3
23.7, CH3
0.99, d (6.5)
0.99, d (6.5)
130.7, CH
130.4, CH
128.3, CH
130.4, CH
130.7, CH
7.28, m
7.29, m
7.20, m
7.29, m
7.28, m
a
Data were obtained in MeOH-d4 solutions at 600 (1H) and 150 (13C) MHz.
configurations and pharmacological effects, the total syntheses
of psammocindoles A−C (1−3) are performed. Along with the
synthesis of psammocindoles, a synthetic enantiomer psammo-
cindole D (4) and the N-lactam analogues isopsammocindoles
A−D (5−8) were also synthesized (Figure 1).
The molecular formula of psammocindole A (1) was deduced
to be C18H22N2O by high-resolution fast atom bombardment
mass spectrometry (HRFABMS) analysis [HRMS (FAB) m/z
[M + H]+ calculated for C18H23N2O, 283.1810; found,
283.1809] with 9 degrees of unsaturation. The 13C nuclear
magnetic resonance (NMR) data showed a signal corresponding
to a carbonyl carbon at δC 176.4, which, in conjunction with a
strong absorption band at 1630 cm−1 in the infrared (IR)
spectrum, was assigned as an amide carbon. The 13C NMR data
also showed 10 deshielded carbons in the region of δC 146.8−
111.5 (Table 1). The corresponding proton signals at δH 7.60−
7.10 in the 1H NMR data, aided by a diagnostic carbon signal at
δC 138.9, revealed the presence of an indole moiety accounting
for 6 degrees of unsaturation. The remaining two deshielded
carbons naturally accounted for a double bond, implying that
compound 1 was a bicyclic compound. In addition, the 13C
NMR data of this compound showed seven aliphatic carbons:
one methine, three methylenes, and three methyl carbons.
On the basis of this information, the structure of compound 1
was determined by combined two-dimensional (2D) NMR
analyses (Figure 2). A preliminary examination of the
heteronuclear single-quantum correlation (HSQC) data
matched all protons with their corresponding carbons.
Subsequently, a 3-alkylindole moiety (C-1−C-8) was readily
established using 1H−1H correlation spectroscopy (COSY) and
heteronuclear multiple-bond correlation (HMBC) data, in
which the proton−proton and proton−carbon correlations
between the aromatic protons and their neighboring carbons
were adequately defined. Meanwhile, the COSY data also
Figure 2. COSY (bold lines) and HMBC (arrows) correlations of
compound (1).
revealed an assembly of five shielded protons forming a 2-
methylbutyl group (C-1′−C-5′). The chemical shifts of the
terminal methylene group (C-1′: δC 50.4, δH 3.44 and 3.38)
suggested an attachment of nitrogen at this position.
The remaining five carbons were an amide carbonyl (δC
176.4), a fully substituted double bond (δC 146.8 and 124.7), a
methylene carbon (δC 55.9, δH 4.52), and a methyl (δC 12.2, δH
2.05) carbon. The HMBCs of the vinyl methyl protons with the
former three carbons revealed the presence of an α-methyl-α,β-
unsaturated amide group. Further long-range correlations of the
methylene protons with all three conjugated amide carbons
constructed a γ-lactam moiety (C-9−C-13): H-12/C-9, C-10,
and C-11. This interpretation was also supported by a
homoallylic proton−proton correlation at H3-13/H2-12 in the
COSY data.
Connection of the lactam moiety at the indole C-2 position
was confirmed by the HMBCs between these: H-1/C-11 and
H3-13/C-2. Similarly, the linkage of the 2-methylbutane group
at lactam nitrogen was confirmed by the HMBCs across
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nitrogen: H2-1′/C-9 and C-12. Thus, the planar structure of
psammocindole A (1) was determined to be an alkaloid of a new
structural class, consisting of an indole and a N-pentenyllactam
moiety. The absolute configuration at the C-2′ stereogenic
center of compound 1, indicated by the specific rotation ([α]D25
of +14.0), was assigned by chemical synthesis, as described later.
The molecular formula of psammocindole B (2) was
established as C18H22N2O by HRFABMS analysis [HRMS
(FAB) m/z [M + H]+ calculated for C18H23N2O, 283.1810;
found, 283.1808], identical to compound 1. The spectroscopic
data were also very similar to those of compound 1, suggesting
Scheme 1. Total Synthesis of Psammocindoles
the same alkyl indole-γ-lactam nature. A comparison of the 13
C
1
and H NMR data between these compounds readily revealed
replacement of the 2′-methylbutyl group of compound 1 with a
3-methylbutyl group in compound 2 (δC 23.7, 2 × CH3; δH 0.99,
6H, d, J = 6.5 Hz; Table 1). This structural difference was
confirmed by combined 2D NMR experiments, including crucial
HMBCs at H3-4′(5′)/C-2′ and C-3′. Thus, the structure of
psammocindole B (2) was defined as an alkyl chain variant of
psammocindole A (1).
The molecular formula of psammocindole C (3) was
established as C21H20N2O by HRFABMS data [HRMS (FAB)
m/z [M + H]+ calculated for C21H21N2O, 317.1654; found,
317.1655]. The 13C and 1H NMR data showed the presence of
the same indole and γ-lactam moieties as in compounds 1 and 2.
The most conspicuous differences in the NMR data occurred at
the N-alkyl group, which apparently consisted of eight carbons
in compound 3: six aromatic carbons in δC 141.3−128.3 and two
methylenes at δC 46.1 and 36.8 (Table 1). Combined 2D NMR
analyses readily defined this as a phenethyl group (C-1′−C-8′),
and its attachment to lactam nitrogen was confirmed through
the HMBCs at H2-1′/C-9 and C-12. Thus, the structure of
psammocindole C (3) was determined to contain a phenethyl
moiety, possibly derived from phenylalanine, a derivative of
psammocindole A (1).
Structurally, the psammocindoles are a linear assembly of
three moieties, namely, an indole, a γ-lactam, and a N-alkyl
group, which are possibly derived from the amino acids
isoleucin, leucine, and phenylalanine, respectively. In addition
to the apparent contribution of tryptophan to the indole moiety,
the alternative presence of N-alkyl chains strongly supports the
amino-acid-derived biogenesis of these compounds. Through
the literature studies, there were several natural products bearing
indole-lactam moieties, such as bisindolylmaleimides.12,13 To
the best of our knowledge, this is an unprecedented framework
not only among sponge-derived natural products but within
natural product chemistry more broadly. The unique structural
features of these compounds prompted us to consider a wide
range of bioassays that would be possible by total syntheses
overcoming the limited amounts of natural products. In this way,
it would also unambiguously assign the absolute configuration at
the C-2′ stereogenic center of compound 1.
a
Reagents and conditions: (a) ethyl bromoacetate, CH2Cl2, Et3N, rt,
2 h, 90−93%; (b) propionyl chloride, Et3N, 0 °C to rt, 1.5 h, 94−
95%; (c) NaH, THF, reflux, 12 h, 83−86%; and (d) indole, BF3−
Et2O, 4 Å MS, PhCl, 100 °C, 1.5 h, 27−31%.
the 13C and H NMR analyses, these were found to exist as
1
mixtures of two rotamers (2.7−2.9:1). Subsequently, N-alkyl-
α,β-unsaturated γ-lactams (21−24) were prepared by intra-
molecular Claisen condensation of the amides (yields of 83−
86%).17 Finally, the indole condensation of the lactams occurred
at both C-3 and nitrogen of the indole moiety to afford a pair of
psammocindoles (1−4) and the N-alkyl isomers isopsammo-
cindoles (5−8) in similar amounts (compound 1−4 yields of
28−31% and compound 5−8 yields of 27−31%).18 The
spectroscopic data of synthetic psammocindoles were fully
identical to those of natural products, supporting the
spectroscopic interpretation. In addition, between the enantio-
meric psammocindoles 1 and 4, the specific rotations
(compound 1 [α]D25 of +11.9 and compound 4 [α]2D5 of
−15.6) unambiguously assigned the 2′R configuration for the
natural product ([α]D25 of +14.0). Similarly, enantiomeric
isopsammocindoles showed opposite specific rotations (com-
pound 5 [α]2D5 of +10.0 and compound 8 [α]2D5 of −10.4).
In our pursuit for the bioactivity of psammocindoles (1−4)
and isopsammocindoles (5−8), attempts were focused on the
effects on adiponectin biosynthesis because hypoadiponectine-
mia is a major symptom of diverse human metabolic diseases,
such as obesity, type 2 diabetes, atherosclerosis, and non-
alcoholic steatohepatitis.19 Therefore, compounds that stim-
ulate adiponectin secretion could be helpful in the treatment of
metabolic diseases.20,21 To evaluate the therapeutic potentials
for metabolic diseases, the adiponectin-secretion-stimulating
activities of compounds 1−8 were investigated in human bone
marrow mesenchymal stem cells (hBM-MSCs) using an
adipogenic cocktail consisting of insulin, dexamethasone, and
isobutyl methylxanthine (IDX). Compounds 1−8 (10 μM)
significantly increased adiponectin secretion during adipo-
genesis in hBM-MSCs compared to that in the IDX control
(Figure 3A). In a concentration−response analysis, compounds
1 and 2 were more potent (EC50 of 9.86 and 6.20 μM,
respectively) than bezafibrate (EC50 of >10 μM), a currently
Initially, the starting reagent (R)-2-methylbutan-1-amine (9)
was prepared in 88% enantiomer excess (ee) over five-step
synthesis as reported in the literature,14 while the other amines
(10−12), including the 2-(S)-enantiomer (12, 99% ee), were
obtained commercially. Using these amines as starting materials,
a concise four-step synthesis was designed (Scheme 1; see the
Supporting Information for details). Connection of the amines
with ethyl bromoacetate afforded ethyl alkylacetates (13−16;
yields of 90−93%).15 Subsequently, further condensation with
propionyl chloride produced the corresponding N-(1-propion-
yl)-amides (17−20) in high quantities (yields of 94−95%).16 By
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Jongheon Shin − Natural Products Research Institute, College
of Pharmacy, Seoul National University, Seoul 08826,
Republic of Korea; orcid.org/0000-0002-7536-8462;
Email: shinj@snu.ac.kr
Authors
Oh-Seok Kwon − Natural Products Research Institute, College
of Pharmacy, Seoul National University, Seoul 08826,
Republic of Korea
Sungjin Ahn − Natural Products Research Institute, College of
Pharmacy, Seoul National University, Seoul 08826, Republic
of Korea
Ju-eun Jeon − Natural Products Research Institute, College of
Pharmacy, Seoul National University, Seoul 08826, Republic
of Korea
In Guk Park − Natural Products Research Institute, College of
Pharmacy, Seoul National University, Seoul 08826, Republic
of Korea
Tae Hyung Won − Natural Products Research Institute, College
of Pharmacy, Seoul National University, Seoul 08826,
Republic of Korea
Chung J. Sim − Department of Biological Sciences and
Biotechnology, Hannam University, Daejeon 34430, Republic
of Korea
Figure 3. Adiponectin-secretion-stimulating activity of psammocin-
doles (1−4) and isopsammocindoles (5−8) in hBM-MSCs. (A)
Adiponectin-secretion-stimulating activity was determined by co-
treatment of each compound with an IDX medium in hBM-MSCs.
Adiponectin levels were measured by enzyme-linked immunosorbent
assay (ELISA). Aspirin (Asp), pioglitazone (Pio), and bezafibrate
(Beza) were used as positive controls. (B) EC50 values were calculated
by the concentration−response analysis. (C) Effects of compounds 1
and 2 on adipocyte phenotypes were visualized by oil red O (ORO) and
hematoxylin staining. Values represent the mean standard deviation
(SD) (n = 3). (∗) p ≤ 0.05 and (∗∗) p ≤ 0.01.
Hyeung-geun Park − College of Pharmacy, Seoul National
University, Seoul 08826, Republic of Korea; orcid.org/
0000-0002-9645-8221
Dong-Chan Oh − Natural Products Research Institute, College
of Pharmacy, Seoul National University, Seoul 08826,
Republic of Korea; orcid.org/0000-0001-6405-5535
Ki-Bong Oh − College of Agriculture and Life Sciences, Seoul
National University, Seoul 08826, Republic of Korea
prescribed pan-PPAR agonist, while compounds 3−8 were less
significant (EC50 of >10 μM) (Figure 3B). Furthermore,
compounds 1 and 2 increased the lipid accumulation in
differentiated adipocytes in hBM-MSCs compared to that of
the IDX control, suggesting that they improve insulin sensitivity,
like pioglitazone (Figure 3C). Thus, these compounds could be
used as a novel pharmacophore for therapeutic agents treating
human metabolic diseases. Further investigation is currently
undergoing for the molecular mechanisms and therapeutic
advantages of these compounds and will be reported in due
course.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01410
Author Contributions
In summary, psammocindoles A−C (1−3), indole alkaloids,
were isolated from the Korean sponge P. vermis. The structures
of these compounds were determined to be the indole-γ-lactams
of a new structural class derived from three amino acid residues
by combined spectroscopic analyses. These compounds, an
enantiomer psammocindole D (4), and the corresponding N-
lactam isomers isopsammocindoles A−D (5−8) were prepared
by a facile synthesis. The natural products and synthetic
analogues exhibited significant adiponectin-secretion-stimulat-
ing activity as well as the increment of lipid accumulation (1 and
2) in hBM-MSCs.
†Oh-Seok Kwon and Sungjin Ahn contributed equally to this
work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the National Center for Inter-University
Research Facilities, Korea, for providing the high-resolution
mass spectrometric data. This study was supported by the BK21
Plus Program and the National Research Foundation (NRF,
Grants 2021R1A4A2001251 and 2019R1A2C2085749) funded
by the Ministry of Science, Information and Communications
Technology (ICT) & Future Planning, Korea.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01410.
REFERENCES
■
Full experimental procedures of isolation and synthesis,
1D and 2D NMR spectra of compounds 1−8, and 1D
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AUTHOR INFORMATION
Corresponding Authors
■
Minsoo Noh − Natural Products Research Institute, College of
Pharmacy, Seoul National University, Seoul 08826, Republic
of Korea; orcid.org/0000-0002-4020-5372;
Email: minsoonoh@snu.ac.kr
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