Structure-Activity Relationship Study of Majusculamides A and B and Their Analogues on Osteogenic Activity

Article abstract of DOI:10.1021/acs.jnatprod.0c00441

We discovered that majusculamide A (1) and majusculamide B (2), isolated from a marine cyanobacterium collected in Okinawa, induced osteoblast differentiation in MC3T3-E1 cells. Although majusculamide A (1) has a different configuration only at the C-19 stereocenter, bearing a methyl group, compared to majusculamide B (2), the effect of 1 was stronger than that of 2. We synthesized some analogues of the majusculamides (3-15) and evaluated osteogenic activities of these analogues. The structure-activity relationship study of majusculamide analogues suggested that the number of methyls and configuration at C-19 and the nature of the substituent at C-20 of majusculamide A (1) may be important for the osteoblast differentiation-inducing effect of 1.

Full text of DOI:10.1021/acs.jnatprod.0c00441

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Article
Structure−Activity Relationship Study of Majusculamides A and B
and Their Analogues on Osteogenic Activity
Noriyuki Natsume, Kaori Ozaki, Daisuke Nakajima, Satoshi Yokoshima, and Toshiaki Teruya*
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ABSTRACT: We discovered that majusculamide A (1) and
majusculamide B (2), isolated from a marine cyanobacterium
collected in Okinawa, induced osteoblast differentiation in
MC3T3-E1 cells. Although majusculamide A (1) has a different
configuration only at the C-19 stereocenter, bearing a methyl
group, compared to majusculamide B (2), the effect of 1 was
stronger than that of 2. We synthesized some analogues of the
majusculamides (3−15) and evaluated osteogenic activities of
these analogues. The structure−activity relationship study of
majusculamide analogues suggested that the number of methyls
and configuration at C-19 and the nature of the substituent at C-20 of majusculamide A (1) may be important for the osteoblast
differentiation-inducing effect of 1.
keletal health is maintained by bone remodeling through
the resorption of old bone by osteoclasts and the
majusculamide B13 (2) and discovered that 1 and 2 induce
osteoblast differentiation in MC3T3-E1 cells. In this study, we
report the effect of majusculamide A (1), majusculamide B (2),
and its synthetic derivatives (3−15) on osteoblast differ-
entiation of MC3T3-E1 cells.
S
formation of new bone by osteoblasts. An imbalance between
bone resorption and formation causes bone-decreasing
disorders such as osteoporosis, rheumatoid arthritis, and
periodontitis.1 Because most bone diseases are caused by
increased bone resorption, most therapeutic agents are
inhibitors of bone resorption include bisphosphonates,
calcitonin, estrogen, and selective estrogen receptor modulator
(SERMs).1,2 However, bone loss by resorption may far exceed
the effect of the inhibitor. Therefore, developing stimulators of
bone formation is highly desired to treat osteoporosis.1
Marine organisms are rich sources of bioactive substances in
drug discovery.3,4 Marine cyanobacteria are often prolific
producers of secondary metabolites with various bioactivities
reported, including antibacterial, antifungal, and anticancer
natural products.5 In recent years, there is growing interest in
marine cyanobacteria bioactive compounds to treat skeletal
diseases including osteoporosis. For example, biselyngbyaside,
a macrolide glycoside isolated from a Lyngbya sp., inhibited
osteoclastogenesis.6,7 Bromo-honaucin A, a derivative of
honaucin A isolated from a Leptolyngbya crossbyana, inhibited
osteoclastogenic differentiation.8,9 Largazole, a cyclic depsipep-
tide isolated from a Symploca sp., exhibited in vitro and in vivo
osteogenic activity mediated through the increased expression
of Runx2 and bone morphogenetic proteins (BMPs).10,11
As part of our continuing search for new bioactive secondary
metabolites from marine cyanobacteria, we recently isolated
three new malyngamides, which stimulated glucose uptake in
cultured L6 myotubes by activation of AMP-activated protein
kinase (AMPK), from a strain of Moorea producens.12 In this
process, we also isolated majusculamide A13 (1) and
RESULTS AND DISCUSSION
■
The M. producens marine cyanobacterium (200 g, wet weight)
was collected at Bise, Okinawa Prefecture, Japan, and extracted
with MeOH. The extract was filtered, concentrated, and
partitioned between EtOAc and H2O. The EtOAc-soluble
material was further partitioned between 90% aqueous MeOH
and n-hexane. The material obtained from the aqueous MeOH
portion was then subjected to fractionation using reversed-
phase column chromatography (octadecylsilyl (ODS) silica
gel, MeOH−H2O) and repeated reversed-phase HPLC to
yield majusculamide A (1, 3.3 mg) and majusculamide B (2,
32.0 mg).
Majusculamide A (1) and majusculamide B (2) were
obtained as colorless oils. The molecular formulas of 1 and 2
were found to be C28H45N3O5 by HRESIMS. The chemical
1
structures of 1 and 2 were determined from their H NMR
spectra measured in DMSO-d6 and optical specific rotations by
comparison with reported data.13
Received: April 21, 2020
© XXXX American Chemical Society and
American Society of Pharmacognosy
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Figure 1. Structures of majusculamides A (1) and B (2) and synthetic derivatives (3−15).
To evaluate the biological activities of majusculamide A (1)
and majusculamide B (2), we carried out several types of
bioassays and found that 1 and 2 promote osteoblast
differentiation of MC3T3-E1 cells without affecting cell
viability. Although majusculamide A (1) only differs from
majusculamide B (2) in the configuration at C-19, the activity
of 1 was more potent than that of 2. To confirm whether
natural and synthetic 1 and 2 have similar activities, we
measured their alkaline phosphatase (ALP) activities in
MC3T3-E1 cells. Synthetic 1 and 2 were prepared according
to the previously reported synthetic scheme.14 Synthetic 1 and
2 promoted ALP activity to a similar extent to the natural
compounds without affecting cell viability (Figure 2a,b).
In an effort to identify a compound that exhibits a more
potent osteoblast differentiation-inducing activity than majus-
culamide A (1), we synthesized a series of derivatives (Figure
1) and compared their effects on osteoblast differentiation in
MC3T3-E1 cells with synthetic 1 and 2.
the methyl and/or the carbonyl group was modified.
Preparation of the dipeptide unit 16 by our reported
procedure,14 followed by condensations with a variety of
carboxylic acids 17a−g, produced derivatives 3−9 (Scheme 1).
Derivatives having a shorter or longer carbon chain
(compounds 10−12) were synthesized via a two-step sequence
involving condensation of the dipeptide unit 16 with the
corresponding α-methyl-β-hydroxycarboxylic acids 17h−j,
followed by oxidation of the alcohol moiety with Dess−Martin
periodinane (Scheme 2). For preliminary screening of the
amino acid unit, derivatives 13−15 were synthesized by using
D-dichlorotyrosine, L-alanine, or D-phenylalanine, respectively.
Conversion of the dipeptide units into the corresponding α-
methyl-β-hydroxyamides was conducted according to the same
two-step procedure as for the synthesis of 10−12 by
employing 17e as the carboxylic acid unit.
To evaluate the effectiveness of the newly synthesized
derivatives on osteogenic activity, we measured their ability to
modulate ALP activity and mineralization in MC3T3-E1 cells.
Majusculamide B (2) promoted ALP activity and mineraliza-
To clarify the roles of the functional groups on the fatty acid
unit, a series of derivatives (3−9) were synthesized in which
B
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Scheme 2. Preparation of Derivatives 10−12
a
b
Yield for the first step (condensation). Yield for the second step
(oxidation).
tion as visualized by Alizarin Red S staining (Figure 3b,c), but
was less potent than majusculamide A (1). Compound 5,
which does not have a substituent at the C-19 position,
promoted ALP activity to a similar extent to majusculamide A
(1) (Figure 3b), but markedly suppressed mineralization
(Figure 3c). Compound 6, with two methyl groups at the C-19
position, promoted ALP activity to the same level as 1 (Figure
3b), but decreased mineralization (Figure 3c). Compounds 3
and 4, which do not have a carbonyl group at the C-20
position, markedly decreased both ALP activity and mineral-
ization compared with 1 (Figure 3b,c). Additionally, both
compounds significantly reduced cell viability at 30 μM
(Figure 3a). Compounds 7 and 8, where the carbonyl group
at the C-20 position is substituted with a hydroxy group,
promoted ALP activity at 30 μM, but were less potent than 1
(Figure 3b). Compound 8 promoted mineralization to the
same level as 1, whereas compound 7 significantly reduced
mineralization (Figure 3c). Compound 9, which does not have
any substituents at the C-19 and C-20 positions, promoted
ALP activity and mineralization, but was less potent than 1
Figure 2. Comparison of natural and synthetic products of
majusculamides A (1) and B (2) on ALP activity in MC3T3-E1
cells. (a) MC3T3-E1 cells were cultured with or without natural and
synthetic products of majusculamides A (1) and B (2) for 6 days. The
cell viability was measured by MTT assay. (b) MC3T3-E1 cells were
cultured with or without natural and synthetic products of
majusculamides A (1) and B (2) in osteogenic medium (25 μg/mL
ascorbic acid, 10 mM β-glycerophosphate) for 6 days. After the
culture, the cells were fixed and the ALP activity was measured.
Harmine was used as a positive control. The data represent the mean
SEM of three independent experiment. *p < 0.05, **p < 0.01, ***p
< 0.001 vs control cells.
Scheme 1. Preparation of Derivatives 3−9
a
Yield in two steps from the corresponding benzyl ester, which was subjected to hydrogenolysis prior to the condensation. For details, see
Supporting Information.
C
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Figure 3. Effects of majusculamide A (1), majusculamide B (2), and its derivatives (3−15) on osteoblast differentiation in MC3T3-E1 cells. (a)
MC3T3-E1 cells were cultured with or without synthetic compounds 1−15 for 6 days. The cell viability was measured by MTT assay. (b, c)
MC3T3-E1 cells were cultured with or without synthetic compounds 1−15 in osteogenic medium (25 μg/mL ascorbic acid, 10 mM β-
glycerophosphate) for 6 days. After the culture, the cells were fixed and the ALP activity was measured (b). Osteoblastic mineralization was
determined by Alizarin Red S staining (c). Harmine (Har, 10 μM) was used as a positive control. The data represent the mean SEM of three
independent experiment. *p < 0.05, **p < 0.01, ***p < 0.001 vs control cells.
(Figure 3b,c). Additionally, compound 9 significantly reduced
cell viability at 30 μM (Figure 3a).
Compound 15, where the N,O-dimethyltyrosine residue of 1
was substituted with an N-methylphenylalanine residue, had
similar ALP activity to 1 (Figure 3b), but slightly reduced
mineralization (Figure 3c).
Compounds 10 and 11, which have shorter fatty acid carbon
chains than 1, promoted ALP activity at 30 μM (Figure 3b),
but markedly reduced mineralization compared with 1 (Figure
3c). In contrast, compound 12, which has a long fatty acid
carbon chain, promoted ALP activity to the same level as 1 at
15 μM (Figure 3b), but significantly reduced mineralization
(Figure 3c). Additionally, MC3T3-E1 cell viability was
significantly reduced when compound 12 was tested at 30
μM (Figure 3a).
Compound 13, with chloro groups added to the C-12 and
C-14 positions of the N,O-dimethyltyrosine residue, did not
promote ALP activity or mineralization (Figure 3b,c). The cell
viability was significantly reduced when MC3T3-E1 cells were
incubated with 30 μM compound 13 (Figure 3a).
In terms of the structure−activity relationships, the results
indicated that the configuration and presence of the methyl
group at the C-19 position played a very important role in the
osteoblast differentiation-inducing action of majusculamide A
(1). Furthermore, the nature of the substituent at C-20
strongly affected the cytotoxicity toward MC3T3-E1 cells.
Additionally, changes in the fatty acid carbon chain length and
types of amino acid residues may slightly affect the level of
mineralization induction. It is well known that the length of the
fatty acid carbon chain affects its bioactivity. For instance, it
has been reported that the carbon chain length of saturated
fatty acids affects the activity of caspase 3 involved in apoptosis
induction.15 This report is consistent with the increased
cytotoxicity of compound 12, which has a long fatty acid
carbon chain. Salinosporamide A (anticancer agent), vanco-
mycin (antibiotic), and rebeccamycin (antibacterial agent) are
halogenated compounds.16 The presence of halogen groups in
Compound 14, where the N-methylvaline residue of 1 was
substituted with an N-methylalanine residue, had similar ALP
activity. On the other hand, compound 14 (7.5 μM, 15 μM)
promoted mineralization similar to 1, but was significantly
suppressed at 30 μM (Figure 3c).
D
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10 × 250 mm), 60% MeCN at 4.0 mL/min, UV detection at 215 nm]
to yield majusculamide A (1, 3.3 mg, tR = 13.0 min). Furthermore,
fraction 4 (tR = 21.2 min) was subjected to further HPLC [Cosmosil
5C18-AR-II (ϕ 20 × 250 mm), 60% MeCN at 5.0 mL/min, UV
detection at 215 nm] to yield majusculamide B (2, 32.0 mg, tR = 41.4
min).
organic compounds is known to have a significant effect on
their pharmacological activities. For example, deschloro-
rebeccamycin has no antibacterial activity.17 In contrast,
halogenation of resveratrol, from grapes, increases the
antioxidant and antibacterial activities.18 However, compound
13, having a chloro group, did not exhibit any osteoblast
differentiation-inducing action. This suggests that the addition
of a halogen group to 1 strongly decreases its osteoblast
differentiation-inducing action.
In this study, we found that majusculamide A (1) and
majusculamide B (2), which were isolated from a collection of
the marine cyanobacterium M. producens, induced osteoblast
differentiation of MC3T3-E1 cells. In particular, 1 had a strong
osteoblast differentiation-inducing effect. Structure−activity
relationship studies suggested that the number of methyls
and configuration at C-19 and the nature of the substituent at
C-20 of 1 may be important for the osteoblast differentiation-
inducing effect of 1. However, none of the synthetic derivatives
in this study showed a stronger osteoblast differentiation-
inducing effect than 1. Although further research is needed,
majusculamide A (1) is expected to be promising as a lead
compound for the development of therapeutic agents for bone
metabolic diseases such as osteoporosis.
Majusculamide A (1): colorless oil; [α]26 +21.3 (c 0.27, EtOH)
D
{lit.13 [α]26 +19.3 (c 1.14, EtOH)}; HRESIMS m/z [M + Na]+
D
526.3237 (calcd for C28H45N3NaO5, 526.3257).
Majusculamide B (2): colorless oil; [α]26 +21.2 (c 1.00, EtOH)
D
{lit.13 [α]26 +14.6 (c 0.82, EtOH)}; HRESIMS m/z [M + Na]+
D
526.3282 (calcd for C28H45N3NaO5, 526.3257).
Culturing of MC3T3-E1 Cells. MC3T3-E1 cells, an osteoblastic
cell line from mouse calvaria, were obtained from the RIKEN Cell
Bank. MC3T3-E1 cells were cultured in MEM-α supplemented with
10% fetal bovine serum (FBS) and antibiotics (100 units/mL
penicillin and 10 μg/mL streptomycin) at 37 °C under a humidified
5% CO2 atmosphere.
Cell Viability. In the cell viability assay, MC3T3-E1 cells were
seeded in 96-well plates at a cell density of 5000 cells/well and
cultured for 2 days. After reaching confluency, the cells were further
incubated with or without compounds for 6 days. The cell viability
was determined as an indicator of living cells using an MTT reagent
(Thiazolyl Blue tetrazolium bromide). The absorbance was measured
at 480 nm using a microplate reader.
Osteoblast Differentiation. MC3T3-E1 cells were seeded in 96-
well plates at a cell density of 5000 cells/well and cultured for 2 days.
After reaching confluency, the cells were further incubated with or
without compounds for 6 days and fixed with ice-cold 100% MeOH.
The fixed cells were incubated in ALP substrate buffer (100 mM Tris-
HCl pH 8.5, 2 mM MgCl2, 7.3 mM 4-nitrophenyl phosphate) at room
temperature. The absorbance at 405 nm was measured as the ALP
activity using a microplate reader.
MC3T3-E1 cells were incubated with or without compounds in
osteogenic medium (25 μg/mL ascorbic acid, 10 mM β-
glycerophosphate) for 6 days and fixed with ice-cold 100% MeOH.
Mineralization of the extracellular matrix was determined by Alizarin
Red S staining, which stains calcium. After cell fixation, 1% Alizarin
Red S solution was added and incubated at rt. Alizarin Red was
solubilized by incubation in 10% acetic acid at rt. The absorbance at
490 nm was measured using a microplate reader.
EXPERIMENTAL SECTION
■
General Experimental Procedures. Melting points (mp) were
determined on a Yanaco micro melting point apparatus. Optical
rotations were measured on a JASCO P-1010 or JASCO P-2200
1
polarimeter. H NMR spectra were recorded on a Bruker AVANCE
III 500 MHz NMR spectrometer (500 MHz), a JEOL-ECS400
instrument (400 MHz), or a JEOL-ECZ400 instrument (400 MHz).
Chemical shifts are reported as δ values in parts per million relative to
the residual solvent signal (DMSO-d6: δH 2.50; CDCl3: δH 7.26). 13
C
NMR spectra were recorded on a Bruker AVANCE III 500 MHz
NMR spectrometer (125 MHz), a JEOL-ECS400 instrument (100
MHz), or a JEOL-ECZ400 instrument (100 MHz) with CDCl3 as a
solvent. Chemical shifts are reported in parts per million from the
solvent signal (CDCl3: δC 77.2). HRESIMS was performed on a
Waters Micromass Q-TOF spectrometer or JEOL JMS-T100LP
AccuTOF LC-Plus. HPLC was carried out with a JASCO PU-2080
Plus Intelligent HPLC pump and a JASCO UV-2075 Plus Intelligent
UV/vis detector. Analytical thin layer chromatography (TLC) was
performed on Merck precoated analytical plates, 0.25 mm thick, with
silica gel 60 F254. Preparative TLC separations were performed on
Merck analytical plates (0.25 or 0.50 mm thick) precoated with silica
gel 60 F254 unless otherwise noted. Flash chromatography
separations were performed on Kanto Chemical silica gel 60
(spherical, 40−100 mesh) unless otherwise noted. The absorbance
of the assay mixture was determined using a BioTek ELx 800
absorbance microplate reader. Chemicals and solvents were the best
grade available and used as received from commercial sources.
Extraction and Isolation. Samples of the M. producens marine
cyanobacterium were collected by hand from the coast of Bise,
Okinawa Prefecture, Japan (26°42′ N, 127°52′ E), in April 2016.10
Approximately 200 g (wet weight) of the cyanobacterial samples were
extracted with MeOH (650 mL) at room temperature (rt) for 1 day.
The extract was filtered, and the filtrate was concentrated. The residue
was partitioned between H2O (0.2 L) and EtOAc (0.2 L × 3). The
material obtained from the organic layer was further partitioned
between 90% aqueous MeOH (0.1 L) and n-hexane (0.1 L × 3). The
aqueous MeOH fraction (589.0 mg) was separated by column
chromatography on ODS (6.0 g) using 40% aqueous MeOH, 60%
aqueous MeOH, 80% aqueous MeOH, and MeOH. The fraction
(308.0 mg) eluted with 80% MeOH was subjected to reversed-phase
HPLC [Cosmosil 5C18-AR-II (ϕ 20 × 250 mm), 85% MeOH at 5.0
mL/min, UV detection at 215 nm] to give 10 fractions. Fraction 2 (tR
= 20.9 min) was subjected to further HPLC [Cosmosil 5C18-AR-II (ϕ
Statistical Analysis. All data are expressed as the mean SEM.
Differences between groups were compared by using one-way
ANOVA with a post-Tukey test. p < 0.05 was considered statistically
significant.
Total Synthesis Procedures. Syntheses of the dipeptide unit 16
and derivatives 7 and 8 were recently reported.14 Preparations of
carboxylic acids 17a−j and other dipeptide units for the synthesis of
derivatives 13−15 are described in the Supporting Information.
General Procedure for Preparation of Derivatives 3−9 via
Condensation of the Dipeptide Unit 16 and Carboxylic Acids.
To a solution of the dipeptide unit 16 (1 equiv), a carboxylic acid (1
equiv), and N,N-diisopropylethylamine (3 equiv) in N,N-dimethyl-
formamide (DMF, 0.1 M) was added 1-[bis(dimethylamino)-
methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluoro-
phosphate (HATU, 1.1 equiv) at 0 °C. After stirring for the
designated time at rt, the reaction was quenched with saturated
aqueous ammonium chloride solution, and the resulting mixture was
extracted three times with EtOAc. The combined organic phases were
washed successively with aqueous sodium bicarbonate solution and
with 10% aqueous sodium chloride solution, dried over anhydrous
sodium sulfate, and concentrated under reduced pressure. The crude
product was purified by preparative thin layer chromatography to give
the pure amide.
General Procedure for Preparation of Derivatives 10−15 (α-
Methyl-β-keto Derivatives). To a solution of an α-methyl-β-
hydroxycarboxylic acid (1−1.5 equiv) in DMF (0.15 M) were added
HATU (1.1 equiv) and N,N-diisopropylethylamine (1 equiv) at 0 °C.
After stirring for 15 min at the same temperature, a solution of a
dipeptide unit (1 equiv) and N,N-diisopropylethylamine (2 equiv) in
E
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DMF (0.15 M) was added dropwise at 0 °C. After stirring for the
designated time at rt, the reaction was quenched with 10% aqueous
sodium chloride solution. The resulting mixture was extracted three
times with EtOAc. The combined organic phases were washed with
aqueous sodium bicarbonate solution, dried over anhydrous sodium
sulfate, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography to give the β-
hydroxyamide. To a solution of the β-hydroxyamide (1 equiv) in
CH2Cl2 (0.15 M) were added sodium bicarbonate (1.9 equiv) and
Dess−Martin periodinane (1.5 equiv) at 0 °C. After stirring for 1 h at
rt, aqueous solutions of sodium bicarbonate and sodium thiosulfate
were added to the reaction mixture. The resulting mixture was
extracted three times with EtOAc. The combined organic layer was
dried over anhydrous sodium sulfate and concentrated under reduced
pressure. The residue was purified by preparative thin layer
chromatography to give the α-methyl-β-keto derivatives.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.jnatprod.0c00441.
■
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NMR spectra of natural 1, natural 2, and synthetic
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AUTHOR INFORMATION
Corresponding Author
■
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Mehmeti, I.; Lenzen, S. Biochim. Biophys. Acta, Mol. Basis Dis. 2019,
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Toshiaki Teruya − Graduate School of Engineering and Science,
University of the Ryukyus, Nishihara, Okinawa 903-0213,
Japan; Faculty of Education, University of the Ryukyus,
Nishihara, Okinawa 903-0213, Japan; orcid.org/0000-
0002-7018-7734; Email: t-teruya@edu.u-ryukyu.ac.jp
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(17) Pereira, E. R.; Belin, L.; Sancelme, M.; Prudhomme, M.; Ollier,
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M.; Rapp, M.; Severe, D.; Riou, J. F.; Fabbro, D.; Meyer, T. J. Med.
Chem. 1996, 39, 4471−4477.
(18) Li, X. Z.; Wei, X.; Zhang, C. J.; Jin, X. L.; Tang, J. J.; Fan, G. J.;
Zhou, B. Food Chem. 2012, 135, 1239−1244.
Authors
Noriyuki Natsume − Graduate School of Engineering and
Science, University of the Ryukyus, Nishihara, Okinawa 903-
0213, Japan
Kaori Ozaki − Graduate School of Engineering and Science,
University of the Ryukyus, Nishihara, Okinawa 903-0213,
Japan; orcid.org/0000-0002-8668-5260
Daisuke Nakajima − Graduate School of Pharmaceutical
Sciences, Nagoya University, Nagoya 464-8601, Japan
Satoshi Yokoshima − Graduate School of Pharmaceutical
Sciences, Nagoya University, Nagoya 464-8601, Japan;
orcid.org/0000-0003-4036-0062
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.jnatprod.0c00441
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported in part by a Grant-in-Aid for Young
Scientists (B) (15K01803) from the Ministry of Education,
Culture, Sports, Science and Technology, Japan, by a
University of the Ryukyus Strategic Research Grant, and by
the Platform Project for Supporting Drug Discovery and Life
Science Research (Basis for Supporting Innovative Drug
Discovery and Life Science Research; BINDS) from the
Japan Agency for Medical Research and Development
(AMED) under Grant Number JP19am0101099.
REFERENCES
(1) Rodan, G. A.; Martin, T. J. Science 2000, 289, 1508−1514.
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J. Nat. Prod. XXXX, XXX, XXX−XXX