Flabelliferins A and B, sesterterpenoids from the south pacific sponge Carteriospongia flabellifera

Article abstract of DOI:10.1021/np3003518

Two new sesterterpenoids named flabelliferins A (1) and B (2) were isolated from the lipophilic extract of the sponge Cateriospongia flabellifera, collected in the South Pacific near Vanuatu. The structure and absolute configuration of these two compounds were assigned by a combination of one- and two-dimensional NMR spectroscopy and by Mosher's ester analysis. Flabelliferin A (1) has a rare 25-homocheilanthane carbon skeleton, while flabelliferin B (2) is a 24-nor-25-homoscalarane sesterterpenoid.

Full text of DOI:10.1021/np3003518

Note
pubs.acs.org/jnp
Flabelliferins A and B, Sesterterpenoids from the South Pacific
Sponge Carteriospongia flabellifera
Thushara Diyabalanage,† Ranjala Ratnayake,† Heidi R. Bokesch,†,‡ Tanya T. Ransom,†
Curtis J. Henrich,†,‡ John A. Beutler,† James B. McMahon,† and Kirk R. Gustafson*,†
†Molecular Targets Laboratory, Center for Cancer Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland
21702, United States
‡Basic Science Program, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702,
United States
S
* Supporting Information
ABSTRACT: Two new sesterterpenoids named flabelliferins A (1)
and B (2) were isolated from the lipophilic extract of the sponge
Cateriospongia flabellifera, collected in the South Pacific near Vanuatu.
The structure and absolute configuration of these two compounds
were assigned by a combination of one- and two-dimensional NMR
spectroscopy and by Mosher’s ester analysis. Flabelliferin A (1) has a
rare 25-homocheilanthane carbon skeleton, while flabelliferin B (2) is
a 24-nor-25-homoscalarane sesterterpenoid.
arine sponges are a rich source of novel secondary
compound or mixture of compounds. However, a side fraction
Mmetabolites with remarkable chemical diversity and a exhibited cytotoxic activity, and purification of this material
broad range of biological activities.1,2 These compounds are
provided flabelliferins A (1) and B (2).
C. flabellifera specimens were collected near Tutuba Island,
Vanuatu, in December 2000 and extracted using the standard
NCI protocol for marine invertebrate animals.10 The sponge
sample (216 g) provided quite a high yield of lipophilic extract
(9.5 g), and a 1 g portion of this material was sequentially
fractionated by batch elution from diol solid-phase media, size
exclusion chromatography on Sephadex LH-20, and C18 HPLC
to afford two new compounds, flabelliferins A (1) and B (2).
believed to play a pivotal role in defending sponges from
predation, biofouling, and microbial attack, and they apparently
provide a selective advantage in the competition for space and
other resources for their sponge hosts.3 Sponges belonging to
the order Dictyoceratida are relatively soft bodied, as they lack
calcareous or silaceous spicules, which can provide structural
rigidity and some protection from predation. These sponges
often contain sesterterpene metabolites, and they evidently rely
on a chemical defense strategy that includes an arsenal of
sesterterpenoids.4 Many of the compounds isolated from
Dictyoceratid sponges have exhibited a range of biological
activities in laboratory and field assays such as ichthyotoxicity,
cytotoxicity, antifeedant, antibacterial, and anti-inflammatory
properties, which supports the notion they play important
ecological roles for the sponges.5,6 Carteriospongia flabellifera is
a Dictyoceratid sponge that is distributed in a wide corridor of
the Indo-Pacific Ocean ranging from Indonesia and Papua New
Guinea to the Southern Great Barrier Reef.7 There are only a
few reports in the chemical literature for this sponge species,
but one previous chemical study did describe a linear difurano
sesterterpene, 12,13-didehydrofurospongin-1, and a tetracyclic
homosesterterpene aldehyde, 16β-acetoxy-24-methyl-1,2-dioxo-
scalaran-25-al.8 An extract of C. flabellifera from the NCI
Natural Products Repository showed some initial activity in a
high-throughput screen for inhibitors of the oncogenic
transcription factor HIF-2α.9 It was selected for detailed
chemical investigation based on this observed activity and the
limited prior studies of this sponge species. During bioassay-
guided separation of the extract, the HIF-2α activity gradually
diminished and could not be tracked to an individual
The (+)-HRESIMS spectrum of flabelliferin A (1) had an [M
+ Na]+ ion at m/z 527.3352, which established a molecular
formula of C30H48O6, requiring seven unsaturation equivalents.
1
The H and 13C NMR data for 1 (Table 1) suggested it was a
sesterterpene derivative. The 13C NMR spectrum contained
five sp2 carbon resonances that were assigned to a ketone (δC
213.4), two ester carbonyls (δC 170.6, 171.0), and an olefin (δC
111.8, 145.6); thus it must be tricyclic. 13C NMR resonances
for an additional seven methyls, nine aliphatic methylenes
including one that was oxygenated (δC 62.7), six methines
including two oxymethines (δC 70.5, 76.4), and three
Received: May 17, 2012
Published: July 26, 2012
© 2012 American Chemical Society and
American Society of Pharmacognosy
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Note
Table 1. NMR Spectroscopic Data for Flabelliferins A (1) and B (2) in CDCl3
flabelliferin A (1)
flabelliferin B (2)
δH (J in Hz)
a
a
position
1a
δC, type
δH (J in Hz)
HMBC
δC, type
HMBC
40.1, CH2 0.72, m
1.54, m
10
39.9, CH2 0.62, m
1.55, m
1b
2a
18.7, CH2 1.37, m
1.56, m
1.39, m
3
2b
18.7, CH2 1.58, m
42.2, CH2 1.10, m
1.35, m
3a
42.1, CH2 1.11, m
1.34, m
2, 4, 20
2, 4, 20
4, 5
3b
4
33.4, C
33.5, C
5
56.4, CH
0.88, m
4, 20, 21
56.9, CH
0.83, m
3, 4, 7, 20
4, 5, 7, 10
5, 8
6a
19.2, CH2 1.33, m
1.60, m
18.3, CH2 1.38, m
1.56, m
6b
7a
40.5, CH2 1.18, m
1.71, m
41.1, CH2 0.96, ddd (3.4, 12.3, 13.1) 5, 8, 14, 22
7b
5, 6, 8, 9, 23
1.81, dt (3.1, 13.1)
5, 8, 9, 22
8
39.6, C
37.2, C
53.2, CH
37.4, C
9
53.3, CH
37.4, C
1.48, m
1.23, m
5, 11, 14
10
11a
28.0, CH2 1.48, m
1.87, m
22.5, CH2 1.70, m
1.72, m
8, 13
11b
12
8, 9, 13
12
76.4, CH
145.6, C
5.37, dd (2.8, 2.8)
9, 11, 13, 14, 24, 12-CO2CH3
76.8, CH
5.00, dd (2.8, 2.9)
9, 13, 14, 18, 12-CO2CH3
13
41.7, C
b
14
48.0, CH
2.36 bd (11.4)
8, 13, 15, 16, 23
47.5, CH2 1.47, m
26.6, CH2 1.46, m
2.11, m
15
15a
29.3, CH2 1.47, m
8, 13, 14, 16
16
15b
b
16
70.5, CH
55.4, CH
3.62, dd (7.4, 10.7)
14, 17, 25
68.3, CH
139.0, C
4.58, dd (7.5, 8.7)
17, 18, 24
b
17
2.67, ddd (3.8, 6.4, 10.5) 16, 18, 19, 25
18a
28.2, CH2 1.89, m
2.01, m
16, 17, 19, 25
16, 17, 19, 25
152.5, CH
6.55, s
12, 13, 14, 17, 24
3, 4, 5
18b
19a
62.7, CH2 4.06, ddd (6.7, 11.3, 17.7) 19-CO2CH3
4.08, ddd (6.3,11.5, 17.7) 19-CO2CH3
21.5, CH2 0.79, s
19b
20
21.6, CH3 0.78, s
33.5, CH3 0.83, s
16.1, CH3 0.76, s
15.0, CH3 0.63, s
111.8, CH2 4.56, bs
5.12, bs
3, 4, 5
33.5, CH3 0.84, s
16.2, CH3 0.80, s
17.3, CH3 0.88, s
21.3, CH3 1.16, s
202.4, C
3, 4, 5
21
3, 4, 5
1, 9, 10
22
1, 9, 10
8, 9, 14
12, 13, 14
12, 13, 14
7, 8, 9, 14
12, 13, 14, 18
23
24a
24b
25
213.4, C
26
32.1, CH3
25
21.8, CH3 2.23, s
171.0, C
24
12-CO2CH3
12-CO2CH3
19-CO2CH3
19-CO2CH3
170.6, C
21.6, CH3 2.03, s
171.0, C
12-CO2CH3
21.5, CH3 2.04, s
12-CO2CH3
21.1, CH3 2.02, s
19-CO2CH3
a
b
HMBC correlations are from proton(s) to stated carbons. Coupling constants measured in CD3OD.
quaternary sp3 carbons were observed. The 1H NMR spectrum
showed seven methyl singlets that could be assigned to a
methyl ketone (δH 2.21), two acetate groups (δH 2.02, 2.03),
and four aliphatic methyls (δH 0.63, 0.76, 0.78, 0.83). These
data along with extensive 2D NMR studies suggested that 1 was
a bisacetylated homosesterterpene with a cheilanthane carbon
skeleton.11 The structure and trans junction of the A and B
rings in 1 were assigned by comprehensive analysis of the NMR
data, which were in good agreement with the reported A and B
ring chemical shift values for several structurally related
sesterterpenoids.12−17
The C ring of compound 1 was assembled by a combination
of COSY coupling data and HMBC correlations observed for
H-12 (C-9, C-11, C-13, C-14) and H-14 (C-8, C-13).
Attachment of an acetyl group at C-12 was suggested by the
downfield shift of H-12 (δH 5.37) and confirmed by an HMBC
correlation between H-12 and an ester carbonyl at δC 170.6
(12-CO2CH3). Broadened olefinic singlets at δH 4.56 (H-24a)
and 5.12 (H-24b), which had HMBC correlations with C-12,
C-13, and C-14, were indicative of an exomethylene group
involving carbons 13 and 24. The presence of a C ring
exomethylene at C-13 has been reported previously in three
cheilanthane sesterterpenes isolated from the Australian sponge
Ircinia sp.17 and one from a South African nudibranch.12
Extension of the carbon side chain substituted on C-14 was
established by HMBC correlations from H-14 (δH 2.36) to the
C-15 (δC 29.3) methylene and C-16 (δC 70.5) hydroxymethine
resonances. The connectivity between H-16/H-17, H-17/H2-
18, and H2-18/H2-19 was evident from COSY correlations and
HSQCTOCSY data. A methyl ketone was connected to C-17
on the basis of HMBC correlations from H-16, H-17, H2-18,
and H3-26 to C-25 (δC 213.4). The downfield chemical shifts of
H-19a (δH 4.06) and H-19b (δH 4.08) and HMBC correlations
from each of these protons to an ester carbonyl at δC 171.0
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Note
revealed the presence of an acetyl group at C-19. These data
were consistent with the planar structure assigned for
flabelliferin A (1), a tricyclic homocheilanthane sesterterpene-
diacetate with the additional carbon appended to C-25.
The relative configuration of the A, B, and C rings and their
substituents in 1 was assigned by a series of 1D ROESY
1
experiments (Figure 1) and by comparison of the H and 13C
Figure 3. Newman projections of the two possible configurations at C-
17 with key ROESY interactions illustrated for C-17S.
molecular formula of C27H42O4, which required seven degrees
1
of unsaturation. The H and 13C NMR data of 2 revealed a
trisubstituted olefin (δC 139.0, δC/H 152.5/6.55), a methyl
ketone (δC 202.4, δC/H 21.8/2.23), and an acetate group (δC
171.0, δC/H 21.5/2.04); thus it was tetracyclic. Further NMR
analysis revealed that 2 was also a sesterterpenoid and that the
composition of rings A and B was identical to that of
compound 1. The bottom portion of the C ring of flabelliferin
B (2) was supported by HMBC correlations from H3-22 (δH
0.88) to C-8, C-9, and C-14, while HMBC correlations from H-
12 (δH 5.00) to C-9, C-13, C-14, and 12-COCH3 secured the
structure of ring C, with an acetate substituent on C-12. The
H3-23 methyl group (δH 1.16) displayed HMBC correlations
with C-12, C-13, C-14, and C-18, which helped establish the
connectivity of the C/D rings. The D ring was further
elaborated by HMBC correlations from H-15a to C-14 and H-
15b to an oxymethine at C-16. The double bond between C-17
and C-18 was supported by HMBC correlations from H-18 to
C-12, C-13, C-14, C-17, and C-24. The chemical shift of C-24
(δC 202.4) and an HMBC correlation from H3-25 (δH 2.23) to
C-24 confirmed the presence of an α,β-unsaturated methyl
ketone functionality. Thus, the planar structure of flabelliferin B
(2) was assigned as a 24-homo-25-norscalarane sesterterpenoid
with an acetate group at C-12 and a hydroxy substituent at C-
16. This structure was very similar to C28 scalarane derivative 3
recently reported from the sponge Phyllospongia papyracea,
which has an extra methyl group appended to C-20.19 The
relative configuration of 2 was assigned by comparison of its 1H
and 13C NMR data with this compound and other closely
related sesterterpenoids14,16 and by analysis of its ROESY data
(Figure 4). The β-orientation of the C-16 hydroxy group was
Figure 1. Some key 1D ROESY correlations for 1.
NMR data of 1 with other related sesterterpenoids.12−17
Selective irradiation of H3-23 provided ROESY enhancements
for H3-22, H-6a, and H2-15, which affirmed they were located
on the top face of the molecule. H-14 showed ROESY
interactions with H-7a, H-9, and H-16, which established that
they were oriented toward the bottom face. The equatorial
nature of H-12 was defined by ROESY correlations with H-11a,
H-11b, and H-24b and by the small coupling (2.8 Hz) it had
with both H-11 protons.
The absolute configuration of the secondary hydroxy group
at C-16 was then deduced using the modified Mosher’s
method.18 Comprehensive analysis of the 1H NMR resonances
of the R- and S-MTPA ester derivatives of 1 revealed a
systematic distribution of ΔδS−R values (δS − δR in ppm) that
established a 16S configuration (Figure 2). The S configuration
Figure 2. ΔδS−R values for the Mosher’s ester derivatives of flabelliferin
A (1).
at C-16 could then be related to the tricyclic portion of 1 via a
ROESY interaction between H-16 and H-14, which thus
established the absolute configuration as 5S, 8R, 9S, 10S, 12S,
and 14S.
The remaining stereogenic center at C-17 was defined by
coupling constant analysis and ROESY data (see S6 in the
Supporting Information for complete ROESY data). H-16 and
H-17 had a large coupling (approximately 10.6 Hz), and they
did not show ROESY correlations with each other, which
indicated they had an anti orientation. ROESY enhancements
from H-16 to both H2-18 and H3-26 were consistent with this
finding (Figure 3). Spectral overlap and crowding complicated
the unambiguous interpretation of ROESY data for H2-15;
however a modest ROESY interaction between H-14 and H2-
18 established that C-15 and C-18 had a gauche orientation.
Thus the absolute configuration at C-17 was established as S,
which completed the structural assignment of flabelliferin A
(1).
Figure 4. Key ROESY correlations for compound 2.
revealed by a ROESY interaction between H-16 and H-14.
Comparison of the NMR data of the C-16 oxymethine in 2
(δC/H 68.3/4.58 dd, J = 7.5, 8.7 Hz) with the corresponding
resonances in compound 3, which has a β hydroxy group (δC/H
68.1/4.59 dd, J = 7.0, 9.0 Hz), and with two recently reported
scalaranes from C. foliascens that have α-substituted hydroxy
groups (δC/H 63.3/4.54 d, J = 4.1 Hz; δC/H 63.2/4.54 d, J = 4.1
Hz)20 confirmed this assignment.
Application of the modified Mosher’s method to determine
the absolute configuration of the secondary alcohol at C-16 in 2
showed that it was R (Figure 5).
An [M + Na]+ pseudomolecular ion at m/z 453.2972 in the
HRESIMS spectrum of flabelliferin B (2) established a
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Note
nm; IR (thin film) 3443 (br), 2860, 1733, 1608, 1452, 1404, 1050,
1
876, 824, 687 cm−1; H and 13C NMR data, see Table 1; HRESIMS
m/z [M + Na]+ 527.3352 (calcd for C30H48O6Na, 527.3343).
Flabelliferin B (2): colorless, amorphous solid; [α]25 3.2 (c 0.91,
D
MeOH); UV (MeOH) λmax (log ε) 203 (4.16), 226 (3.80), nm; IR
(thin film) 3468 (br), 2924, 2859, 1733, 1607, 1452, 1403, 1050, 875,
1
824, 687 cm−1; H and 13C NMR data, see Table 1; HRESIMS m/z
[M + Na]+ 453.2972 (calcd for C27H42O4Na, 453.2975).
Preparation of the MTPA Esters of Flabelliferin A (1). A 300
μg aliquot of 1 was dissolved in 50 μL of anhydrous pyridine. To this
solution was added 1 μL of R-MTPACl dissolved in 100 μL of
anhydrous pyridine and a catalytic amount of 4-N,N-dimethylamino-
pyridine (DMAP). The mixture was allowed to react for 16−20 h at
room temperature (rt) and then quenched by the addition of a few
drop of aqueous MeOH. The solvents were removed under vacuum to
provide a white solid. This solid was triturated with EtOAc, and the
EtOAc-soluble material was passed through a small silica column to
provide the S-MTPA ester of 1: LRMS m/z [M + Na]+ 743.7, [M +
Figure 5. ΔδS−R values for the Mosher’s ester derivatives of flabelliferin
B (2).
Flabelliferins A (1) and B (2) were tested in a HIF-2α
inhibition assay,9 but they were both inactive. In a cytotoxicity
assay employing the human colon tumor cell lines KM12 and
COLO205 neither compound was potent enough to be
considered truly cytotoxic (IC50 < 10 μM). However, they
did exhibit growth inhibitory effects, as compound 1 had IC50
values of 15 and 20 μM, respectively, while 2 had IC50 values of
18 and approximately 20 μM, respectively. The modest growth
inhibitory activity of compounds 1 and 2 and their close
structural resemblance to other bioactive cheilanthane and
scalarane sesterterpenes suggest they may function as part of
the chemical defense mechanism of C. flabellifera.
1
H2O]+ 738.7; H NMR (CDCl3) δ 1.75 (H-14), 1.51 (H2-15), 5.23
(H-16), 3.02 (H-17), 1.73 (H-18a), 2.14 (H-18b), 3.92 (H-19a), 3.98
(H-19b), 4.37 (H-24a), 0.52 (H3-23), 2.11 (H3-26). Flabelliferin A (1)
was reacted in an analogous manner using 5 μL of S-MTPACl to
provide the R-MTPA ester of 1: LRMS m/z [M + Na]+ 743.8, [M +
1
H2O]+ 738.7; H NMR (CDCl3) δ 1.93 (H-14), 1.60 (H2-15), 5.22
(H-16), 2.97 (H-17), 1.60 (H-18a), 2.06 (H-18b), 3.87 (H-19a), 3.91
(H-19b), 4.40 (H-24a), 0.54 (H3-23), 2.09 (H3-26).
Preparation of the MTPA Esters of Flabelliferin B (2). A 200
μg aliquot of 2 in 100 μL of anhydrous pyridine was treated with 5 μL
of R-MTPACl and a small crystal of DMAP. The mixture was allowed
to react for 16−20 h at rt and then quenched by the addition of a few
drops of aqueous MeOH. The solvents were removed under a stream
of N2 to provide a white solid. This solid was triturated with EtOAc,
and the EtOAc-soluble material was passed through a small silica
column to provide the S-MTPA ester of 2: LRMS m/z (M + Na)+
EXPERIMENTAL SECTION
■
General Experimental Procedures. Optical rotations were
measured on a Perkin-Elmer 241 polarimeter using a Na lamp at 25
°C. Ultraviolet−visible spectra were measured on a Varian Cary 50 Bio
UV spectrophotometer. Infrared spectra were obtained with a Perkin-
Elmer Spectrum 2000 FT-IR spectrometer. 1H, 13C, gHSQC,
gHMBC, and 1H−1H COSY NMR spectra were acquired on a Bruker
Avance AV-III spectrometer equipped with a 3 mm TXI cryogenic
probe and operating at 600 MHz for 1H and 150 MHz for 13C.
Selective 1D gROESY spectra were recorded on a Varian Inova 500
NMR spectrometer operating at 500 MHz for H. H chemical shifts
were recorded relative to δ 7.24 (CDCl3), while 13C resonances were
referenced to δ 77.23 (CDCl3). HPLC purifications were performed
with a Rainin Dynamax C18 column (250 × 10 mm), using a Varian
Prostar multisolvent delivery system connected to a Varian Prostar
photodiode array detector.
1
668.8; H NMR (CDCl3) δ 0.99 (H-7a), 4.98 (H-12), 1.51 (H-14),
1.33 (H-15a), 2.37 (H-15b), 6.05 (H-16), 6.62 (H-18), 0.82 (H3-22),
1.05 (H3-23). Flabelliferin B (2) was reacted in an analogous manner
using 10 μL of S-MTPACl to generate the R-MTPA ester of 2: LRMS
m/z (M + Na)+ 668.7, (M + H2O)+ 664.7; 1H NMR (CDCl3) δ 1.12
(H-7a), 4.97 (H-12), 1.55 (H-14), 1.54 (H-15a), 2.38 (H-15b), 6.09
(H-16), 6.53 (H-18), 0.87 (H3-22), 1.03 (H3-23).
Antiproliferative Bioassay. DMSO solutions of flabelliferin A (1)
and flabelliferin B (2) were assayed for antiproliferative activity using
KM12 and COLO205 human colon tumor cell lines. Experimental
details of this two-day, in vitro, XTT-based assay have been described
previously.21
1
1
Animal Material. Samples of the sponge Carteriospongia
flabellifera were collected in Vanuatu, 200 m offshore in shallow
waters near NW Tutuba Island (latitude 167°16.59′ E; longitude
15°33.32′ S), on Dec 2, 2000. The sponge was identified by Lori J. B.
Colin (Coral Reef Research Foundation, Koror, Palau), and a voucher
specimen is maintained by the Smithsonian Institution, Washington,
D.C. (collection number 0CDN7742).
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR, 13C NMR, HSQC, HMBC, and ROESY data for
compounds 1 and 2. This material is available free of charge via
the Internet at http://pubs.acs.org.
Sponge Extraction and Isolation. Ground animal material (214
g) was extracted with MeOH−CH2Cl2 (1:1) and subsequently with
100% MeOH, according to the standard extraction protocol used by
the NCI Natural Products Support Group.10 The extract solutions
were combined and evaporated under reduced pressure to provide 9.5
g of crude organic solvent extract (NSC #C021349). A portion of this
extract (1 g) was fractionated by elution using a diol stationary phase
(15 g) with the following series of solvents: (1) hexane; (2) CH2Cl2;
(3) EtOAc; (4) MeOH. The material that eluted with CH2Cl2 was
further separated by size exclusion chromatography on a column of
Sephadex LH-20 eluted with hexane−CH2Cl2−MeOH (2:5:1). Final
purification by C18 HPLC using a contiguous series of CH3CN−H2O
gradients (10−90% CH3CN over 10 min; 90−100% CH3CN over 5
min; 100% CH3CN for 25 min) afforded compounds 1 (3.5 mg) and 2
(1.1 mg).
AUTHOR INFORMATION
Corresponding Author
*Tel: (301) 846-5197. Fax: (301) 846-6851. E-mail: gustafki@
mail.nih.gov.
Notes
■
The authors declare no competing financial interests.
ACKNOWLEDGMENTS
■
We gratefully acknowledge D. Newman (NCI) and T.
McCloud (SAIC-Frederick) for the sponge extracts and M.
Dyba and S. Tarasov (Biophysics Resource, Structural
Biophysics Laboratory, CCR) for assistance in acquiring high-
resolution mass spectra. This research was supported in part by
the Intramural Research Program of NIH, Frederick National
Flabelliferin A (1): colorless, amorphous solid; [α]25 4.8 (c 0.25,
D
MeOH); UV (MeOH) λmax (log ε) 251 (2.99), 257 (2.98), 263 (2.85)
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Laboratory for Cancer Research, Center for Cancer Research.
This project has been funded in whole or in part with Federal
funds from the Frederick National Laboratory for Cancer
Research, National Institutes of Health, under contract
HHSN261200800001E. The content of this publication does
not necessarily reflect the views or policies of the Department
of Health and Human Services, nor does mention of trade
names, commercial products, or organizations imply endorse-
ment by the U.S. Government.
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