Rubiyunnanins A and B, two novel cyclic hexapeptides from Rubia yunnanensis

Article abstract of DOI:10.1016/j.tetlet.2010.07.066

Two novel cyclic hexapeptides, named rubiyunnanins A (1) and B (2), were isolated from the roots of Rubia yunnanensis (Franch.) Diels. Their structures were elucidated extensively by spectroscopic analysis and theoretical computation. Possible biosynthetic pathways for RAs, 1, and 2 were proposed. Compound 2 showed moderate cytotoxicities against 11 cancer cell lines and inhibited nitric oxide (NO) production in LPS and IFN-γ-induced RAW 264.7 murine macrophages.

Full text of DOI:10.1016/j.tetlet.2010.07.066

Tetrahedron Letters 51 (2010) 6810–6813
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Rubiyunnanins A and B, two novel cyclic hexapeptides from Rubia yunnanensis
Jun-Ting Fan , Yi-Shan Chen , Wen-Yan Xu a,b,c, Liangcheng Du , Guang-Zhi Zeng , Yu-Mei Zhang ,
a,b
a,b
c
a
a
a
a
a,
*
Jia Su , Yan Li , Ning-Hua Tan
a
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650204, PR China
Graduate School of Chinese Academy of Sciences, Beijing 100039, PR China
Department of Chemistry, University of Nebraska-Lincoln, Lincoln, Nebraska 68588, USA
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Two novel cyclic hexapeptides, named rubiyunnanins A (1) and B (2), were isolated from the roots of
Rubia yunnanensis (Franch.) Diels. Their structures were elucidated extensively by spectroscopic analysis
and theoretical computation. Possible biosynthetic pathways for RAs, 1, and 2 were proposed. Compound
Received 27 May 2010
Revised 11 July 2010
Accepted 13 July 2010
Available online 16 July 2010
2
showed moderate cytotoxicities against 11 cancer cell lines and inhibited nitric oxide (NO) production
in LPS and IFN- -induced RAW 264.7 murine macrophages.
c
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Rubia yunnanensis
Rubiyunnanin A
Rubiyunnanin B
Cyclopeptides
Cytotoxicity
Inhibition of NO production
The genus Rubia is a prolific source of rubiaceae-type bicyclic
hexapeptides, anthraquinones, and arborinane-type triterpenoids.
Rubiyunnanin A (1)11 was obtained as an amorphous solid. Its
1
50 6 9
molecular formula was determined to be C40H N O by positive
+
Among them, rubiaceae-type bicyclic hexapeptides (RA-series
cyclopeptides, RAs) attracted great interest for their distinctive
bicyclic structural feature and potential antitumor activities
HRESIMS (m/z 781.3545, [M+Na] , calcd 781.3536), indicating 19
degrees of unsaturation. Its UV spectrum showed the existence of
phenyl groups based on the absorptions at 204 and 285 nm. The
IR spectrum exhibited absorption bands at 3440, 3385, and
2
,3
in vivo and in vitro. Regular RAs are homodicyclohexapeptides
ꢀ
1
1
13
mainly composed of one
D
-a
-alanine, one
L-
a-alanine, three modi-
1656 cm ascribable to OH, NH, and CO groups. The H and
NMR spectra of 1 in methanol-d (Table 1) displayed some charac-
teristics of RAs and demonstrated the presence of two conformers
C
fied N-methyl- -tyrosines, and another
L
-
a
L-
a-amino acid. The most
4
unusual feature is a 14-membered ring formed by a phenolic oxy-
gen linkage between two adjacent tyrosines with a cis peptide
bond, and the 14-membered ring is fused to the 18-membered cyc-
lic hexapeptide ring. Up to now, 30 RAs have been isolated only
from four Rubiaceae plants, that is, Bouvardia ternifolia, Rubia cor-
difolia, R. akane, and R. yunnanensis.4 R. yunnanensis is native to
Yunnan province, China, and its roots are widely used as a Chinese
traditional medicine for the treatment of tuberculosis, menoxenia,
1
2,13
in a ratio of 90:10.
Further analysis of 1D and 2D NMR spectral
data of 1 displayed the major conformer’s signals for three meth-
yls, three amide N-methyl signals, one O-methyl signal, three
methylenes, six a-amino methines, one 1,4-disubstituted benzene
ring, one 1,2,4-trisubstituted benzene ring, and six amide carbon-
yls, which allowed five amino acid residues to be established, that
is, three alanines and two N-methyl tyrosines. Except for the sig-
–7
8
rheumatism, contusion, hematemesis, anemia, and lipoma. Previ-
nals mentioned above, two oxymethines (d
H
/d
C
4.28/64.5, 4.87/
/d 2.20,
H C
2.40/28.9), and two olefinic carbons (d /d 5.58/120.0, 136.1) re-
ously, one new RA (RY-II) and two known RAs (RA-V and RA-XII)
85.3), one methine (d /d 3.67/44.3), one methylene (d
H
C
H
C
were reported from R. yunnanensis.4
,9,10
In our search for structur-
ally and pharmacologically interesting cyclopeptides from Chinese
medicinal plants, two new cyclic hexapeptides, rubiyunnanins A
mained unknown.
An extensive comparison of 1D and 2D NMR data of 1 with those
1
4
(1) and B (2), with the unique skeletons, were isolated from the
of RA-XII (3) strongly suggested a similar structure for the 18-
1
2
titled plant roots (Fig. 1). Herein, we describe their isolation, struc-
tural elucidation, possible biosynthetic pathways, and bioactivities.
membered ring of both compounds, that is, D-Ala , Ala , N-Me
3
4
Tyr , and Ala , which were deduced from the similar carbon and
proton chemical shifts, proton coupling constants, and NOE correla-
tions. Sequencing the amino acid residues in 1 was mainly accom-
plished by HMBC correlations of the NCH
3
proton or NH proton of
*
Corresponding author. Tel./fax: +86 871 5223800.
E-mail address: nhtan@mail.kib.ac.cn (N.-H. Tan).
one amino acid residue with the carbonyl carbon of the neighboring
0
040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.066

J.-T. Fan et al. / Tetrahedron Letters 51 (2010) 6810–6813
6811
δ
ε
δ
ε
β
R1
O
O
OR2
β
β
O
O
OCH
3
β
α
HN
O
O
OCH
γ
ξ
3
N
γ
ξ
α
N
α
2
1
3
N
α
2
1
3
HN
O
HN
O
2
3
HN
4
O
HN
4
HN
4
R
7
β
β
α
α
NH
O
β
1
α
β
NH
O
α
O
N
NH
O
O
O
N
6
5
6
5
N
O
O
N
N
Hb
R6
R
3
6
5
H
a
α
α
O
N
β
O
β
H
b
R
4
H
H
δa
a
α
β
α
Hb
δa
εa
Ha
γ
γ
β
δb δa
εb εa
δb
b
γ
δa
H
a
δb εa
γ
6
'
εb
H
HO
HO
ξ
O
ξ
εa2
δb
5'
O
OR
5
εb
ξ
4'
HO
OH
H
ξ
O
εb
εa1
RAs
2'
OH
3'
1'
OH
RA-XII (3): R =R =R =CH ,R =R =R =H,
1
5
2
7
3
3
4
6
Rubiyunnanin A (1)
Rubiyunnanin B (2)
R =
β
-D-Glc
Figure 1. Structures of 1, 2, 3, and RAs.
Table 1
Table 1 (continued)
1
H and 13C NMR data of compounds 1 and 2 in methanol-d4 (d in ppm, J in Hz)
Position
1a
2b
Position
1a
2b
d
H
d
C
d
H
d
C
d
H
d
C
d
H
d
C
Glc
1
D
-Ala
0
1
5.02 (d, 7.0)
3.49 (overlap)
3.49 (overlap)
3.38 (m)
3.49 (overlap)
3.70 (dd, 12.0, 6.0)
3.91 (dd, 12.0, 2.0)
103.8 d
75.0 d
77.6 d
71.3 d
78.4 d
62.5 t
a
b
C@O
4.09 (q, 6.8)
1.39 (d, 6.8)
50.5 d
19.9 q
174.2 s
4.48 (q, 7.0)
1.32 (d, 7.0)
48.5 d
20.6 q
174.0 s
0
2
0
3
0
4
2
0
Ala
a
b
C@O
5
0
4.47 (q, 6.8)
1.29 (d, 6.8)
46.7 d
16.1 q
174.7 s
4.58 (m)
1.30 (d, 7.0)
46.3 d
16.1 q
174.7 s
6
a
1
13
H NMR recorded at 400 MHz, C NMR recorded at 100 MHz.
H NMR recorded at 500 MHz, C NMR recorded at 100 MHz.
3
Tyr
b
1
13
a
b
c
3.87 (dd, 10.0, 6.0)
3.21 (m)
68.7 d
33.8 t
3.83 (dd, 9.0, 7.0)
3.22 (m)
68.6 d
33.8 t
131.5 s
131.5 d
115.0 d
160.0 s
171.5 s
40.5 q
55.6 q
131.5 s
131.5 d
115.0 d
160.0 s
171.3 s
40.5 q
55.6 q
3
2
*
residue. In the HMBC spectrum, cross-peaks of Tyr -NMe/Ala -CO,
d 2
7.06 (d, 8.4)
6.85 (d, 8.4)
7.05 (d, 8.5)
6.85 (d, 8.5)
5
4
6
5
*
Tyr -NMe/Ala -CO, and Residue -NMe/Tyr -CO demonstrated the
e
f
2
2
3
4
5
6
connectivities of the Ala -Tyr and Ala -Tyr -Residue . Then NMR
experiments were reperformed in DMSO-d due to the absence of
amide-NH signals in methanol-d (see Supplementary data). The
C@O
NMe
OMe
6
2.86 (s)
3.75 (s)
2.86 (s)
3.75 (s)
4
1
6
2
1
HMBC correlations of Ala -NH/Residue -CO, Ala -NH/Ala -CO, and
4
Ala
a
b
C@O
4
3
Ala -NH/Tyr -CO were observed. So all obtained HMBC correlations
4.92 (overlap)
1.00 (d, 6.8)
47.7 d
18.1 q
174.0 s
4.85 (m)
0.99 (d, 6.5)
47.6 d
18.9 q
172.4 s
confirmed the 18-membered ring. Then study of the 1H– H COSY
1
spectrum starting from the olefinic proton at d
revealed the presence of a spin-system H-6da/H-6
H-6db (@CH–CH –CH–CH–CH–). This information coupled with
the HMBC correlations of H-6da/C-6b, C-6db, C-6f, and H-6db/
C-6da, C-6 indicated the existence of a substituted cyclohexene
ring. Furthermore, C-6f (d 64.5) and C-6 b (d 85.3) presented at
H
5.58 (H-6da)
a/H-6f/H-6 b/
5
e
e
Tyr
a
ba
bb
c
4.61 (dd, 12.0, 5.6)
3.08 (dd, 12.0, 5.6)
3.15 (overlap)
58.7 d
36.3 t
5.71 (d, 9.5)
2.29 (d, 14.5)
4.02 (dd, 14.5, 9.5)
55.6 d
35.2 t
2
c
127.7 s
128.9 d
130.2 d
130.6 s
110.1 d
160.1 s
175.0 s
32.6 q
130.4 s
141.2 d
129.8 d
128.7 s
116.4 d
153.5 s
173.3 s
31.2 q
C
e
C
da
db
7.20 (s)
7.17 (d, 8.0)
6.30 (d, 2.0)
6.96 (dd, 8.5, 2.0)
low field ascribed as bearing hydroxyl and phenolic oxygen groups,
respectively. Considering the 19 degrees of unsaturation of 1, one
more ring was required. The crucial HMBC correlations of H-6db/
C-5f, C-5ea, and H-5da/C-6db gave another rigid oxygen-containing
five-membered ring. Thus, the planar structure of
e
e
f
a
b
6.64 (d, 8.0)
3.20 (s)
6.68 (d, 8.5)
2.99 (s)
C@O
NMe
1 was
determined.
6
Residue
a
ba
bb
c
The amino acid analysis of the hydrolyzate of 1 showed that it
contained -Ala and -Ala in the ratio of 1:2 according to the Mar-
fey’s method, which confirmed the D(R), L(S), and L(S) configura-
3.69 (d, 11.2)
3.02 (d, 15.6)
2.59 (dd, 15.6, 11.2)
70.1 d
29.4 t
5.39 (dd, 11.5, 4.0)
3.47 (overlap)
3.11 (dd, 16.0, 11.5)
61.6 d
36.3 t
D
L
1
5
136.1 s
120.0 d
44.3 d
28.9 t
129.9 s
130.4 d
141.8 d
117.0 d
1
2
4
tions of Ala , Ala , and Ala similar to those of RAs. In the ROESY
da
db
5.58 (d, 5.2)
3.67 (d, 7.2)
2.20 (m)
2.40 (br d, 17.6)
4.87 (overlap)
4.28 (br s)
7.16 (overlap)
6.72 (br s)
7.16 (overlap)
3
spectrum, the presence of NOE correlations of Tyr -NMe with H-
3
2a
and H-3
a
indicated the L(S)-configuration of Tyr . Interestingly,
e
e
e
f
a
a
b
1
2
unlike regular RAs, no NOE correlations were seen between H-5a
a whereas correlations of Residue -NMe with H-5a and
H-6 were observed, respectively, which suggested that the N-
methyl peptide bond between Tyr and Residue was trans. Fur-
thermore, in order to confirm the absolute configuration of Tyr
and Residue , two isomers (L-Tyr /L-Residue and D-Tyr /D-Resi-
6
85.3 d
64.5 d
171.2 s
39.9 q
131.3 s
155.3 s
171.7 s
31.7 q
and H-6
a
C@O
NMe
5
6
2.24 (s)
2.78 (s)
5
6
5
6
5

6
812
J.-T. Fan et al. / Tetrahedron Letters 51 (2010) 6810–6813
6
*
2
3
4
1
due ) of 1 were optimized at the B3LYP/6-31G level using GAUSSIAN
Ala , N-Me Tyr , and Ala . The absolute configurations of Ala ,
1
6
2
4
0
3 program package. Our calculation results indicated that the
L
-
Ala , and Ala were also identified as D(R), L(S), and L(S), respec-
5
6
Tyr /
correlations (see Supplementary data). For the absolute stereo-
chemistry at C-6db, C-6 b, C-6f, firstly, H-6bb was suggested to
be b-oriented based on the coupling constant of H-6bb/H-6 (dd,
J = 15.6, 11.2 Hz). Then considering the NOE correlations of H-
bb/H-6db and H-6 b/H-6db and the rigidity of oxygen-containing
five-membered ring, H-6db and H-6 b were placed at b orienta-
tion. However, the ROESY spectrum in methanol-d could not iden-
tify the absolute configuration at C-6f. Fortunately, NOE
correlation of H-6f with H-6db was clearly observed in DMSO-d
which implied that H-6f was also b-oriented. So the absolute
configurations of C-6db, C-6 b, and C-6f were assigned as R, S,
L
-Residue isomer was in accordance with the observed NOE
tively, by application of the Marfey’s method. Furthermore, it pos-
sessed two 1,2,4-trisubstituted benzene rings and
additional signals arising from a glucopyranosyl moiety.
HMBC cross-peaks of Tyr -NMe/Ala -CO and Tyr -NMe/Tyr -
CO revealed the sequence of the two tyrosines. Then crucial
a
set of
e
5
4
6
5
a
6
e
HMBC correlations of H-5da/C-6
with NOE correlations of H-5da/H-6db indicated the linkage of
C-5 a and C-6 b. As for the glucopyranosyl moiety of 2, HMBC
correlation of the anomeric proton (d 5.02, d, J = 7.0 Hz) (b-form)
eb and H-6db/C-5ea, together
e
4
e
e
H
6
,
with C-6f indicated that the sugar group was ligated to f-position
of Tyr-6. Enzymatic hydrolysis of 2 with b-glucosidase yielded
e
D-glucose, which was detected by TLC and optical rotation,
1
9
and R, respectively. Therefore, through the above-mentioned
NMR and DFT analysis, the structure of 1 was determined as shown
in Figure 2.
½
aꢁ
+103.7 (c 0.10 H
2
O).
In the ROESY spectrum, NOE correlation that was apparently
observed between H-5 and H-6 suggested that the N-methyl
peptide bond between Tyr and Tyr was cis. Similarly, two geom-
D
a
a
Rubiyunnanin B (2)17 was obtained as an amorphous solid and
5
6
5
6
5
6
possessed the molecular formula C46
41.3917, [M+Na] , calcd 941.3908), with 21 degrees of unsatura-
tion. The H and C NMR spectra of 2 in methanol-d
showed some characteristics of RAs and demonstrated the pres-
ence of two conformers in a ratio of 84:16. An extensive compari-
H
58
N
6
O
14 by HRESIMS (m/z
etries (
L-Tyr /L-Tyr and D-Tyr /D-Tyr ) of 2 were optimized, and
+
5
6
9
the calculation results supported the L-Tyr /L-Tyr structure (see
Supplementary data). Moreover, H-5da exhibited NOE correlation
with Tyr -NMe, which indicated that the benzene ring of Tyr
was at the left angle of the benzene ring of Tyr . Consequently,
based on the above-mentioned NMR and DFT analysis, the struc-
ture of 2 was determined as shown in Figure 2.
1
13
4
(Table 1) also
6
5
6
son of 1D and 2D NMR data of 2 with those of 1 and RA-XII (3) also
established the presence of the 18-membered ring, that is,
1
D
-Ala ,
Comparing with all known 30 RAs, both 1 and 2 have unique
skeletons. Except for the 18-membered ring, compound 1 has extra
5
6
two rings formed between Tyr and Residue via a phenolic oxygen
linkage and a new carbon–carbon bond. In addition, compound 2 is
discovered for the first time that it lacks the typical phenolic oxy-
gen linkage, but rather has a carbon–carbon bond at the ortho-posi-
5
6
tions of the hydroxyl groups of Tyr and Tyr .
The biosynthetic mechanism for plant cyclopeptides has not
1
8
been well established, except for the cyclotides. The hexapep-
tide precursor of RAs could be synthesized via a non-ribosomal
4
,19
peptide biosynthetic mechanism.
To form a mature RA, sev-
eral modification steps are expected to take place, among which
is the phenolic coupling step that leads to the most characteris-
tic structural feature of RAs. It is well established that the cou-
pling is via a free radical mechanism, typically at ortho–ortho,
5
ortho–para, or para–para position. The hydroxyl of Tyr and the
6
ortho-carbon of Tyr can generate free radicals. An oxygen–car-
bon coupling would lead to the 14-membered cycloisodityrosine
moiety that is found in all RAs. For compound 2, the coupling is
between two ortho-carbons. To form the very unusual three-ring
6
system of compound 1, the aromatic ring of Tyr of a RA
precursor needs to be reduced first. This sets a stage for an
electrophilic aromatic substitution-like reaction, using the
6
meta-carbon of Tyr as the electrophile to add to the ortho-
5
carbon of Tyr . This step could be facilitated by a protonation
6
on Tyr ring and the lone-pair electrons on the oxygen bridge
between the two tyrosine residues. An elimination of the proton
5
on Tyr ring driven by the restoration of the aromatic ring of
5
Tyr would lead to the formation of the new carbon–carbon
bond of 1. Possible biosynthetic pathways for RAs, 1 and 2 are
shown in Figure 3.
Cytotoxicities of 1 and 2 against 11 cancer cell lines (HepG2,
BEL-7402, SMMC-7721, MDA-MB-231, DU-145, PC-3, A549, BGC-
8
23, Hela, U251, and B16) were measured by SRB assay with the
2
0
maximum concentration of 50 lg/mL. Only compound 2 exhib-
ited moderate cytotoxicities with IC50 values of 31.3, 13.2, 33.7,
.3, 16.3, 21.9, 4.8, 5.6, 21.3, 6.5, and 3.6 g/mL, respectively. Fur-
thermore, the inhibitory effects of 1 and 2 on NO production in LPS
and IFN- -induced RAW 264.7 murine macrophages were exam-
ined. Only compound 2 was found to inhibit NO production with
IC50 value of 10.7 g/mL.
7
l
c
Figure 2. Selected 2D NMR correlations of 1 and 2.
l

J.-T. Fan et al. / Tetrahedron Letters 51 (2010) 6810–6813
6813
Linear Peptide precursor
O
N
O
N
O
N
O
O
N
O
N
N
N
N
a
O
O
O
O
O
O
N
O
O
N
O
O
H
H
b
O
O
O
N
N
N
N
O
O
O
O
O
N
O
O
N
O
O
N
Glycosyl-
transfer
O
O
O
N
N
2
N
O
O
O
O
O
O
O
OH
OH
OH
RAs
Isomeization
1
O
N
O
N
O
N
N
N
N
N
N
NAD(P)H
O
O
O
O
H
H
H
H
H+
O
O
O
O
H
H
HO
H
HO
H
HO
H
OH
H-
H+
Figure 3. Proposed biosynthetic pathways for RAs, 1, and 2.
6
7
.
.
Lee, J. E.; Hitotsuyanagi, Y.; Takeya, K. Tetrahedron 2008, 64, 4117–4125.
Lee, J. E.; Hitotsuyanagi, Y.; Fukaya, H.; Kondo, K.; Takeya, K. Chem. Pharm. Bull.
008, 56, 730–733.
Acknowledgments
2
This work was financially supported by the National Natural
Science Foundation of China (30725048), National Basic Research
Program of China (2009 CB522300), the Innovative Group Program
from the Science and Technology Department of Yunnan Province
8. Lan, M. In Dian Nan Ben Cao; Yunnan People’s Publishing House: Kunming,
1978; pp 349–351.
9.
Zou, C.; Hao, X. J.; Zhou, J. Acta Bot. Yunnanica 1993, 15, 399–402.
1
1
0. He, M.; Zou, C.; Hao, X. J.; Zhou, J. Acta Bot. Yunnanica 1993, 15, 408.
2
8
1. Rubiyunnanin A (1): ½ ) 204
a
ꢁ
ꢀ115.8 (c 0.11, MeOH); UV (MeOH) kmax (log
e
D
(
2008OC011), and the Fund of State Key Laboratory of Phytochem-
(4.75), 285 (3.73) nm; IR (KBr) mmax 3440, 3385, 2932, 1656, 1512, 1488,
ꢀ
1
1
13
+
1
(
242 cm
100), 164 (30), 121 (11); HRESIMS m/z 781.3545 [M+Na]+ (calcd for
Na, 781.3536).
; H and C NMR data, see Table 1; positive FABMS m/z [M+H] 759
istry and Plant Resources in West China, Kunming Institute of Bot-
any, Chinese Academy of Sciences.
40 50 6 9
C H N O
1
1
1
1
2. Bates, R. B.; Cole, J. R.; Hoffmann, J. J.; Kriek, G. R.; Linz, G. S.; Torrance, S. J. J.
Am. Chem. Soc. 1983, 105, 1343–1347.
3. Morita, H.; Kondo, K.; Hitotsuyanagi, Y.; Takeya, K.; Itokawa, H.; Tomioka, N.;
Itai, A.; Iitaka, Y. Tetrahedron 1991, 47, 2757–2772.
Supplementary data
4. Morita, H.; Yamamiya, T.; Takeya, K.; Itokawa, H. Chem. Pharm. Bull. 1992, 40,
Supplementary data (detailed experimental section, DFT com-
putational results, copies of NMR and MS spectra of 1 and 2) asso-
ciated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.07.066.
1352–1354.
5. Marfey, P. Carlsberg Res. Commun. 1984, 49, 591–596.
16. Frisch, M. J. et al. GAUSSIAN 03, Revision C.02; Gaussian, Inc.: Wallingford, CT,
2005 (see Supplementary data for the complete reference).
1
2
4
7. Rubiyunnanin B (2): ½
4.74), 284 (3.78) nm; IR (KBr) mmax 3427, 2932, 1639, 1512, 1246, 1075 cm ;
+
a
ꢁ
ꢀ205.8 (c 0.30 MeOH); UV (MeOH) kmax (log e) 203
D
ꢀ
1
(
References and notes
1
13
H and C NMR data, see Table 1; positive FABMS m/z [M+H] 919 (100), 757
11), 593 (7), 501 (8), 409 (18); HRESIMS m/z 941.3917 [M+Na] (calcd for
+
(
1
2
.
.
Singh, R.; Geetanjali; Chauhan, S. M. S. Chem. Biodivers. 2004, 1, 1241–1264.
Itokawa, H.; Takeya, K.; Mori, N.; Hamanaka, T.; Sonobe, T.; Mihara, K. Chem.
Pharm. Bull. 1984, 32, 284–290.
C H N O14Na, 941.3908).
18. Jennings, C.; West, J.; Waine, C.; Craik, D.; Anderson, M. Proc. Natl. Acad. Sci.
U.S.A. 2001, 98, 10614–10619.
46 58 6
3
.
Itokawa, H.; Takeya, K.; Mori, N.; Sonobe, T.; Serisawa, N.; Hamanaka, T.;
Mihashi, S. Chem. Pharm. Bull. 1984, 32, 3216–3226.
19. Du, L. C.; Tan, N. H.; Xu, W. Y.; Lou, L. L. Acta Bot. Yunnanica 2009, 31,
374–382.
4
5
.
.
Tan, N. H.; Zhou, J. Chem. Rev. 2006, 106, 840–895.
Lee, J. E.; Hitotsuyanagi, Y.; Kim, I. H.; Hasuda, T.; Takeya, K. Bioorg. Med. Chem.
Lett. 2008, 18, 808–811.
20. Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon, J.; Vistica, D.;
Warren, J. T.; Bokesch, H.; Kenney, S.; Boyd, M. R. J. Natl. Cancer Inst. 1990, 82,
1107–1112.