- Email: [email protected]
Gelsochalotine, a novel indole ring-degraded monoterpenoid indole alkaloid from Gelsemium elegans
Tetrahedron Letters 54 (2013) 887–890
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Gelsochalotine, a novel indole ring-degraded monoterpenoid indole alkaloid from Gelsemium elegans Shuang Liang a,⇑, Chun-Yong He a, László F. Szabó b,z, Yi Feng a,⇑, Xiao Lin a, Yuan Wang a a b
Shanghai University of Traditional Chinese Medicine Engineering Research Center of Modern Preparation Technology of TCM, Ministry of Education, Shanghai 201203, PR China Department of Organic Chemistry, Semmelweis University, Budapest H-1092, Hungary
a r t i c l e
i n f o
Article history: Received 17 August 2012 Revised 30 October 2012 Accepted 27 November 2012 Available online 3 December 2012 Keywords: Indole alkaloid Gelsochalotine Gelsemium elegans Benth.
a b s t r a c t A phytochemical investigation of Gelsemium elegans Benth. led to the isolation of a novel alkaloid, gelsochalotine (1), as the first example of an indole ring-degraded monoterpenoid indole alkaloid from the family Loganiaceae. The structure of 1 was elucidated by spectroscopic analysis, and confirmed by single crystal X-ray diffraction. Studies on the biogenetic derivation of 1 were performed and its cytotoxic activities against human cancer cell lines, BEL-7420 and MDA-MD-435 cell, were evaluated with the MTT assay. Ó 2012 Elsevier Ltd. All rights reserved.
Gelsemium elegans Benth. (Loganiaceae), which is native to Southeast Asia, is known to be a toxic plant and has been used for the treatment of pain, spasticity, tumor, and skin ulcers.1 In addition, the pharmacological effects of the G. elegans alkaloids including anti-inflammatory, analgesic, and antitumor activities have been reported.2 In recent years, several novel monoterpenoid indole alkaloids have been isolated from G. elegans.3 As part of our investigation on structurally and pharmacologically interesting secondary metabolites from Chinese medicinal plants, a novel indole ring-degraded monoterpenoid indole alkaloid, gelsochalotine (1) (Fig. 1), was isolated from this plant. Herein, we describe the isolation, structural elucidation, and biogenetic derivation of 1, and its cytotoxic activities against the human cancer cell lines, BEL-7420 and MDA-MD-435. Compound 14 was obtained as colorless prismatic needles. The IR spectrum of 1 suggested the presence of hydroxyl (3415 cm1), carbonyl (1759 cm1) and ester carbonyl (1732 cm1) groups. Its molecular formula was established as C14H19NO4 on the basis of the HRESIMS ([M+H]+ at m/z 266.1390, calc. 266.1392) in conjunction with the 13C NMR spectrum, which requires six degrees of unsaturation. The 1H, 13C and DEPT NMR spectra of 1 (Table 1) showed 14 carbon resonances due to two methyls, four methylenes, four methines, and four quaternary carbons, of which the signals of a ketone carbonyl [dC 214.6], an ester carbonyl [dC 174.0], a propenyl [dH 1.55 (3H, d, J = 6.8 Hz), 5.34 (1H, q, J = 6.8 Hz); dC 12.5, 116.5, 137.7], a hydroxymethyl [dH 3.62 (1H, d, J = 11.2 Hz), 3.81 ⇑ Corresponding authors. Tel./fax: +86 21 51323094. z
E-mail addresses: [email protected] (S. Liang), [email protected] (Y. Feng). Deceased.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2012.11.122
(1H, d, J = 11.2 Hz); dC 68.6], and a methoxy [dH 3.71 (3H, s); dC 52.0] group are typical. The NMR data were analogous to those of 19(Z)-akuammidine (2, Fig. 1),5 a known compound obtained from G. elegans, with the exception of signals attributable to an indole ring in compound 2. Furthermore, the 1H–1H COSY correlations of H-5 (dH 3.27) with H-6a (dH 2.60) and H-6b (dH 2.18), and the HMBC correlations of C-7 (dC 214.6) with H-3 (dH 3.30), H-6 (dH 2.18 and 2.60), and H-14 (dH 1.89 and 2.26), allowed the assignment of a 3-oxo-pyrrolidin ring (Table 1). The planar constitution and the absolute configuration of 1 was finally confirmed by X-ray diffraction using graphite-monochromated Cu Ka radiation and named gelsochalotine. Compound 1 represents the first example of an indole ring-degraded monoterpenoid indole alkaloid from the family Loganiaceae, which has a structure evidently derived from secologanin and possibly from trypamine, but without an indole subunit. It is well known that the general biogenetic route to the terpenoid indole alkaloids derives from secologanin (A) and tryptamine (B) (or tryptophane) in a Mannich-type reaction in which strictosidine (C) is immediately formed as a general precursor (Scheme 1).6 The indole ring might be lost during the subsequent biogenetic steps. Therefore, a plausible biogenetic pathway for gelsochalotine is proposed in Scheme 1, and the mechanism might be interpreted in brief as follows: To date, it is clear that 19(Z)-akuammidine (2) is a representative monoterpenoid indole alkaloid from the family Loganiaceae, which derives from strictosidine.7 In our study, we also isolated 19(Z)-akuammidine from the title plant. Therefore, it may be an important intermediate of compound 1. From 19(Z)-akuammidine, akuammidan oxindole intermediate (E) will be generated through
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S. Liang et al. / Tetrahedron Letters 54 (2013) 887–890
6 7
O
OMe
O H
5
4 3
H 14
N
15
22 17 OH 16 21
H 20
4
22 17 OH 16
N
3
21
H
14
2
1
OMe
O
6
N H H
18 19
H
7
18
19
Figure 1. Structures of compounds 1–2, and X-ray crystal structure of 1.
the b-oxidation and successive rearrangement.6 Then, the transformation maybe involved in the cleavage of the pyrrolidine ring in E, the hydrolysis of the O, N-acetal group in F, and the subsequent retro-cyclization of the pyrrolidine ring to provide intermediate
H. Finally, oxidation cleaves the C-7/C-8 double bond and provides compound 1, as well as a hypothetic quinoid product, J. It is logical to also suppose an alternative route in which an aliphatic aminoaldehyde, such as ornithine (K), 4-aminobutanal,
Table 1 13 C and 1H NMR spectroscopic data of compound 1a
a
No.
dC
dH (Mult., J Hz)
COSY
HMBC
NOESY
3 5 6
61.4 d 58.9 d 41.8 t
3.30 (m) 3.27 (d, 7.6), Ha: 2.60 (dd, 7.6, 18.8) Hb: 2.18 (d, 18.8)
Ha-14, Hb-14 Ha-6, Hb-6 H-5, Hb-6 H-5, Ha-6
C-6, C-3, C-5, C-7,
Ha-14, Ha-21 Ha-6, Ha-17 H-5, Hb-6 Ha-6
7 14
214.6 s 28.2 t
15 16 17
36.4 d 52.7 s 68.6 t
Ha: 2.26 (dt, 2.4, 14.0) Hb: 1.89 (dd, 2.4, 14.0) 2.77 (t, 2.4)
H-3, Hb-14, H-15 H-3, Ha-14, H-15 Ha-14, Hb-14
C-7, C-20 C-3, C-7, C-16, C-20 C-3, C-20
H-3, Hb-14, H-15 Ha-14, H-15 Ha-14, Hb-14, H-19
18 19 20 21
12.5 q 116.5 d 137.7 s 47.0 t
Ha: 3.81 (d, 11.2) Hb: 3.62 (d, 11.2) 1.55 (d, 6.8) 5.34 (q, 6.8)
Hb-17 Ha-17 H-19 H-18
C-15, C-15, C-19, C-15,
H-5, Hb-17 Ha-17 H-19, Ha-21 H-15, H-18
Ha: 3.72 (d, 11.2) Hb: 3.52 (br s)
Hb-21 Ha-21
C-3, C-20 C-3, C-5, C-20
22 OMe
174.0 s 52.0 q
3.71 (s) 13
O 13
OGlc + MeO
N
3
H
D
HO NH
E
H
H
H 15 21
H
16
OH Me
H
7
O N
H I
OH
Me
N H
OMe 7
O
21
H
OMe OH
N
O H
O NH
N
H
Me
H
1
Scheme 1. Plausible biogenetic pathway for gelsochalotine (1).
N
1 8
+
H
18
19
G O H
OH
N
OMe
O OH H N
4 3 14
2
22 17 OH 16
6
N H H
17
F
H
N
OGlc
O
OMe
OMe Me
7
14
O C
73 N
H
N H H
73 N
H
OH
4NH
OMe
O H
6
2
22
O H
O
H
O H
1
A
OH Me 1 N
N
8
MeO
OMe
O OH H
Me
O O
B
H-3, H-18, Hb-21 Ha-21
C NMR.
9
NH2
C-16, C-22 C-16, C-22 C-20 C-18, C-21
C-22
Data were recorded in CDCl3 at 400 MHz for 1H and 100 MHz for
N H
C-7, C-15 C-6, C-7, C-17 C-7, C-16 C-16
J
O
OMe OH
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S. Liang et al. / Tetrahedron Letters 54 (2013) 887–890
O HO
NH 2 -CO 2
NH 2
O
-NH 3
NH 2
+ 'O'
K
Mannich Reaction
O O A
5
NH
OMe
O N
O
16
H
O
OH N
O
H
OMe
O
OH N
H
L
OMe
O
'O'
OH
OGlc
O
+ 'O'
OGlc MeO
MeO
- CO2
O
H
H
H
1
Scheme 2. Plausible biogenetic pathway for gelsochalotine (1) from ornithine.
5
O
H
17
16 7 4 3 NMe15 14
H 3
O
21
5
19
20 18
O
HO
H
17
O
16 7 4 21 3 NMe 15 20 H 14 19 O 18
Me
4
O 6 N1 2
13
8 9
HO
7 4
N
3 15 14 H
H
17
5 16 21
O
22
OMe
O Me
20
19 18
5
N
5
H
17
16 7 4 3 NH 15 14
H
21
O
19
20 18
O
6
Figure 2. Structures of representative compounds 3–6.
or 5-amonopentanal, would be the component of the Mannichtype reaction of secologanin. In this case, compound 1 would be formed through a hypothetic intermediate, L, as shown in Scheme 2. However, it is important to note that two indole ring-degraded monoterpenoid indole alkaloids, angustimalal (3)8 and angustimalin (4) (Fig. 2),9 have been isolated from the Amsonia species. The C7 has an oxo group in 3 and a hydroxy group in 4. They belong to the macroline-type alkaloids, in which the N-4/C-21 bond of the akuammidan substructure is cleaved and a new oxacycle is formed. As in both alkaloids 3 and 4, the structural position of C-6 is the same, as in compound 1. Their derivation might be completely analogous to the derivation of 1 from the akuammidan oxindole derivative, E, in Scheme 1. Unfortunately, the relationship of macroline alkaloids to the akuammidan skeleton is not yet completely clear. In addition, some oxindole derivatives, such as voachalotine oxindole (5)10 and alstonal (6) (Fig 2),11 have been found in natural plants, which are similar to E of Scheme 1. These interesting natural compounds strongly support the biosynthetic route through strictosidine (Scheme 1). Therefore, we believe that the classical route is more reasonable, based on the isolated intermediates and standard organic reaction mechanisms. It is clear from this classical route that strictosidine is the beginning. In this manner, gelsochalotine (1), angustimalal (3), and angustimalin (4) are three representative alkaloids of the novel type of indole ring-degraded monoterpenoid indole alkaloids, which we named as the gelsochalotine-type alkaloids. G. elegans has been used traditionally for thousands of years for the treatment of tumours, and promising antitumor activity of certain alkaloids and crude alkaloids from G. elegans has been reported.2c,d,12 Therefore, we evaluated the cytotoxic activity of 1 against the human cancer cell lines, BEL-7420 and MDA-MD435, with the MTT assay. The results showed weak inhibitory effects on cell growth with an IC50 of 33 lM and 110 lM, respectively.
Acknowledgments The work was supported by grants from the Key Project of Chinese Ministry of Education (211060) and Shanghai Leading Academic Discipline Project (J50302). Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012. 11.122. References and notes 1. An Editorial Committee of the Administration Bureau of Traditional Chinese Medicine. Chinese Materia Medica (Zhonghua Bencao), Shanghai Science & Technology Press: Shanghai, China, 2000; Vol. 6, pp 213–215. 2. (a) Lounasmaa, M.; Hanhinen, P.; Westersund, M. In The Alkaloids: Chemistry and Pharmacology; Geoffrey, A. C., Ed.; Academic Press: California, USA, 1998; Vol. 52,. Chapter 2 (b) Takayama, H.; Sakai, S. I. In The Alkaloids: Chemistry and Pharmacology; Geoffrey, A. C., Ed.; Academic Press: California, USA, 1997; Vol. 49,. Chapter 1 (c) Rujjanawate, C.; Kanjanapothi, D.; Panthong, A. J. Ethnopharmacol. 2003, 89, 91; (d) Kitajima, M.; Nakamura, T.; Kogure, N.; Ogawa, M.; Mitsuno, Y.; Ono, K.; Yano, S.; Aimi, N.; Takayama, H. J. Nat. Prod. 2006, 69, 715. 3. (a) Ouyang, S.; Wang, L.; Zhang, Q. W.; Wang, G. C.; Wang, Y.; Huang, X. J.; Zhang, X. Q.; Jiang, R. W.; Yao, X. S.; Che, C. T.; Ye, W. C. Tetrahedron 2011, 67, 4807; (b) Zhang, B. F.; Zhang, Q. P.; Liu, H.; Chou, G. X.; Wang, Z. T. Phytochemical 2011, 72, 916; (c) Zhang, Z.; Di, Y. T.; Wang, Y. H.; Zhang, Z.; Mu, S. Z.; Fang, X.; Zhang, Y.; Tan, C. J.; Zhang, Q.; Yan, X. H.; Guo, J.; Li, C. S.; Hao, X. J. Tetrahedron 2009, 65, 4551; (d) Yamada, Y.; Kitajima, M.; Kogure, N.; Takayama, H. Tetrahedron 2008, 64, 7690; (e) Kogure, N.; Kobayashi, H.; Ishii, N.; Kitajima, M.; Wongseripipatana, S.; Takayama, H. Tetrahedron Lett. 2008, 49, 3638. 4. Gelsochalotine (1): ½a17 D 105 (c 0.18, CH3OH); IR (KBr) mmax 3415, 3215, 2951, 1759, 1732, 1454, 1225, 1081, 839 cm1; 1H and 13C NMR data, see Table 1; positive HRESIMS m/z 266.1390 (calcd for C14H20NO4, 266.1392). Crystallographic data of gelsochalotine have been deposited at the Cambridge Crystallographic Data Centre (deposition no. CCDC 846062). Copies of these data can be obtained free of charge via www.ccdc.cam.an.uk/ conts/retrieving.html.
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S. Liang et al. / Tetrahedron Letters 54 (2013) 887–890
5. Ponglux, D.; Wongseripipatana, S.; Subhadhirasakul, S.; Takayama, H.; Yokota, M.; Ogata, K.; Phisalaphong, C.; Aimi, N.; Sakai, S. I. Tetrahedron 1988, 44, 5075. 6. Martina, R.; Christiane, K. F.; Husson, H. P.; Stöckigt, J.; Meinhart, H. Z. J. Chem. Soc., Chem. Commun. 1979, 22, 1016. 7. Szabó, L. F. Molecules 2008, 13, 1875. 8. Kam, T. S.; Choo, Y. M.; Komiyama, K. Tetrahedron 2004, 60, 3957.
9. Kam, T. S.; Jayashankar, R.; Sim, K. M.; Yoganathan, K. Tetrahedron Lett. 1997, 38, 477. 10. Braekman, J. C.; Tirions-Lampe, M.; Pecher, J. Bull. Soc. Chim. Belg. 1969, 78, 523. 11. Wong, W. H.; Lim, P. B.; Chuah, C. H. Phytochemical 1996, 41, 313. 12. (a) Xu, Y. K.; Yang, S. P.; Liao, S. G.; Zhang, H.; Lin, L. P.; Ding, J.; Yue, J. M. J. Nat. Prod. 2006, 69, 1347; (b) Zhao, Q. C.; Hua, W.; Zhang, L.; Guo, T.; Zhao, M. H.; Yan, M.; Shi, G. B.; Wu, L. J. J. Asian Nat. Prod. Res. 2010, 12, 731.
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Gelsochalotine, a novel indole ring-degraded monoterpenoid indole alkaloid from Gelsemium elegans Shuang Liang a,⇑, Chun-Yong He a, László F. Szabó b,z, Yi Feng a,⇑, Xiao Lin a, Yuan Wang a a b
Shanghai University of Traditional Chinese Medicine Engineering Research Center of Modern Preparation Technology of TCM, Ministry of Education, Shanghai 201203, PR China Department of Organic Chemistry, Semmelweis University, Budapest H-1092, Hungary
a r t i c l e
i n f o
Article history: Received 17 August 2012 Revised 30 October 2012 Accepted 27 November 2012 Available online 3 December 2012 Keywords: Indole alkaloid Gelsochalotine Gelsemium elegans Benth.
a b s t r a c t A phytochemical investigation of Gelsemium elegans Benth. led to the isolation of a novel alkaloid, gelsochalotine (1), as the first example of an indole ring-degraded monoterpenoid indole alkaloid from the family Loganiaceae. The structure of 1 was elucidated by spectroscopic analysis, and confirmed by single crystal X-ray diffraction. Studies on the biogenetic derivation of 1 were performed and its cytotoxic activities against human cancer cell lines, BEL-7420 and MDA-MD-435 cell, were evaluated with the MTT assay. Ó 2012 Elsevier Ltd. All rights reserved.
Gelsemium elegans Benth. (Loganiaceae), which is native to Southeast Asia, is known to be a toxic plant and has been used for the treatment of pain, spasticity, tumor, and skin ulcers.1 In addition, the pharmacological effects of the G. elegans alkaloids including anti-inflammatory, analgesic, and antitumor activities have been reported.2 In recent years, several novel monoterpenoid indole alkaloids have been isolated from G. elegans.3 As part of our investigation on structurally and pharmacologically interesting secondary metabolites from Chinese medicinal plants, a novel indole ring-degraded monoterpenoid indole alkaloid, gelsochalotine (1) (Fig. 1), was isolated from this plant. Herein, we describe the isolation, structural elucidation, and biogenetic derivation of 1, and its cytotoxic activities against the human cancer cell lines, BEL-7420 and MDA-MD-435. Compound 14 was obtained as colorless prismatic needles. The IR spectrum of 1 suggested the presence of hydroxyl (3415 cm1), carbonyl (1759 cm1) and ester carbonyl (1732 cm1) groups. Its molecular formula was established as C14H19NO4 on the basis of the HRESIMS ([M+H]+ at m/z 266.1390, calc. 266.1392) in conjunction with the 13C NMR spectrum, which requires six degrees of unsaturation. The 1H, 13C and DEPT NMR spectra of 1 (Table 1) showed 14 carbon resonances due to two methyls, four methylenes, four methines, and four quaternary carbons, of which the signals of a ketone carbonyl [dC 214.6], an ester carbonyl [dC 174.0], a propenyl [dH 1.55 (3H, d, J = 6.8 Hz), 5.34 (1H, q, J = 6.8 Hz); dC 12.5, 116.5, 137.7], a hydroxymethyl [dH 3.62 (1H, d, J = 11.2 Hz), 3.81 ⇑ Corresponding authors. Tel./fax: +86 21 51323094. z
E-mail addresses: [email protected] (S. Liang), [email protected] (Y. Feng). Deceased.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2012.11.122
(1H, d, J = 11.2 Hz); dC 68.6], and a methoxy [dH 3.71 (3H, s); dC 52.0] group are typical. The NMR data were analogous to those of 19(Z)-akuammidine (2, Fig. 1),5 a known compound obtained from G. elegans, with the exception of signals attributable to an indole ring in compound 2. Furthermore, the 1H–1H COSY correlations of H-5 (dH 3.27) with H-6a (dH 2.60) and H-6b (dH 2.18), and the HMBC correlations of C-7 (dC 214.6) with H-3 (dH 3.30), H-6 (dH 2.18 and 2.60), and H-14 (dH 1.89 and 2.26), allowed the assignment of a 3-oxo-pyrrolidin ring (Table 1). The planar constitution and the absolute configuration of 1 was finally confirmed by X-ray diffraction using graphite-monochromated Cu Ka radiation and named gelsochalotine. Compound 1 represents the first example of an indole ring-degraded monoterpenoid indole alkaloid from the family Loganiaceae, which has a structure evidently derived from secologanin and possibly from trypamine, but without an indole subunit. It is well known that the general biogenetic route to the terpenoid indole alkaloids derives from secologanin (A) and tryptamine (B) (or tryptophane) in a Mannich-type reaction in which strictosidine (C) is immediately formed as a general precursor (Scheme 1).6 The indole ring might be lost during the subsequent biogenetic steps. Therefore, a plausible biogenetic pathway for gelsochalotine is proposed in Scheme 1, and the mechanism might be interpreted in brief as follows: To date, it is clear that 19(Z)-akuammidine (2) is a representative monoterpenoid indole alkaloid from the family Loganiaceae, which derives from strictosidine.7 In our study, we also isolated 19(Z)-akuammidine from the title plant. Therefore, it may be an important intermediate of compound 1. From 19(Z)-akuammidine, akuammidan oxindole intermediate (E) will be generated through
888
S. Liang et al. / Tetrahedron Letters 54 (2013) 887–890
6 7
O
OMe
O H
5
4 3
H 14
N
15
22 17 OH 16 21
H 20
4
22 17 OH 16
N
3
21
H
14
2
1
OMe
O
6
N H H
18 19
H
7
18
19
Figure 1. Structures of compounds 1–2, and X-ray crystal structure of 1.
the b-oxidation and successive rearrangement.6 Then, the transformation maybe involved in the cleavage of the pyrrolidine ring in E, the hydrolysis of the O, N-acetal group in F, and the subsequent retro-cyclization of the pyrrolidine ring to provide intermediate
H. Finally, oxidation cleaves the C-7/C-8 double bond and provides compound 1, as well as a hypothetic quinoid product, J. It is logical to also suppose an alternative route in which an aliphatic aminoaldehyde, such as ornithine (K), 4-aminobutanal,
Table 1 13 C and 1H NMR spectroscopic data of compound 1a
a
No.
dC
dH (Mult., J Hz)
COSY
HMBC
NOESY
3 5 6
61.4 d 58.9 d 41.8 t
3.30 (m) 3.27 (d, 7.6), Ha: 2.60 (dd, 7.6, 18.8) Hb: 2.18 (d, 18.8)
Ha-14, Hb-14 Ha-6, Hb-6 H-5, Hb-6 H-5, Ha-6
C-6, C-3, C-5, C-7,
Ha-14, Ha-21 Ha-6, Ha-17 H-5, Hb-6 Ha-6
7 14
214.6 s 28.2 t
15 16 17
36.4 d 52.7 s 68.6 t
Ha: 2.26 (dt, 2.4, 14.0) Hb: 1.89 (dd, 2.4, 14.0) 2.77 (t, 2.4)
H-3, Hb-14, H-15 H-3, Ha-14, H-15 Ha-14, Hb-14
C-7, C-20 C-3, C-7, C-16, C-20 C-3, C-20
H-3, Hb-14, H-15 Ha-14, H-15 Ha-14, Hb-14, H-19
18 19 20 21
12.5 q 116.5 d 137.7 s 47.0 t
Ha: 3.81 (d, 11.2) Hb: 3.62 (d, 11.2) 1.55 (d, 6.8) 5.34 (q, 6.8)
Hb-17 Ha-17 H-19 H-18
C-15, C-15, C-19, C-15,
H-5, Hb-17 Ha-17 H-19, Ha-21 H-15, H-18
Ha: 3.72 (d, 11.2) Hb: 3.52 (br s)
Hb-21 Ha-21
C-3, C-20 C-3, C-5, C-20
22 OMe
174.0 s 52.0 q
3.71 (s) 13
O 13
OGlc + MeO
N
3
H
D
HO NH
E
H
H
H 15 21
H
16
OH Me
H
7
O N
H I
OH
Me
N H
OMe 7
O
21
H
OMe OH
N
O H
O NH
N
H
Me
H
1
Scheme 1. Plausible biogenetic pathway for gelsochalotine (1).
N
1 8
+
H
18
19
G O H
OH
N
OMe
O OH H N
4 3 14
2
22 17 OH 16
6
N H H
17
F
H
N
OGlc
O
OMe
OMe Me
7
14
O C
73 N
H
N H H
73 N
H
OH
4NH
OMe
O H
6
2
22
O H
O
H
O H
1
A
OH Me 1 N
N
8
MeO
OMe
O OH H
Me
O O
B
H-3, H-18, Hb-21 Ha-21
C NMR.
9
NH2
C-16, C-22 C-16, C-22 C-20 C-18, C-21
C-22
Data were recorded in CDCl3 at 400 MHz for 1H and 100 MHz for
N H
C-7, C-15 C-6, C-7, C-17 C-7, C-16 C-16
J
O
OMe OH
889
S. Liang et al. / Tetrahedron Letters 54 (2013) 887–890
O HO
NH 2 -CO 2
NH 2
O
-NH 3
NH 2
+ 'O'
K
Mannich Reaction
O O A
5
NH
OMe
O N
O
16
H
O
OH N
O
H
OMe
O
OH N
H
L
OMe
O
'O'
OH
OGlc
O
+ 'O'
OGlc MeO
MeO
- CO2
O
H
H
H
1
Scheme 2. Plausible biogenetic pathway for gelsochalotine (1) from ornithine.
5
O
H
17
16 7 4 3 NMe15 14
H 3
O
21
5
19
20 18
O
HO
H
17
O
16 7 4 21 3 NMe 15 20 H 14 19 O 18
Me
4
O 6 N1 2
13
8 9
HO
7 4
N
3 15 14 H
H
17
5 16 21
O
22
OMe
O Me
20
19 18
5
N
5
H
17
16 7 4 3 NH 15 14
H
21
O
19
20 18
O
6
Figure 2. Structures of representative compounds 3–6.
or 5-amonopentanal, would be the component of the Mannichtype reaction of secologanin. In this case, compound 1 would be formed through a hypothetic intermediate, L, as shown in Scheme 2. However, it is important to note that two indole ring-degraded monoterpenoid indole alkaloids, angustimalal (3)8 and angustimalin (4) (Fig. 2),9 have been isolated from the Amsonia species. The C7 has an oxo group in 3 and a hydroxy group in 4. They belong to the macroline-type alkaloids, in which the N-4/C-21 bond of the akuammidan substructure is cleaved and a new oxacycle is formed. As in both alkaloids 3 and 4, the structural position of C-6 is the same, as in compound 1. Their derivation might be completely analogous to the derivation of 1 from the akuammidan oxindole derivative, E, in Scheme 1. Unfortunately, the relationship of macroline alkaloids to the akuammidan skeleton is not yet completely clear. In addition, some oxindole derivatives, such as voachalotine oxindole (5)10 and alstonal (6) (Fig 2),11 have been found in natural plants, which are similar to E of Scheme 1. These interesting natural compounds strongly support the biosynthetic route through strictosidine (Scheme 1). Therefore, we believe that the classical route is more reasonable, based on the isolated intermediates and standard organic reaction mechanisms. It is clear from this classical route that strictosidine is the beginning. In this manner, gelsochalotine (1), angustimalal (3), and angustimalin (4) are three representative alkaloids of the novel type of indole ring-degraded monoterpenoid indole alkaloids, which we named as the gelsochalotine-type alkaloids. G. elegans has been used traditionally for thousands of years for the treatment of tumours, and promising antitumor activity of certain alkaloids and crude alkaloids from G. elegans has been reported.2c,d,12 Therefore, we evaluated the cytotoxic activity of 1 against the human cancer cell lines, BEL-7420 and MDA-MD435, with the MTT assay. The results showed weak inhibitory effects on cell growth with an IC50 of 33 lM and 110 lM, respectively.
Acknowledgments The work was supported by grants from the Key Project of Chinese Ministry of Education (211060) and Shanghai Leading Academic Discipline Project (J50302). Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012. 11.122. References and notes 1. An Editorial Committee of the Administration Bureau of Traditional Chinese Medicine. Chinese Materia Medica (Zhonghua Bencao), Shanghai Science & Technology Press: Shanghai, China, 2000; Vol. 6, pp 213–215. 2. (a) Lounasmaa, M.; Hanhinen, P.; Westersund, M. In The Alkaloids: Chemistry and Pharmacology; Geoffrey, A. C., Ed.; Academic Press: California, USA, 1998; Vol. 52,. Chapter 2 (b) Takayama, H.; Sakai, S. I. In The Alkaloids: Chemistry and Pharmacology; Geoffrey, A. C., Ed.; Academic Press: California, USA, 1997; Vol. 49,. Chapter 1 (c) Rujjanawate, C.; Kanjanapothi, D.; Panthong, A. J. Ethnopharmacol. 2003, 89, 91; (d) Kitajima, M.; Nakamura, T.; Kogure, N.; Ogawa, M.; Mitsuno, Y.; Ono, K.; Yano, S.; Aimi, N.; Takayama, H. J. Nat. Prod. 2006, 69, 715. 3. (a) Ouyang, S.; Wang, L.; Zhang, Q. W.; Wang, G. C.; Wang, Y.; Huang, X. J.; Zhang, X. Q.; Jiang, R. W.; Yao, X. S.; Che, C. T.; Ye, W. C. Tetrahedron 2011, 67, 4807; (b) Zhang, B. F.; Zhang, Q. P.; Liu, H.; Chou, G. X.; Wang, Z. T. Phytochemical 2011, 72, 916; (c) Zhang, Z.; Di, Y. T.; Wang, Y. H.; Zhang, Z.; Mu, S. Z.; Fang, X.; Zhang, Y.; Tan, C. J.; Zhang, Q.; Yan, X. H.; Guo, J.; Li, C. S.; Hao, X. J. Tetrahedron 2009, 65, 4551; (d) Yamada, Y.; Kitajima, M.; Kogure, N.; Takayama, H. Tetrahedron 2008, 64, 7690; (e) Kogure, N.; Kobayashi, H.; Ishii, N.; Kitajima, M.; Wongseripipatana, S.; Takayama, H. Tetrahedron Lett. 2008, 49, 3638. 4. Gelsochalotine (1): ½a17 D 105 (c 0.18, CH3OH); IR (KBr) mmax 3415, 3215, 2951, 1759, 1732, 1454, 1225, 1081, 839 cm1; 1H and 13C NMR data, see Table 1; positive HRESIMS m/z 266.1390 (calcd for C14H20NO4, 266.1392). Crystallographic data of gelsochalotine have been deposited at the Cambridge Crystallographic Data Centre (deposition no. CCDC 846062). Copies of these data can be obtained free of charge via www.ccdc.cam.an.uk/ conts/retrieving.html.
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