Carbamate derivatives and sesquiterpenoids from the South China Sea gorgonian Melitodes squamata

  1. Li-Si Huang1,
  2. Fei He1,
  3. Hui Huang1,2,
  4. Xiao-Yong Zhang1 and
  5. Shu-Hua Qi1,§

1Key Laboratory of Marine Bio-resources Sustainable Utilization/Guangdong Key Laboratory of Marine Materia Medica/RNAM Center for Marine Microbiology, South China Sea Institute of Oceanology, The Chinese Academy of Sciences, 164 West Xingang Road, Guangzhou 510301 Guangdong, China
2Hainan Key Laboratory of Tropical Marine Biology and Technology, South China Sea Institute of Oceanology, The Chinese Academy of Sciences, 164 Xingangxi Road, Guangzhou 510301, China

  1. Corresponding author email

§ Tel.: +86-20-89022112; Fax: +86-20-84458964

Associate Editor: D. Trauner
Beilstein J. Org. Chem. 2012, 8, 170–176. https://doi.org/10.3762/bjoc.8.18
Received 05 Aug 2011, Accepted 10 Jan 2012, Published 31 Jan 2012

Abstract

Five carbamate derivatives, obtucarbamates C and D (1, 2), dimethyl ((carbonylbis(azanediyl))bis(2-methyl-5,1-phenylene))dicarbamate (3), obtucarbamates A and B (4, 5), and four aromadendrane-type sesquiterpenoids, (+)-4β-N-methenetauryl-10β-methoxy-1β,5α,6β,7β-aromadendrane (6), (−)-4β-N-methenetauryl-10β-methoxy-1β,5β,6α,7α-aromadendrane (7), (−)-4α,10β-aromadendranediol (8), (+)-4β,10β-aromadendranediol (9) were obtained from the South China Sea gorgonian coral Melitodes squamata Nutting. Compounds 1, 2, 6, and 7 were new, and their structures were established by spectroscopic analyses. Compounds 6 and 7 contained a taurine group that was rarely found in marine natural compounds, and 7 showed moderate antibacterial activity. The possible biosynthesis routes of 15 were conjectured.

Keywords: carbamate; gorgonian; Melitodes squamata; sesquiterpenoid

Introduction

Gorgonians are recognized to mainly produce acetogenins, sesquiterpenoids, diterpenoids, prostanoids, and steroids [1,2]. However, nitrogen-containing compounds were relatively few obtained from gorgonians. Gorgonian Melitodes squamata Nutting belonging to Melithaea family is a kind of pharmaceutical coral that has the efficacy of relieving cough, bleeding, and diarrhea, soothing nerves, and calming scare, etc [3]. A previous study on the chemical constituents of Melithaea family gorgonians led to the isolation of four new steroids melithasterols A–D from Melithaea ocracea [4].

Results and Discussion

In order to further obtain new bioactive compounds from gorgonians, we studied the chemical constituents of the South China Sea gorgonian M. squamata, which led to the obtainment of five carbamate derivatives, obtucarbamates C and D (1, 2), ((carbonylbis(azanediyl))bis(2-methyl-5,1-phenylene))dicarbamate (3) [5], obtucarbamate A (4) [6], obtucarbamate B (5) [6], and four aromadendrane-type sesquiterpenoids, (+)-4β-N-methenetauryl-10β-methoxy-1β,5α,6β,7β-aromadendrane (6), (−)-4β-N-methenetauryl-10β-methoxy-1β,5β,6α,7α-aromadendrane (7), (−)-4α,10β-aromadendranediol) (8) [7], (+)-4β,10β-aromadendranediol) (9) [7] (Figure 1) from the EtOH/CH2Cl2 extracts of M. squamata. Compounds 1, 2, 6, and 7 have not been previously reported. The cytotoxicity of 19 against human malignant melanoma A735 and cervical carcinoma HeLa cell lines, and the antibacterial activity of 15 and 7 towards bacteria Escherichia coli, Bacillus subtilis and Micrococcus luteus were evaluated. The possible biosynthesis routes of 15 were conjectured.

[1860-5397-8-18-1]

Figure 1: Structures of compounds 19.

Compound 1 showed the same molecular formula of C19H22N4O5 as 3, which was determined by its HRMS–ESI (m/z 409.1568 [M + Na]+) and NMR spectra. The 1H NMR spectrum of 1 (Table 1) exhibited signals for three ABX system aromatic protons at δH 7.50 (s, 1H), 7.19 (dd, J = 2.0, 8.0 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), three ABC system aromatic protons at δH 7.57 (d, J = 8.0 Hz, 1H), 7.08 (t, J = 8.0 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), two methyl groups at δH 2.12 (s, 3H), 2.07 (s, 3H), and two methoxy groups at δH 3.63 (s, 3H), 3.64 (s, 3H). It also showed four –NH protons at δH 8.90 (s), 8.78 (s) and 8.52 (s, 2H). The 13C NMR and DEPT 135 spectral data (Table 1) showed the presences of 19 carbons, including three carbonyl carbons (δC 154.5, 154.6, 152.7), 12 aromatic carbons, two methyl carbons (δC 16.9, 12.4), and two methoxy carbons at δC 51.5. The NMR data of 1 were very similar to those of compounds 35 [5,6]. Compound 3 is a symmetric urea derivative that was formed from the amidation of two molecules of 4 [6]. Comparison of the NMR data of 1 with 35 suggested that 1 was an asymmetric urea derivative that was formed from the amidation of 4 and 5 [5,6].

Table 1: 1H (500 MHz) and 13C NMR (125 MHz) data of 1 and 2 (in DMSO-d6, δ in ppm, J in Hz).

C 1   2  
  δH δC δH δC
1 136.5, C 136.3, C
2 7.50 (s) 114.0, CH 7.54 (s) 113.8, CH
3 138.3, C 138.0, C
4 7.19 (dd, 2.0, 8.0) 114.5, CH 7.19 (br d, 8.0) 114.0, CH
5 7.06 (d, 8.0) 130.1, CH 7.06 (d, 8.0) 130.1, CH
6 124.3, C 124.0, C
1’ 137.1, C 137.5, C
2’ 124.0, C 7.93 (s) 111.4, CH
3’ 137.1, C 137.0, C
4’ 7.57 (d, 8.0) 119.2, CH 7.04 (d, 8.0) 112.5, CH
5’ 7.08 (t, 8.0) 125.2, CH 7.07 (d, 8.0) 129.8, CH
6’ 6.99 (d, 8.0) 121.8, CH 121.7, C
7–CH3 2.12 (s) 16.9, CH3 2.12 (s) 17.2, CH3
7’–CH3 2.07 (s) 12.4, CH3 2.16 (s) 16.9, CH3
OCH3 3.64 (s) 51.5, CH3 3.64 (s) 51.5, CH3
  3.63 (s) 51.5, CH3 3.63 (s) 51.3, CH3
–NHCONH– 8.78 (s)
8.90 (s)
152.7, C 8.78 (s)
9.46 (s)
152.5, C
–NHCOO– 8.52 (s)
8.52 (s)
154.5, C
154.6, C
8.53 (s)
8.53 (s)
154.6, C
154.2, C

The suggestion was supported by the HMBC correlations (Figure 2). In the HMBC spectrum of 1, correlations of Me-7 (s, 2.12) with δC 130.1 (d, C-5), 124.3 (s, C-6), 136.5 (s, C-1) and Me-7’ (s, 2.07) with δC 124.0 (s, C-2’), 137.1 (s, C-1’), 137.1 (s, C-3’) indicate a methyl group attached at both C-6 and C-2’. The HMBC correlations of δH 3.64 (s) with δC 154.5 (s) and δH 3.63 (s) with δC 154.6 (s) revealed the presence of two –NHCOOMe groups. The HMBC correlations of δH 8.78 (NH) with δC 124.3 (C-6), 114.0 (C-2), δH 8.90 (NH) with δC 124.0 (C-2’), 119.2 (C-4’), and δH 8.52 (2NH) with δC 114.0 (C-2), 114.5 (C-4), 121.8 (C-6’), 124.0 (C-2’), suggest that the four –NH groups are attached at C-1, C-3, C-1’, C-3’ of two aromatic rings. Based on the above data analysis, the structure of 1 was elucidated to be as shown above and named as obtucarbamate C.

[1860-5397-8-18-2]

Figure 2: Key HMBC correlations of 1.

Compound 2 also exhibited the molecular formula of C19H22N4O5 as deduced from NMR and HRMS–ESI (m/z 409.1576 [M + Na]+). The 1H NMR data of 2 (Table 1) exhibited signals for two ABX aromatic systems, including six aromatic protons at δH 7.54 (s, 1H), 7.19 (br d, J = 8.0 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 7.93 (s, 1H), 7.07 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H). The 1H and 13C NMR spectral data of 2 show similarities to those of 3 [5] (Table 1). Comparison of the NMR data of 2 and 3 suggests that 2 is an asymmetric urea derivative that was formed from the amidation of two molecules of 4 [5,6], and the only difference between 2 and 3 is the amidation position of the two molecules of 4. Based on the 1H NMR, 13C NMR HSQC, HMBC and 1H–1H COSY spectral data analysis, the structure of 2 was elucidated to be as shown above and named as obtucarbamate D.

Urea derivatives are closely related in structure to carbamates. Urea is synthesized in the body of many organisms as part of the urea cycle, which is namely a cycle of biochemical reactions occurring in many animals that produces urea ((NH2)2CO) from ammonia (NH3). According to the reactions of the urea cycle [5], we made conjectures about the possible biosynthesis routes of compounds 24 as shown (Figure 3). The possible biosynthesis routes to 1, 5 and 2–4 are essentially the same, except starting from 4-methylbenzene-1,3-diamine in place of 2-methybenzene-1,3-diamine. This is the first time that carbamate derivatives from gorgonians have been reported.

[1860-5397-8-18-3]

Figure 3: Possible biosynthesis routes of compounds 24.

Compound 6 was assigned the molecular formula of C19H35NSO4 as deduced from NMR spectra and HRMS–ESI (m/z 372.2170 [M − H]). The 1H NMR data (Table 2) indicate an aromadendrane skeleton with two cyclopropyl protons resonating at δH 0.44 (t, J = 10.0 Hz, 1H) and 0.67 (ddd, J = 6.5, 10.0, 11.5 Hz, 1H) [7-11]. The 1H NMR spectrum also showed four singlet methyl groups (δH 0.93, 1.02, 1.11, 1.11) and a methoxy group (δH 3.16). The 13C NMR spectrum (Table 2) displayed 19 carbon signals, including five methyl carbons (δC 16.6, 28.7, 17.6, 17.8, 48.3), seven methylene carbons (δC 24.0, 37.0, 19.5, 37.2, 45.8, 45.9, 58.9), four methine carbons (δC 50.1, 46.0, 25.6, 26.6), and three quaternary carbons (δC 19.6, 44.0, 79.1). These NMR data (Table 2) showed similarities to those of (–)-4α,10β-aromadendranediol (8), (+)-4β,10β-aromadendranediol (9) and other analogues [7-11], which suggests that 6 is an aromadendrane-type sesquiterpenoid with a methoxy group and a side chain that contained three methylene carbons.

Table 2: 1H (500 MHz) and 13C NMR (125 MHz) data of 6 and 7 (in CDCl3, δ in ppm, J in Hz).

No. 6 7
  δH δC δH δC
1 2.23 (dd, 8.0, 17.0) 50.1, CH 2.09 (m) 52.2, CH
2 1.73 (m) 24.0, CH2 1.67 (m) 25.2, CH2
3 1.37 (t, 11.0),
1.80 (overlap)
37.0, CH2 1.61 (overlap) 33.4, CH2
4 44.0, C 44.3, C
5 0.98 (br t, 10.0) 46.0, CH 1.72 (overlap) 41.7, CH
6 0.44 (t, 10.0) 25.6, CH 0.22 (t, 9.5) 24.3, CH
7 0.67 (ddd, 6.5, 10.0, 11.5) 26.6, CH 0.62 (m) 28.7, CH
8 0.84 (ddd, 6.5, 12.5, 13.5),
1.87 (ddd, 6.5, 11.5,13.5)
19.5, CH2 1.14 (m)
1.59 (m)
18.2, CH2
9 1.59 (t, 12.5)
1.67 (dd, 6.5, 14.5)
37.2, CH2 1.48 (t, 12.0),
1.83 (dd, 6.5, 14.5)
32.8, CH2
10 79.1, C 79.1, C
11 19.6, C 19.3, C
12 0.93 (s) 28.7, CH3 1.01 (s) 28.3, CH3
13 1.02 (s) 16.6, CH3 0.99 (s) 16.0, CH3
14 1.11 (s) 17.6, CH3 1.20 (s) 21.8, CH3
15 1.03 (s) 17.8, CH3 1.10 (s) 24.4, CH3
16 2.72 (d, 12.0),
2.94 (d, 12.0)
58.9, CH2 2.86 (d, 12.5),
3.04 (d, 12.5)
58.3, CH2
17 3.54 (t, 5.0) 45.8, CH2 3.27 (br s) 45.9, CH2
18 3.31 (t, 5.0) 45.9, CH2 3.44 (br s), 3.53 (br s) 45.7, CH2
OCH3 3.16 (s) 48.3, CH3 3.10 (s) 48.1, CH3

This suggestion was proved by the HMBC correlations (Figure 4). In the HMBC spectrum of 6, correlation of MeO– (δH 3.16, s) with δC 79.1 indicates the methoxygenation of C-10. The HMBC correlations of H-16 [δH 2.72 (d, J = 12 Hz), 2.94 (d, J = 12 Hz)] with C-3 (δC 37.0)/C-4 (δC 44.0)/C-5 (δC 46.0)/Me-14 (δC 17.6) indicate that there is a side chain at C-4 instead of a –OH group. The HMBC spectrum also shows correlations of H-16 with C-17 (δC 45.8) and H-17 [δH 3.54 (t, J = 5.0 Hz)] with C-16 (δC 45.8)/C-18 (δC 45.8). In the 1H–1H COSY spectrum (Figure 4), correlation of H-17 with H-18 [δH 3.31 (t, J = 5.0 Hz)] is observed. The above HMBC and 1H–1H COSY spectral data, combined with the molecular formula of C19H35NSO4, suggest the presence of a –CH2NHCH2CH2SO3H group. The suggestion was supported by the 1H and 13C NMR data comparison of the –CH2NHCH2CH2SO3H group in 6 with literature data [12,13]. The IR spectrum of 6 contains two strong bands at 1217 and 1041 cm−1, which supports the presence of a sulfonic acid group. The –NHCH2CH2SO3H group has rarely been found in marine natural compounds, such as N-methyltaurine, taurine, and spongidine D from sponges [12,13].

[1860-5397-8-18-4]

Figure 4: Key HMBC and 1H–1H COSY correlations of 6.

The relative stereochemistry of H-1, H-5, H-6, H-7, Me-14 and Me-15 in 6 was determined by NMR data comparison with literature data and NOESY spectral analysis. The chemical shifts (δC 16.6, 28.7) of the methyl groups of Me-12 and Me-13 correlate well with those previously assigned to the corresponding methyl groups in 8, 9 and other analogues [7-11], which suggests the cis-orientation of the cyclopropane ring [7,8]. The coupling constants (J = 10.0 Hz) between H-5 and H-1/H-6 indicate the trans-relationship of H-5 with H-1 and H-6. By comparison with the known chemical-shift data and shift parameters [7-11], the β-orientation of H-1, H-6, H-7 and α-orientation of H-5 were assigned. In the seven-numbered ring, the methyl group C-15 (δC 17.8) appears at a high field, reflecting that Me-15 is not in the same orientation as H-6 and H-7 [7]. In the NOESY spectrum, correlations of OMe-10 with H-1, H-6, H-7 are observed (Figure 5), which suggest that OMe-10, H-1, H-6, H-7 are in β-orientation, meanwhile, the presence of correlations between H-5 and Me-14/Me-13 indicates that H-5, Me-14, Me-13 are in α-orientation. Thus, the structure of 6 was elucidated to be as shown and named as (+)-4β-N-methenetauryl-10β-methoxy-1β,5α,6β,7β-aromadendrane.

[1860-5397-8-18-5]

Figure 5: Key NOESY correlations of 6 and 7.

Compound 7 showed the same molecular formula of C19H35NSO4 as 6 on the basis of NMR spectra and HRMS–ESI (m/z 372.2172 [M − H]). The 1H and 13C NMR spectral data of 7 (Table 2) showed similarities to those of 6, except for some obvious differences in the chemical shift data of H-5 (from δH 0.98 to δH 1.72), C-3 (from δC 37.0 to δC 33.4), C-5 (from δC 46.0 to δC 41.7), C-9 (from δC 37.2 to δC 32.8), and C-15 (from δC 17.8 to δC 24.4), which were caused by the stereochemistry change. In the 1H–1H COSY spectrum, no correlation between H-1 and H-5 is observed, which suggests a small coupling constant and the cis relationship between H-1 and H-5. The coupling constant (J = 9.5 Hz) between H-5 and H-6 indicates the trans-relationship of H-5 with H-6. In the NOESY spectrum, H-16 shows correlations with H-1/H-5, which suggests that H-16, H-1, and H-5 are in β-orientation; meanwhile, correlations of H-6 with H-7/Me-14/Me-13 indicate that H-6, H-7, Me-14 and Me-13 are in α-orientation. The chemical shift of Me-15 (δC 24.4) appears at a slightly lower field reflecting that Me-15 is at the same α-orientation as H-6 and H-7 [7]. Thus, the structure of 7 was elucidated to be as shown and named as (−)-4β-N-methenetauryl-10β-methoxy-1β,5β,6α,7α-aromadendrane.

The cytotoxicity of compounds 19 against human malignant melanoma A735 and cervical carcinoma HeLa cell lines was evaluated by MTT assay. The results show that 19 does not exhibit cytotoxicity against A735 and HeLa cell lines with IC50 > 200 μg/mL. Antibacterial activity of compounds 15 at a concentration of 25 μg/disc (diameter 6 mm) was measured against bacteria Escherichia coli, Bacillus subtilis, and Micrococcus luteus strains by using standard disc-diffusion assay. The results show that 15 exhibit no inhibitory effects towards all tested bacteria at 25 μg/disc, 7 can inhibit the growth of B. subtilis and M. luteus with inhibition zones of 6.3 mm and 6.2 mm, respectively, at 25 μg/disc, while 7 has no effect towards E. coli at 25 μg/disc. It was reported that taurine and its derivatives have a number of physiological functions, including interference with GABA and glycine receptors, antinociceptic effects, anticonvulsive actions, neuroprotective actions, etc. [14]. In this study, because of the limited quantity of compound, we did not further test the other bioactivities of 6 and 7.

Experimental

General experimental procedures

Optical rotations were measured with a Horiba SEAP-300 spectropolarimeter. UV spectra were measured with a Shimadzu double-beam 210A spectrophotometer in MeOH solution. 1H, 13C NMR and 2D NMR spectra were recorded on a Bruker AV-500 MHz NMR spectrometer with TMS as internal standard. MS spectral data were obtained on an LCQDECA XP HPLC/MSn spectrometer for ESIMS. Silica gel (200–300 mesh) for column chromatography and GF254 for TLC were obtained from the Qindao Marine Chemical Factory, Qindao, People’s Republic of China.

Animal material

The South China Sea gorgonian coral Melitodes squamata Nutting was collected in Sanya, Hainan province, China in July 2008 and identified by Prof. Huang H., the South China Sea Institute of Oceanology, Academia Sinica. A voucher specimen (No. 0802) was deposited in the South China Sea Institute of Oceanology, Academia Sinica, Guangzhou, China.

Extraction and isolation

The frozen specimen of the South China Sea gorgonian coral M. squamata (20 kg, wet weight) was extracted with EtOH/CH2Cl2 (2:1) three times at room temperature and the solvent was evaporated in vacuo. The residue was partitioned in H2O and extracted with EtOAc and n-BuOH three times each. The extracts of each respective solvent were combined. The EtOAc and n-BuOH extracts were concentrated in vacuo to afford 35.17 g and 16.85 g of residue, respectively. The EtOAc extract was subjected to silica-gel column chromatography (column A), eluted with CHCl3/MeOH (from 1:10 to 0:10). By combining the fractions with TLC (GF254) monitoring, 17 fractions were obtained. Fraction A-5 was applied to a Sephadex LH-20 column (column B), eluted with CHCl3/MeOH (1:1), to obtain four fractions. Fraction B-4 was further purified by HPLC (MeOH/H2O 45:100) to yield 1 (1.8 mg, tR = 23.5 min), 2 (1.8 mg, tR = 41.2 min), 3 (2.8 mg, tR = 38.2 min), 4 (2.7 mg, tR = 13.8 min) and 5 (1.8 mg, tR = 9.0 min), separately. Fraction B-3 was further purified by RP-18 reverse-phase silica-gel column chromatography (column C), eluted with MeOH/H2O (30:100), to yield 8 (14.8 mg) and 9 (9.5 mg). Fraction A-11 was separated by a Sephadex LH-20 column (column D), eluted with CHCl3/MeOH (1:1) to give five fractions. Fraction D-2 was subjected to silica-gel column chromatography (column E), eluted with CHCl3/MeOH (10:1), to yield 6 (4.2 mg) and three other fractions. Fraction E-2 was furthered purified by a Sephadex LH-20 column (MeOH/H2O 95:5) to yield 7 (4.8 mg).

Obtucarbamate C (1): White powder; UV (MeOH): 258, 216 nm; 1H and 13C NMR data, see Table 1; (+)-ESIMS (m/z): 409.0 [M + Na]+, 795.0 [2M + Na]+; HRMS–ESI (m/z): [M + Na]+ calcd for C19H23N4O5Na, 409.1590; found, 409.1568.

Obtucarbamate D (2): White powder; UV (MeOH): 258, 216 nm; 1H and 13C NMR data, see Table 1; (+)-ESIMS (m/z): 409.1 [M + Na]+, 795.3 [2M + Na]+; HRMS–ESI (m/z): [M + Na]+ calcd for C19H23N4O5Na, 409.1590; found, 409.1576.

(+)-4β-N-methenetauryl-10β-methoxy-1β,5α,6β,7β-aromadendrane (6): White powder; [α]D20 +26.4° (c 0.28, MeOH); 1H and 13C NMR data, see Table 2; (−)-ESIMS (m/z): 372.1 [M − H], 745.4 [2M − H]; HRMS–ESI (m/z): [M − H] calcd for C19H34NSO4, 372.2209; found, 372.2170.

(−)-4β-N-methenetauryl-10β-methoxy-1β,5β,6α,7α-aromadendrane (7): White powder; [α]D20 −7.5° (c 0.48, MeOH); 1H and 13C NMR data, see Table 2; (−)-ESIMS (m/z): 372.2 [M − H], 745.4 [2M − H]; HRMS–ESI (m/z): [M − H] calcd for C19H34NSO4, 372.2209; found, 372.2172.

Acknowledgements

The authors are grateful to the National Science Foundation of China (grant 20872151), the research supported by the CAS/SAFEA International Partnership Program for Creative Research Teams (grant KZCX2-YW-T001), the National Basic Research Program of China (grant 2010CB8338-00-G), the National Science Foundation of China (grant 40976090 and 40910093), the Knowledge Innovation Program of Chinese Academy of Science (grant KSCX2-EW-G-12B), and the Hi-tech Research and Development Program of China (grant SQ2007AA09Z409) for financial support.

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