Mar. Drugs 2014, 12(2), 672-681; doi:10.3390/md12020672

Communication
Six New Tetraprenylated Alkaloids from the South China Sea Gorgonian Echinogorgia pseudossapo
Zhang-Hua Sun 1, Ying-Hong Cai 1, Cheng-Qi Fan 2, Gui-Hua Tang 1, Hai-Bin Luo 1 and Sheng Yin 1,*
1
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, China; E-Mails: sysuszh@126.com (Z.-H.S.); caiyinghong88@163.com (Y.-H.C.); tanggh5@mail.sysu.edu.cn (G.-H.T.); luohb77@mail.sysu.edu.cn (H.-B.L.)
2
East China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Shanghai 200090, China; E-Mail: chengqifan92@pku.org.cn
*
Author to whom correspondence should be addressed; E-Mail: yinsh2@mail.sysu.edu.cn; Tel./Fax: +86-20-3994-3090.
Received: 25 November 2013; in revised form: 10 December 2013 / Accepted: 13 January 2014 /
Published: 27 January 2014

Abstract

: Six new tetraprenylated alkaloids, designated as malonganenones L–Q (16), were isolated from the gorgonian Echinogorgia pseudossapo, collected in Daya Bay of Guangdong Province, China. The structures of 16 featuring a methyl group at N-3 and a tetraprenyl chain at N-7 in the hypoxanthine core were established by extensive spectroscopic analyses. Compounds 16 were tested for their inhibitory activity against the phosphodiesterases (PDEs)-4D, 5A, and 9A, and compounds 1 and 6 exhibited moderate inhibitory activity against PDE4D with IC50 values of 8.5 and 20.3 µM, respectively.
Keywords:
gorgonian; Echinogorgia pseudossapo; tetraprenylated alkaloids; phosphodiesterases

1. Introduction

Tetraprenylated purine alkaloids and their derivatives are relatively uncommon in nature [1,2]. They are structurally characterized by a methyl group at N-3 and a tetraprenyl chain at N-7 in the hypoxanthine core. Malonganenone A [3], the first typical representative of this series, was isolated from the gorgonian Leptogorgia gilchristi, collected in Ponto Malongane, Mozambique in 2006. Until now, only 14 analogues have been reported from marine organisms [3,4,5], some of which exhibited antitumor activity [4,5]. Although the genus Echinogorgia is highly prolific in the South China Sea, only a few species of Echinogorgia have been chemically investigated, which led to the isolation of a series of metabolites including sterols [6,7,8,9,10,11,12], alkaloids [11,12,13,14], sesquiterpenes [14,15,16], ceramides [17], and coumarins [18]. In our screening program aimed at discovering new biologically active natural products from marine organisms of the South China Sea [19], a fraction of the CH2Cl2/MeOH extract of E. pseudosassapo showed inhibitory activity towards phosphodiesterases (PDEs)-4D, 5A, and 9A. Subsequent chemical investigation resulted in the purification of six new tetraprenylated alkaloids, malonganenones L–Q (16, Figure 1, Supplementary Figures S1–S31). The resulting inhibitory activity screening against PDE4D, PDE5A, and PDE9A showed that compounds 1 and 6 exhibited moderate activities against PDE4D with IC50 values of 8.5 and 20.3 µM, respectively. The present report describes the isolation, structure elucidation, and PDEs inhibitory activities of these tetraprenylated alkaloids.

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Figure 1. Structures of malonganenones L–Q (16).

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Figure 1. Structures of malonganenones L–Q (16).
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2. Results and Discussion

2.1. Structural Elucidation of New Compounds

The CH2Cl2/MeOH (v/v, 1:1) extract of the gorgonian was subjected to chromatography using Sephadex LH-20 followed by silica gel and HPLC separations to yield compounds 16.

Compound 1, a colorless oil, exhibited a molecular formula of C26H36N4O2 as determined by HRESIMS ([M + Na]+, 459.2721, calcd. 459.2736), implying 11 double bond equivalents (DBE). The IR absorption bands at 1709 and 1610 cm−1 indicated the presence of two carbonyls. The 1H NMR spectrum of 1 (Table 1) showed signals for two aromatic singlets [δH 8.26 (H-2) and 7.69 (H-8)], four olefinic protons [δH 6.07 (H-14′), 5.45 (H-2′), 5.19 (H-10′), and 5.05 (H-6′)], five vinylic methyls [δH 2.10 (H-17′), 1.84 (H-16′), 1.77 (H-20′), 1.58 (H-18′), and 1.56 (H-19′)], one heteroatom-functionalized methyl [δH 3.86 (H-10)], and a series of aliphatic methylene multiplets. The 13C NMR spectrum of 1 (Table 2) resolved 26 resonances attributable to five double bonds (δC 155.5 C, 122.9 CH; 147.3 C, 115.0 C; 143.4 C, 117.6 CH; 135.5 C, 123.5 CH; and 129.6 C, 129.0 CH), two carbonyls (δC 199.3 and 162.0), two imines (δC 147.7 and 140.3), five vinylic methyls (δC 27.7, 20.6, 16.5, 16.4, and 16.0), a N-methyl (δC 35.0), and six sp3 methylenes (δC 55.3, 44.5, 39.4, 39.3, 26.7, and 26.1). As nine of the eleven DBE were accounted for by abovementioned unsaturated functional groups, the remaining two DBE required that 1 was bicyclic. The collective spectroscopic information pointed clearly to a fused diterpene-N-methylhypoxanthine structure, which bore a high similarity to that of malonganenone D [4]. The N-methylhypoxanthine moiety of 1 was readily identified by comparison of its NMR data with that of malonganenone D, which gave almost identical 13C NMR data regarding to this portion. The tetraprenyl side-chain of 1 was deduced from detailed analysis of COSY and HMBC data (Figure 2). 1H–1H COSY correlations revealed four spin systems: (a) H-1′/H-2′/H-3′/H3-20′; (b) H-4′/H-5′/H-6′/H-7′/H3-19′; (c) H-8′/H-9′/H-10′/H-11′/H3-18′; and (d) H-14′/H-15′/H-16′ or H-17′. The connections from a to c were achieved by HMBC correlations of H-20′/C-4′ and H-19′/C-8′. The fragments c and d were linked via a methylene and a ketone (C-13) by HMBC correlations of H-18′/C-12′, H-12′/C-13′, and H-14′/C-13′. The geometries of the three olefins in the tetraprenyl side-chain were established from analysis of both 13C chemical shift and NOE data. The 13C chemical shifts of the vinylic methyls of C-18′, C-19′, and C-20′ (δC 16.4, 16.0, and 16.5, respectively) suggested the E geometries for ∆10′, ∆6′, and ∆2′ as the vinyl methyl corresponding to Z geometry are known to resonate at around 25 ppm [4]. This was further supported by NOE correlations (Figure 2) of H-9′/H-18′ and H-10′/H-12′, H-5′/H-19′ and H-6′/H-8′, and H-1′/H-20′ and H-2′/H-4′, respectively. Finally, the tetraprenyl side-chain was attached to N-7 by HMBC correlations from H-1′ to C-5 and C-8. Thus, compound 1 was determined as depicted and given the trivial name malonganenone L.

Table Table 1. 1H NMR spectroscopic data for malonganenones L–Q (16) (δ in ppm, J in Hz).

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Table 1. 1H NMR spectroscopic data for malonganenones L–Q (16) (δ in ppm, J in Hz).
No.1 a2 a3 a4 b5 b6 b
1 7.23, brs 7.22, brs
28.26, br s8.57, br s8.62, br s8.23, s8.23, s8.23, s
87.69, s7.73, s7.73, s7.59, s7.59, s7.57, s
103.86, s3.94, s3.95, s3.13, s3.13, s3.13, s
11 2.84, s2.84, s2.84, d (4.7)
1′5.07, d (7.3)5.09, d (7.2)5.08, d (7.4)4.90, d (7.0)4.90, d (7.0)4.89, d (7.1)
2′5.45, t (7.0)5.47, t (6.9)5.47, t (6.9)5.40, t (7.1)5.41, t (7.0)5.39, t (7.0)
4′2.08, m2.11, m2.11, m2.07, m2.08, m2.09, m
5′2.09, m2.11, m2.12, m2.12, m2.13, m2.13, m
6′5.05, m5.08, m5.07, m5.14, t (6.2)5.14, t (6.1)5.14, t (6.3)
8′1.98, m1.99, m1.97, m2.01, m2.01, m2.02, m
9′2.04, m2.07, m1.55, m2.12, m2.12, m1.56, m
10′5.19, t (6.4)5.32, t (6.6)2.06, m5.26, t (6.8)5.30, t (6.3)2.55, br t, (7.9)
12′2.99, s3.09, s6.00, br s3.01, s3.12, s6.08, br s
14′6.07, br s6.06, br s6.04, br s6.17, br s6.15, br s6.10, br s
16′1.84, s1.87, s1.87, d (0.9)1.86, d (1.1)1.87, d (1.1)1.86, d (1.0)
17′2.10, s2.13, s2.13, d (1.0)2.09, d (1.1)2.09, d (1.0)2.12, d (1.0)
18′1.58, s1.69, s2.15, d (1.2)1.61, s1.66, d (1.2)1.87, d (1.3)
19′1.56, s1.58, s1.58, s1.59, s1.60, s1.62, s
20′1.77, s1.79, s1.80, s1.79, s1.79, s1.79, s

a Measured at 400 MHz in CDCl3; b Measured at 400 MHz in Acetone-d6.

Table Table 2. 13C NMR spectroscopic data for malonganenones L–Q (16) (δ in ppm).

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Table 2. 13C NMR spectroscopic data for malonganenones L–Q (16) (δ in ppm).
No.1 a2 a3 a4 b5 b6 b
2147.7148.1148.1163.3163.3163.3
4147.3147.2147.2141.8141.8141.8
5115.0115.2115.2118.2118.2118.2
6162.0160.4160.3160.9160.9161.0
8140.3140.7140.8137.6137.6137.6
1035.035.535.531.931.931.9
11 26.126.126.3
1′44.544.644.745.245.245.2
2′117.6117.3117.4120.5120.5120.4
3′143.4143.7143.7142.0142.0142.0
4′39.439.539.440.140.240.2
5′26.126.126.127.026.926.9
6′123.5123.6123.9124.8124.8124.8
7′135.5135.5135.4135.8135.8136.0
8′39.339.539.140.140.340.6
9′26.726.925.827.427.727.2
10′129.0128.240.8129.4128.733.8
11′129.6129.2157.8130.7130.2158.6
12′55.347.9125.755.848.3126.9
13′199.3198.6191.7198.8198.1191.0
14′122.9123.0126.3123.7124.0127.0
15′155.5155.8154.2155.0155.3154.2
16′27.727.727.727.527.527.6
17′20.620.720.520.520.520.4
18′16.424.119.116.524.425.5
19′16.016.015.916.116.116.0
20′16.516.616.616.516.516.5

a Measured at 100 MHz in CDCl3; b Measured at 100 MHz in Acetone-d6.

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Figure 2. Key 1H–1H COSY (–), HMBC (→) and NOESY (dashed arrows) correlations for 1 and 4.

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Figure 2. Key 1H–1H COSY (–), HMBC (→) and NOESY (dashed arrows) correlations for 1 and 4.
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Compound 2 exhibited the same molecular formula of C26H36N4O2 as 1 on the basis of the HRESIMS data ([M + Na]+, 459.2725, calcd. 459.2736). The NMR spectroscopic data of 2 (Table 1 and Table 2) was very similar to that of 1. In comparison with 1, the 13C NMR spectroscopic data for 2 differed significantly about ∆10′ moiety, with the upfield-shifted carbon at C-12′ and the downfield-shifted vinyl methyl at C-18′ (δC 55.3 and 16.3 in 1; δC 47.9 and 24.1 in 2, respectively). This indicated that ∆10′ in 2 adopts a Z configuration. Similar 13C NMR changes were also reported in malonganenone I [5], which possessed the same Z configuration of ∆10′ as 2. Thus, compound 2 was determined as depicted and named malonganenone M.

Compound 3 had a molecular formula of C26H36N4O2 as established by HRESIMS data. The 1H and 13C NMR data of 3 (Table 1 and Table 2) showed high similarity to those of 1 except that the ∆10′ double bond in 1 was migrated to ∆11′, forming a conjugated system with the C-13′ carbonyl. This was suggested by the significant downfield-shifted carbon at C-11′ and the upfield-shifted carbon at C-13′ as compared with those of 1C 129.6 and 199.3 in 1; δC 157.8 and 191.7 in 3, respectively), and by the presence of a singlet olefinic signal (δH 6.00, H-12′) in the 1H NMR spectra of 3 instead of a triplet olefinic signal (δH 5.19, t, J = 6.4 Hz, H-10′) in 1. The configuration of ∆11′ in 3 was established to be E by the characteristic chemical shift of the vinylic methyl at C-18′ (δC 19.1) and by comparison of its NMR data with those of reported. Therefore, the structure of compound 3 was determined as depicted and given the trivial name malonganenone N.

Compound 4 exhibited an [M − H] ion at m/z 467.3021 (calcd. for C27H39N4O3, 467.3022), suggesting the molecular formula C27H40N4O3 (ten DBE). The 1H and 13C NMR spectra of 4 (Table 1 and Table 2) bore a resemblance to those of 1, with the notable differences occurring in the hypoxanthine core. The NMR spectra of 4 showed the presence of an N-methylamide (δH 2.84, H-11; δC 26.1, C-11) and an N-methylformamide (δH 8.23, H-2 and 3.13, H-10; δC 163.3, C-2 and 31.9, C-10) groups, which were identical to those previously reported in malonganenones B, F, and G, indicating that 4 possessed the same trisubstituted imidazole ring. This was further supported by HMBC correlations (Figure 2) of H3-11/C-6, H3-10/C-4, and H-2/C-10. Thus, the structure of compound 4 was determined as depicted and given the trivial name malonganenone O.

Compound 5 had a molecular formula C27H40N4O3 by analysis of the HRESIMS data. Comparing the NMR data (Table 1 and Table 2) of 5 and 4, it appeared that the former had a Z configuration of ∆10′ instead of an E configuration of ∆10′ in 4. This was suggested by the upfield-shifted carbon at C-12′ and the downfield-shifted vinyl methyl at C-18′ (δC 48.3 and 24.4 in 5; δC 55.8 and 16.5 in 4, respectively). Thus, the structure of compound 5 was determined as depicted and given the trivial name malonganenone P.

The molecular formula of compound 6 was established as C27H40N4O3 by HRESIMS. The NMR data of 6 (Table 1 and Table 2) showed high similarity to that of 4 except that the ∆10′ double bond in 6 was migrated to ∆11′, forming a conjugated system with the C-13′ carbonyl. This was further suggested by the significant downfield-shifted carbon at C-11′ and the upfield-shifted carbon at C-13′ as compared with those of 4C 130.7 and 198.8 in 4; δC 158.6 and 191.0 in 6, respectively), and by the presence of a singlet olefinic signal (δH 6.08, H-12′) in the 1H NMR spectra of 6 instead of a triplet olefinic signal (δH 5.26, t, J = 6.8 Hz, H-10′) in 4. The characteristic chemical shift of the vinylic methyl at C-18′ (δC 25.5) indicated the Z configuration of ∆11′ in 6. Thus, the structure of 6 was determined as depicted and given the trivial name malonganenone Q.

2.2. In Vitro Inhibitory Activity Screening against PDEs

Compounds 16 were screened for their inhibitory activities against PDE4D, PDE5A, and PDE9A by using our previously reported methods [20,21,22,23]. As shown in Table 3, all compounds exhibited inhibition at 50 µM against PDE4D with degree of inhibition from 72% to 85%, while displaying weaker activities against PDE5A and PDE9A. The two most active compounds, 1 and 6, were selected to test for the half maximal inhibitory concentration (IC50), which gave IC50 values of 8.5 and 20.3 µM, respectively (Figure 3).

Table Table 3. Inhibitory activities of compounds 16 at 5 µM and 50 µM towards PDE4D, PDE5A and PDE9A.

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Table 3. Inhibitory activities of compounds 16 at 5 µM and 50 µM towards PDE4D, PDE5A and PDE9A.
CompoundInhibition (%) of Compounds at 50 µM Inhibition (%) of Compounds at 5 µM
PDE4DPDE5APDE9A PDE4DPDE5APDE9A
1855318 1711<10
2723215 <10<10<10
3813527 17<1010
47938<10 18<10<10
5753611 14<10<10
6853815 18<10<10
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Figure 3. Inhibition of phosphodiesterase-4D by compounds 1 and 6 (rolipram as positive control).

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Figure 3. Inhibition of phosphodiesterase-4D by compounds 1 and 6 (rolipram as positive control).
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3. Experimental Section

3.1. General Experimental Procedures

UV spectra were recorded on a Shimadzu UV-2450 spectrophotometer. IR spectra were determined on a Bruker Tensor 37 infrared spectrophotometer with KBr disks. NMR spectra were measured on a Bruker AM-400 spectrometer at 25 °C. ESIMS and HRESIMS were carried out on a Finnigan LC QDECA instrument. A Shimadzu LC-20 AT equipped with an SPD-M20A PDA detector was used for HPLC, a YMC-pack ODS-A column (250 × 10 mm, 5 µm, 12 nm) and a chiral column (Phenomenex Lux, cellulose-2, 250 × 10 mm, 5 µm) was used for semipreparative HPLC separation. Silica gel (300–400 mesh, Qingdao Marine Chemical Co., Ltd., Qingdao, Shandong, China), C18 reversed-phase (Rp-C18) silica gel (12 nm, 50 µm, YMC Co., Ltd., Kyoto, Japan), Sephadex LH-20 gel (Amersham Biosciences, Piscataway, NJ, USA), used for column chromatography (CC). All solvents used were of analytical grade (Guangzhou Chemical Reagents Company, Ltd., Guangzhou, Guangdong, China).

3.2. Animal Material

The gorgonian E. pseudosassapo was collected at a depth of 18–25 m in 29 July 2012 in Daya Bay of Guangdong Province, China and frozen immediately after collection, and were identified by one of the authors (Cheng-Qi Fan). A voucher specimen (accession number: LSH201207) has been deposited at the School of Pharmaceutical Sciences, Sun Yat-sen University, China.

3.3. Extraction and Isolation

Specimens of E. pseudosassapo (550 g, wet weight) were extracted with CH2Cl2/MeOH (1:1, 3 × 1 L) at room temperature (rt) to give 13.7 g of crude extract. The crude extract was subjected to silica gel column chromatography eluted with a CH2Cl2/MeOH gradient (9:1→1:9) to afford five fractions (Fr. I–V). Fr. III (1.4 g) was chromatographed over Sephadex LH-20 (CH2Cl2/MeOH, v/v, 1:1), followed by Rp-C18 silica gel eluted with a CH3CN/H2O gradient (5:5→10:0) to obtain four sub-fractions (Fr. IIIa–IIId). Fr. IIIb was further separated by HPLC equipped with a chiral column (CH3CN, 3 mL/min) to afford 1 (17 mg, tR 17 min) and 2 (4.9 mg, tR 20 min). Fr. IIId was purified by repeating the HPLC conditions described above to yield 4 (11 mg, tR 23 min) and 5 (3.7 mg, tR 27 min). Fr. IIIc was chromatographed by HPLC equipped with an ODS-A column (CH3CN/H2O, 90:10, 3 mL/min) to afford 3 (5.2 mg, tR 15 min) and 6 (5.1 mg, tR 20min).

Malonganenone L (1): colorless oil; UV (MeOH) λmax (log ε) 211 (4.42), 225 (4.38), 253 (4.31) nm; IR νmax 3145, 1709, 1610, 1464, 1250, 1128, 1060 cm−1; 1H and 13C NMR, see Table 1 and Table 2; HRESIMS [M + Na]+ m/z 459.2721 (calcd. for C26H36N4O2Na, 459.2736).

Malonganenone M (2): colorless oil; UV (MeOH) λmax (log ε) 209 (4.22), 225 (4.17), 254 (4.06) nm; IR νmax 3011, 1714, 1607, 1458, 1240, 1123, 1046 cm−1; 1H and 13C NMR, see Table 1 and Table 2; HRESIMS [M + Na]+ m/z 459.2725 (calcd. for C26H36N4O2Na, 459.2736).

Malonganenone N (3): colorless oil; UV (MeOH) λmax (log ε) 208 (3.68), 223 (3.60), 254 (3.16) nm; IR νmax 2937, 1732, 1627, 1439, 1379, 1215, 1136, 1039 cm−1; 1H and 13C NMR, see Table 1 and Table 2; HRESIMS [M + Na]+ m/z 459.2725 (calcd. for C26H36N4O2Na, 459.2736).

Malonganenone O (4): colorless oil; UV (MeOH) λmax (log ε) 211 (4.39), 249 (4.22) nm; IR νmax 2932, 1744, 1654, 1514, 1445, 1218, 1127, 1033 cm−1; 1H and 13C NMR, see Table 1 and Table 2; HRESIMS [M − H] m/z 467.3021 (calcd. for C27H39N4O3, 467.3022).

Malonganenone P (5): colorless oil; UV (MeOH) λmax (log ε) 210 (4.27), 254 (4.02) nm; IR νmax 2933, 1674, 1621, 1437, 1220, 1128, 1018 cm−1; 1H and 13C NMR, see Table 1 and Table 2; HRESIMS [M + Na]+ m/z 491.2994 (calcd. for C27H40N4O3Na, 491.2998).

Malonganenone Q (6): colorless oil; UV (MeOH) λmax (log ε) 212 (4.52), 257 (4.46) nm; IR νmax 2932, 1664, 1623, 1532, 1443, 1224, 1057 cm−1; 1H and 13C NMR, see Table 1 and Table 2; HRESIMS [M + Na]+ m/z 491.2994 (calcd. for C27H40N4O3Na, 491.2998).

4. Conclusions

In our continuing investigation on the chemical constituents of marine invertebrates collected from the South China Sea, six new tetraprenylated alkaloids, designated as malonganenones L–Q (16), were isolated from the gorgonian Echinogorgia pseudossapo. The structures of 16 featuring a methyl group at N-3 and a tetraprenyl chain at N-7 in the hypoxanthine core were established by extensive spectroscopic analyses. Compounds 16 were tested for their inhibitory activity against the phosphodiesterases (PDEs)-4D, 5A, and 9A, and compounds 1 and 6 exhibited moderate inhibitory activity against PDE4D with IC50 values of 8.5 and 20.3 µM, respectively. Phosphodiesterase-4 (PDE4), which specifically catalyzes the hydrolysis of cyclic adenosine monophosphate (cAMP), is a therapeutic target of high interest for central nervous system (CNS), inflammatory, and respiratory diseases [24]. Natural PDE4 inhibitors are very rare. To the best of our knowledge, this is the first investigation of this group of compounds on the inhibitory activity of the phosphodiesterases.

Supplementary Files

  • Supplementary File 1:

    Supplementary Information (PDF, 2550 KB)

  • Acknowledgments

    The authors thank the National Natural Science Foundation of China (No. 81102339) and the Key Laboratory of East China Sea & Oceanic Fishery Resources Exploitation and Utilization, Ministry of Agriculture, China (No. K201203) for providing financial support to this work.

    Conflicts of Interest

    The authors declare no conflict of interest.

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