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Secalonic Acids J – M , Four New Secondary Metabolites from the Marine-derived Fungus Penicillium Oxalicum
| Content Provider | Semantic Scholar |
|---|---|
| Author | Chen, Limin Lu, Zhi-Hao Liu, Qin-Ying Zheng, Qiu-Hong Zhanga, Qiqing |
| Copyright Year | 2019 |
| Abstract | Four new secalonic acid derivatives, secalonic acids J–M (1–4), were isolated from the marine-derived fungus Penicillum oxalicum. The planar structures of these compounds were elucidated by NMR and high-resolution mass spectrometric analyses. The absolute configurations were established by comparison of their experimental and calculated electronic circular dichroism spectra. Finally, these compounds were further evaluated for cytotoxic activities against the selected cancer cell lines in vitro. The results of flow cytometry demonstrated that compound 1 owned moderate activity of inducing apoptosis against HeLa cell. The secalonic acids bearing a xanthone dimers skeleton (ergochrome)1 have been isolated from various fungal genera (e.g. Penicillium oxalicum and Aspergillus ochraceus).2 Since Stoll et al.3 discovered secalonic acid A from a fungus in 1952, totally nine secalonic acid analogues have been reported, namely secalonic acids A–I.4 Naturally occurring secalonic acids have attracted a great deal of attention for their unusual structural features and broad spectrum of biological activities. Comparing with the land, ocean has a quite different environment, which has made the marine-derived fungi evolve highly adapted metabolic systems in the natural selection process.5 Therefore, the emergence of an increasing number of candidates for the development of new therapy drugs becomes possible. Till 2011, fungi from the marine environment have provided more than 1000 new natural products with surprisingly vast number of rare structures and well biological activities.6 Marine-derived fungi, hence, are recognized as a fruitful source of antitumor drugs. So we selected the marine-derived fungi as the target strains to study the second metabolites. In this study, an isolated fungal strain Penicillium oxalicum, obtained from southeast coast of China, was cultured in a nutrient-rich medium. Its mycelia extract displayed significant antitumor activity in vitro. During our previous study,4 two new secalonic acid derivatives, secalonic acids H and I, and the known secalonic acid D have been reported. Further chemical study of this fungus led to the isolation of another four novel secalonic acid derivatives, secalonic acids J–M (1–4). In this paper, the isolation, structural elucidation and bioactivities of these new compounds are reported. Figure 1. Structures of compounds 1–4 isolated from P. oxalicum Secalonic acid J (1) was obtained as yellow gum. The molecular formula was determined to be C32H30O14 on the basis of HRESIMS (m/z: 639.1712 [M + H]+, calcd for C32H31O14, 639.1714). Its NMR data (Tables 1 and 2), combined with DEPT and HMQC spectrum analyses, revealed the presence of thirty-two carbons, including nineteen quaternary carbons, six methines, three methylenes, and four methyls. Compared to sixteen carbon signals observed for the symmetrical structure of secalonic acid D,7 thirty-two carbon signals were detected in the 13C NMR spectrum of 1 indicating the structure of 1 is asymmetrical. All the sixteen carbon signals of secalonic acid D were identified in the thirty-two signals of 1, which was further confirmed by COSY and HMBC spectrum analyses. Thus, it was suggested that a half structure of secalonic acid D was retained in 1. Table 1. 13C NMR Data (125 MHz, δ in ppm) of compounds 1–4 in DMSO-d6 No. 1 2 3 4 1 158.7, C 158.6, C 160.5, C 158.5, C 2 116.2, C 116.0, C 109.3, CH 116.3, C 3 140.9, CH 140.7, CH 140.9, CH 141.2, CH 4 107.8, CH 107.7, CH 114.9, C 107.8, CH 4a 159.0, C 159.1, C 157.3, C 158.9, C 5 75.4, CH 75.2, CH 75.0, CH 75.3, CH 6 29.9, CH 29.9, CH 30.4, CH 29.9, CH 7 35.8, CH2 35.8, CH2 35.9, CH2 35.8, CH2 8 178.2, C 178.2, C 178.6, C 178.0, C 8a 101.6, C 101.8, C 101.9, C 101.7, C 9 186.5, C 186.6, C 186.4, C 186.7, C 9a 106.4, C 106.4, C 106.7, C 106.4, C 10a 85.2, C 85.2, C 84.7, C 85.1, C 11 17.8, Me 17.7, Me 17.7, Me 17.7, Me 12 170.04, C 170.2, C 169.9, C 170.4, C 13 52.9, Me 52.7, Me 52.7, Me 52.7, Me 1' 158.8, C 158.9, C 159.2, C 159.8, C 2' 117.6, C 117.4, C 118.2, C 110.8, CH 3' 149.5, C 149.5, C 149.4, C 149.5, C 4' 109.0, CH 108.8, CH 108.8, CH 116.0, C 4a' 158.3, C 158.3, C 158.0, C 156.8, C 5' 70.3, CH 70.2, CH 70.3, CH 70.0, CH 6' 25.4, CH2 25.4, CH2 25.3, CH2 25.9, CH2 7' 27.5, CH2 27.5, CH2 27.5, CH2 27.5, CH2 8' 178.7, C 178.7, C 178.5, C 179.1, C 8a' 101.3, C 101.3, C 101.4, C 101.6, C 9' 186.2, C 186.2, C 186.1, C 185.9, C 9a' 104.3, C 104.4, C 104.2, C 104.8, C 10a' 84.7, C 84.7, C 84.4, C 84.7, C 11' 21.0, Me 20.8, Me 21.4, Me 20.7, Me 12' 169.95, C 170.0, C 170.4, C 169.9, C 13' 52.9, Me 52.8, Me 52.8, Me 52.8, Me For the other half of the structure, two methine groups (C-3, 140.9; H-3, 7.29; C-6, 29.9; H-6, 2.31) were replaced by a quaternary carbon (C-3', 149.5) and a methylene group (C-6', 25.4; H-6', 2.09, 1.91) respectively, and the obviously downfield shift of H-11' (from 1.04 d to 2.03 s) suggested that Me-11' was moved from C-6' to C-3'. The COSY correlation of H-6' with H-5' and H-7' and the key HMBC correlation from H-11' to C-2', C-3' and C-4' and from H-4' to C-11' further supported this deduction. Finally, the key COSY correlation of H-3 with H-4 and HMBC correlation from H-3 to C-2' revealed that the two independent segments were linked through C-2 and C-2'. Until now, the planar structure of 1 was established (Figure 1). Secalonic acid K (2) was obtained as yellow gum. The molecular formula was determined to be C32H30O14 on the basis of HRESIMS (m/z: 639.1714 [M + H]+, calcd for C32H31O14, 639.1714). After careful comparison the 1D-NMR data of 2 and 1 (Tables 1 and 2) and further analysis the COSY and HMBC correlations of 2 (Figure 2), compound 2 was deduced to own the same planar structure as 1. Table 2. 1H NMR Data (500 MHz, J in Hz and δ in ppm) of compounds 1–4 in DMSO-d6 No. 1 2 3 4 2 6.53, d (8.4) 3 7.29, d (8.1) 7.31, d (8.4) 7.18, d (8.4) 7.65, d (8.5) 4 6.64, d (8.1) 6.63, d (8.4) 6.65, d (8.5) 5 3.81, d (11.0) 3.82, d (11.0) 3.67, d (10.9) 3.81, d (11.1) 6 2.31, m 2.31, m 2.28, m 2.30, m 7a 2.66, dd (19.4, 5.1) 2.65, dd (19.3, 5.9) 2.61, dd (19.3, 6.2) 2.65, dd (19.2, 6.0) 7b 2.46, dd (19.4, 8.4) 2.47, dd (19.3, 10.5) 2.46, dd (19.3, 10.8) 2.46, dd (19.2, 10.9) 11 1.04, d (5.6) 1.04, d (6.4) 0.97, d (6.5) 1.03, d (6.4) 13 3.63, s 3.59, s 3.55, s 3.59, s 1-OH 11.51, s 11.41, s 11.25, brs 11.42, s 5-OH 6.00b, brs 8-OH 13.74a, brs 13.72a, brs 13.90a, brs 13.96a, brs 2' 6.48, s 4' 6.56, s 6.56, s 6.54, s 5' 4.19, dd (11.2, 3.7) 4.20, dd (12.0, 5.0) 4.18, dd (12.1, 4.9) 4.02, dd (11.7, 4.8) 6'a 2.09, m 2.09, m 2.09, m 2.04, m 6'b 1.91, m 1.91, m 1.91, m 1.83, m 7'a 2.80, m 2.80, m 2.80, m 2.73, m 7'b 2.54, m 2.52, m 2.53, m 2.52, m 11' 2.03, s 2.05, s 2.19, s 1.99, s 13' 3.64, s 3.62, s 3.62, s 3.64, s 1'-OH 11.41, s 11.36, s 11.30, s 11.12, s 5'-OH 5.75b, s 8'-OH 13.60a, s 13.62a, brs 13.83a, brs 13.66a, brs a,b exchangeable signals Secalonic acid L (3) was obtained as yellow gum. The molecular formula was determined to be C32H30O14 on the basis of HRESIMS (m/z: 661.1537 [M + Na]+, calcd for C32H30NaO14, 661.1533). The same molecular formula and similar NMR data implied that the structure of 3 was similar to those of 1 and 2. After careful analysis the COSY and HMBC correlations of 3, the two independent segments of 1 were reserved in 3 respectively. However, their binding site was changed from 2-2' in 1 to 4-2' in 3, considering the key COSY correlation of H-2 with H-3 and HMBC correlation from H-3 to C-2'. Thus, the planar structure of 3 was established (Figure 1). Secalonic acid M (4) was obtained as yellow gum. The molecular formula was determined to be C32H30O14 on the basis of HRESIMS (m/z: 661.1535 [M + Na]+, calcd for C32H30NaO14, 661.1533). After careful comparison the 1D-NMR data of 4 and 1 (Tables 1 and 2) and further analysis the COSY and HMBC correlations of 4 (Figure 2), the two independent segments of 1 were also reserved in 4. However, the key COSY correlation of H-3 with H-4 and HMBC correlation from H-3 to C-4' revealed that the two independent segments were linked through C-2 and C-4'. Until now, the planar structure of 4 was determined (Figure 1). Figure 2. COSY and HMBC correlations for compounds 1–4 The relative configurations of 1–4 were proposed by selected NOE experiments. In the NOE spectrum (Figure 3) of 1, correlations of H-5 with Me-11, H-6 with Me-13, H-6'b with H-5' and H-6'a with Me-13' help to determine the configurations of two cyclohexene rings, which were further supported by these coupling constants (J5,6 = 11.0 Hz, J5',6'a = 11.2 Hz, and J5',6'b = 3.7 Hz). The similar phenomena and coupling constants were also observed in 2–4, suggesting the relative configurations of compounds 1–4 were the same. Figure 3. NOE correlations for compounds 1–4 The absolute configurations of compounds 1–4 were further determined by comparison their experimental CD spectra with the computed spectra. Considering 1 and 2 owned the same planar structures and similar relative configurations, there were four possible assemblies for two compounds. After careful comparison the experimental CD spectra of 1 and 2, 2 was excluded to be the enantiomer of 1. Furthermore, the CD spectra of these four possible assemblies were calculated, respectively. Finally, the experimental CD spectra of 1 and 2 matched well with two among them. Thus, the absolute configurations of 1 and 2 were determined to be 5R, 6S, 10aR, 5'R, 10a'R and 5R, 6S, 10aR, 5'S, 10a'S (Figures 4 and 5). In addition, the similar CD spectra of 1 and secalonic acid D2 and the reverse CD spectra of 1 and secalonic acid A8 further confirmed this conclusion. The experimental CD spectra of 3 and 4 agreed well with the experimental spectra of 1 and secalonic acid D2 suggesting that the absolute configurations of 3 and 4 were similar to 1 and secalonic acid D, which were also fully supported by quantum chemical ECD calculation (Figures 4 and 5). These new compounds were further tested for cyto |
| File Format | PDF HTM / HTML |
| DOI | 10.3987/com-19-14081 |
| Alternate Webpage(s) | https://heterocycles.jp/newlibrary/downloads/PDF/26324/98/7 |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
