Abstract
Three new dimeric polyketides, i.e., phaeochromycins I–K (1–3, respectively) and a known polyketide phaeochromycin F (4), were isolated from the culture broth of a saline Qinghai–Tibet Plateau permafrost soil-derived Streptomyces sp. 166#. The structures were determined by analyzing one-dimensional and two-dimensional NMR as well as HRESIMS data. Compounds 2 and 3 exhibited a selective antiproliferative activity against H1299 and HUCCT1 cell lines, exhibiting IC50 values ranging from 8.83 to 10.52 μM.
1. Introduction
Polyketides are recognized as a rich source of pharmaceutical and agrochemical lead compounds.1 New and bioactive polyketide analogues are continuously isolated and identified, such as doxorubicin,2 rapamycin,3 lovastatin,4 flavonoids,5 pafuranones A and B,6 and cladodionen.7 The genus Streptomyces was determined to be one of the best producers of polyketides owing to its well-studied biosynthesis pathway.8
Phaeochromycins are type II polyketide derivatives, mainly produced by Streptomyces sp. However, only eight compounds named as phaeochromycins, namely phaeochromycins A–E9 and F–H,10 have been reported. Among these compounds, phaeochromycins A and C are weak inhibitors of MAPKAP kinase-2, and phaeochromycin H exhibits a modest inhibitory rate (46.0%) against the HeLa cell line at a concentration of 10 μg/mL. Our previous study reported four type II polyketide analogues from Streptomyces sp. 166#.11 Further isolation led to the identification of three new phaeochromycins: I–K (1–3, respectively) and the previously reported phaeochromycin F (4) (Figure 1),10 from the fermentation broth of the Streptomyces sp. 166#. Herein, we report the isolation, structure elucidation, cytotoxic activity, and plausible biosynthetic pathway of the new phaeochromycins I–K (1–3, respectively).
Figure 1.
Structures of compounds 1–4.
2. Results and Discussion
Phaeochromycin I (1) was obtained as a colorless powder. Its molecular formula was determined as C37H28O12 based on the HRESIMS peak observed at m/z 665.1660 [M + H]+ (calcd. 665.1654), indicating 24 degrees of unsaturation. The 1H and 13C NMR and HSQC spectra suggested the presence of four carbonyls, seventeen nonprotonated olefinic carbons, eleven olefinic methines, three sp3 methylenes, and two methyl groups (Table 1). The 13C NMR data search in the MICRONMR database (www.nmrdata.com) revealed that compound 1 contains a SEK34b moiety12 and a SEK43 moiety,13 which could be verified by the key 1H–1H COSY and HMBC correlations (Figure 2). Furthermore, 13C NMR comparison revealed that two nonprotonated carbons (δC-2 99.8 and δC-2′ 100.1) substituted the corresponding olefinic methines of SEK34b (δC/H 88.0/5.14)12 and SEK43 (δC/H 88.6/5.14).13 Moreover, the obvious shifts for C-1, C-3, C-4, and C-5 in SEK34b and SEK43, as well as an additional methylene (−CH2−) signal (δC/H 18.3/3.18), were observed. These data indicated that SEK34b and SEK43 combined by a −CH2– linker at the two 2-positions to form compound 1, which was confirmed by the key HMBC correlations of the methylene protons (δH-15 3.18) to C-1/1′ (δC 165.7, 165.7) and C-2/2′ (δC 99.8, 100.1) (Figure 2). Consequently, phaeochromycin I (1) could be identified as 5-((3-((6-(2-(2,4-dihydroxy-6-methylbenzoyl)-3-hydroxybenzyl)-4-hydroxy-2-oxo-2H-pyran-3-yl)methyl)-4-hydroxy-2-oxo-2H-pyran-6-yl)methyl)-2-methyl-4H-chromen-4-one.
Table 1. 1H (500 MHz) and 13C (125 MHz) NMR Data of Compounds 1–3.
|
1 (in DMSO-d6) |
2 (in DMSO-d6) |
3 (in CD3OD) |
||||
|---|---|---|---|---|---|---|
| no. | δc, type | δH (J in Hz) | δc, type | δH (J in Hz) | δc, type | δH (J in Hz) |
| 1 | 165.7, C | 178.5, C | 169.8, C | |||
| 2 | 99.8, C | 99.8, C | 102.4, C | |||
| 3 | 165.5, C | 165.6, C | 162.7, C | |||
| 4 | 103.8a, CH | 5.29, s | 111.2, CH | 6.14a, s | 105.0, CH | 5.60, s |
| 5 | 161.2, C | 160.9, C | 164.6, C | |||
| 6 | 37.5, CH2 | 4.36, s | 37.1, CH2 | 4.02, d (15.8) | 38.7, CH2 | 4.19, brs |
| 4.15, d (15.8) | ||||||
| 7 | 136.8, C | 137.1, C | 137.7, C | |||
| 8 | 128.3, CH | 7.23, d (7.4) | 124.2, CH | 6.83, d (7.4) | 126.0, CH | 6.89, d (7.3) |
| 9 | 133.3, CH | 7.69, t (7.9) | 134.9, CH | 7.47, t (7.8) | 136.3, CH | 7.46, t (7.9) |
| 10 | 117.8, CH | 7.52, d (8.5) | 117.7, CH | 6.92, d (8.2) | 119.5, CH | 6.95, d (8.2) |
| 10a | 157.5, C | 159.7, C | 161.6, C | |||
| 11 | 165.4, C | 100.8, C | 101.8, C | |||
| 12 | 111.2, C | 6.14, s | 49.7, CH2 | 2.62, d (15.9) | 63.9, CH2 | 2.66, s |
| 3.05, d (15.9) | 2.95, s | |||||
| 13 | 178.5, C | 193.2, C | 195.2, C | |||
| 13a | 120.9, C | 118.5, C | 119.8, C | |||
| 14 | 19.6, CH3 | 2.34, s | 27.6, CH3 | 1.58, s | 20.1, CH3 | 1.65, s |
| 15 | 18.3, CH2 | 3.18, s | 18.2, CH2 | 3.21, s | 18.6, CH2 | 3.42, s |
| 1′ | 165.7, C | 178.5, C | 169.8, C | |||
| 2′ | 100.1, C | 99.8, C | 102.4, C | |||
| 3′ | 165.4, C | 165.6, C | 163.0, C | |||
| 4′ | 105.2a, CH | 5.51, s | 111.2, CH | 6.14a, s | 105.0, CH | 5.65, s |
| 5′ | 159.3, C | 160.9, C | 164.4, C | |||
| 6′ | 36.0, CH2 | 3.42, brs | 37.1, CH2 | 4.02, d (15.8) | 38.7, CH2 | 4.45, s |
| 4.15, d (15.8) | ||||||
| 7′ | 133.5, C | 137.1, C | 137.3, C | |||
| 8′ | 130.8, C | 124.2, CH | 6.83, d (7.4) | 130.0, CH | 7.29, d (7.3) | |
| 9′ | 153.7, C | 134.9, CH | 7.47, t (7.8) | 134.7, CH | 7.69, brs | |
| 10′ | 114.3, CH | 6.76, d (8.2) | 117.7, CH | 6.92, d (8.2) | 119.3, CH | 7.51, d (8.1) |
| 10′a | 159.7, C | 159.4, C | ||||
| 11′ | 130.0, CH | 7.18, t (7.9) | 100.8, C | 168.0, C | ||
| 12′ | 120.4, CH | 6.68, d (7.7) | 49.7, CH2 | 2.62, d (15.9) | 111.9, CH | 6.13, s |
| 3.05, d (15.9) | ||||||
| 13′ | 200.2, C | 193.2, C | 181.4, C | |||
| 13′a | 118.5, C | 122.0, C | ||||
| 14′ | 115.5, C | 27.6, CH3 | 1.58, s | 28.0, CH3 | 2.38, s | |
| 15′ | 165.4, C | |||||
| 16′ | 100.8, CH | 6.14, s | ||||
| 17′ | 163.4, C | |||||
| 18′ | 111.8, CH | 6.11, s | ||||
| 19′ | 143.2, C | |||||
| 20′ | 21.7, CH3 | 1.83, s | ||||
| 11/11′-OH | 6.99, s | |||||
| 15′-OH | 12.82, s | |||||
Confirmed by HSQC and HMBC spectra.
Figure 2.
Key COSY and HMBC correlations of compounds 1–3.
The molecular formula of compound 2 was established as C33H28O12 based on the HRESIMS peak observed at m/z 617.1654 [M + H]+ (calcd. 617.1654), indicating an index of hydrogen deficiency (IHD) of 20. However, the 1H and 13C NMR spectra showed only half the number of expected signals along with an additional methylene signal (δC/H 18.2/3.21), implying that compound 2 was a symmetrical dimer. Similar to compound 1, the 1H and 13C NMR data of compound 2 were almost the same as those for SEK34,12 apart from the substitution of a nonprotonated olefinic carbon (δC-2 99.8) for sp2-methine (δC/H 88.2/5.18)12 and the noticeable changes of chemical shifts for C-1, C-3, C-4, and C-5 (Table 1). Furthermore, the key HMBC correlations of the methylene proton (δH-15 3.21) to C-2/2′ (δC 99.8) and C-3/3′ (δC 165.6) were observed (Figure 2), suggesting that the two SEK34 units were connected at C-2 and C-2′ by a methylene (−CH2−) linkage to form compound 2. Thus, phaeochromycin J (2) could be elucidated as 5,5′-((methylenebis(4-hydroxy-2-oxo-2H-pyran-3,6-diyl))bis(methylene))bis(2-hydroxy-2-methylchroman-4-one).
The molecular formula of phaeochromycin K (3) was determined as C33H26O11 based on the HRESIMS peak observed at m/z 599.1544 [M + H]+ (calcd. 599.1548), indicating an IHD of 21. The comparison of 1H and 13C NMR data (Table 1) and two-dimensional NMR patterns (Figure 2) of compound 3 with compounds 1 and 2 revealed that compound 3 contains SEK34 and SEK34b fragments. The presence of the methylene (CH2-15) between C-2 and C-2′ was confirmed via the key HMBC correlations of the methylene proton (δH-15 3.42) to C-1/1′ (δC 169.8) and C-2/2′ (δC 102.4) (Figure 2). Thus, phaeochromycin K (3) could be determined as 5-((4-hydroxy-3-((4-hydroxy-6-((2-hydroxy-2-methyl-4-oxochroman-5-yl)methyl)-2-oxo-2H-pyran-3-yl)methyl)-2-oxo-2H-pyran-6-yl)methyl)-2-methyl-4H-chromen-4-one.
Compound 2 comprised three stereoisomers (R,S; S,R; R,R or S,S) and was a symmetric homodimer with two chiral centers. However, compound 3 was an unsymmetric heterodimer 1 with one chiral center. Both compounds 2 and 3 did not show optical rotation. Therefore, compounds 2 and 3 were subjected to chiral separation using an NB chiral column. Each isomer (2a/2b/2c and 3a/3b) was purified by collecting the corresponding peak and was then subjected to a purity check independently at the same conditions (Figure 3). The results indicate that compounds 2 and 3 were inseparable stereoisomers, and compound 2 could slowly dehydrate to form compound 3. Meanwhile, the three stereoisomers 2a, 2b, and 2c of 2 could spontaneously be converted to each other (Figure 3A), and so could the two stereoisomers 3a and 3b of 3 (Figure 3B). SEK34 and SEK43 were reported as the products of the polyketide synthase pathway.12−14 The methylene linkages in heterodimer 1 and homodimer 2 were caused by formaldehyde and were presumed to form via the Michael addition between SEK43 and SEK34b or two SEK34, respectively.15,16 High-performance liquid chromatography (HPLC) analysis (Figure 3) confirmed that compound 2 was subjected to intramolecular dehydration to generate compounds 3 and 4 spontaneously via the loss of one and two H2O molecules (Scheme 1). Thus, the physico, spectral, and cytotoxic data of compounds 2 and 3 were acquired as soon as possible after they were purified.
Figure 3.
Chiral analysis of compounds 2 and 3 using an NB chiral column eluted with n-C6H14–EtOH (65/35 for 2 and 60/40 for 3, v/v) at 1 mL/min. (A) Three isomers of compound 2 (2a/2b/2c) could be converted into each other spontaneously, and all of them can slowly dehydrate to form 3. (B) Two isomers of 3 (3a/3b) could be converted into each other spontaneously, and both can slowly dehydrate to form 4.
Scheme 1. Plausible Biosynthetic Pathway of 1–4.
The cytotoxic activities of new dimers 1–3 were evaluated against the tumor cells A549, N87, H1299, HUCCT1, 143B, B16F10, SPC-A1, and HCT-116 via the CTG assay.17,18 The cytotoxic activity of the known dimer 4 was evaluated against MCF-7, A549, and HCT-116 tumor cell lines via the MTT assay17 using doxorubicin (DOX) as the positive control. Only compounds 2 and 3 showed cell proliferation inhibition against H1299 (human lung adenocarcinoma) and HUCCT1 (human bile duct cancer) cell lines with the IC50 values of 10.52 and 10.41 μM for 2 and 9.33 and 8.83 μM for 3, respectively (Table 2 and Figure S1). No inhibitory activity was observed for other compounds and tumor cell lines (IC50 > 100 μM).
Table 2. Cytotoxic Activities of Compounds 1–4.
| IC50 (μM) |
||||||||
|---|---|---|---|---|---|---|---|---|
| compounds | A549 | N87 | H1299 | HUCCT1 | 143B | B16F10 | SPC-A1 | HCT-116 |
| 1 | >100 | >100 | >100 | >100 | >100 | >100 | >100 | >100 |
| 2 | >100 | >100 | 10.52 | 10.41 | >100 | >100 | >100 | >100 |
| 3 | >100 | >100 | 9.33 | 8.83 | >100 | >100 | >100 | >100 |
| 4a | >100 | >100 | ||||||
| DOX | 0.109 | 0.047 | 0.504 | 0.048 | 0.101 | 0.016 | 0.181 | 0.104 |
IC50 values for 4 and DOX against MCF-7 cells were >100 and 0.45 μM, respectively.
3. Conclusions
In addition to the reported phaeochromycin F (4), we identified three new polyketide dimers within a methylene linkage, phaeochromycins I–K (1–3, respectively). According to the literature, phaeochromycin F (4) was the sole phaeochromycin possessing the SEK34b dimer joined by a methylene linkage.10 Phaeochromycins J (2) and K (3) with one or two hemiacetal groups exhibited selective antiproliferative activities against H1299 and HUCT1 cell lines, indicating that SEK34b with a hemiacetal group at C-11 was the pharmacophore or bioactive function unit against these two tumor cells.
4. Experimental Section
4.1. General Experimental Procedures
Ultraviolet (UV) data were obtained using a Waters 2487 dual λ absorbance detector. Infrared (IR) spectra were measured on a Nicolet Nexus 470 spectrophotometer using KBr disks. NMR spectra were recorded using a Varian System 500. The corresponding residual solvent signals (δH/C 2.50/39.5 for DMSO-d6, 7.26/77.2 for CDCl3, or 3.31/49.2 for CD3OD) were used to reference the chemical shifts in NMR spectra. Furthermore, HRESIMS spectra were measured using a Q-TOF Ultima Global GAA076 LC mass spectrometer, and LRESIMS spectra were obtained using a Waters SQ Detector 2 mass spectrometer. Semipreparative HPLC was performed using a phenyl column (YMC-pack Ph, 10 mm × 250 mm) or a π-NAP column (COSMOSIL, 10 mm × 250 mm). TLC was performed on plates precoated with silica gel GF254 (10–40 μm). Column chromatography (CC) was performed over silica gel (200–300 mesh, Qingdao Marine Chemical Factory) and Sephadex LH-20 (Amersham Biosciences). Finally, vacuum liquid chromatography (VLC) was performed using silica gel H (Qingdao Marine Chemical Factory).
4.2. Fermentation and Extraction
The fermentation and extraction of Streptomyces sp. 166# were described in detail in our previous report.11
4.3. Purification
The ethyl acetate (EtOAc) extract (5.0 g) of the fermentation broth was separated into 12 fractions (Fr.1–Fr.12) via VLC using a silica gel column. The column was eluted with a step gradient of petroleum ether (PE)–CH2Cl2 (1:0, 1:1, and 0:1, v/v) and then of CH2Cl2–MeOH (100:1, 80:1, 70:1, 60:1, 40:1, 20:1, 15:1, 10:1, and 1:1, v/v). Fr.10 (407 mg) was separated into 13 subfractions (Fr.10.1–Fr.10.13) via CC using Sephadex LH-20. The column was eluted with MeOH–CH2Cl2 (1:1, v/v). Fr.10.13 (20 mg) was further purified via HPLC using the semipreparative π-NAP column. This column was eluted with 30% MeCN–H2O containing 0.05% trifluoroacetic acid (TFA) at a flow rate of 4 mL/min to obtain compounds 1 (2.8 mg; tR = 12.1 min) and 2 (3.2 mg; tR = 15.2 min). Similarly, Fr.11 (151 mg) was separated into eight subfractions (Fr.11.1–Fr.11.8) via CC using Sephadex LH-20. The column was eluted with MeOH–CH2Cl2 (1:1, v/v). Fr.11.6 (18 mg) was purified via HPLC using a phenyl column. This column was eluted with 30% MeCN–H2O (with 0.05% TFA) at a flow rate of 4 mL/min to obtain compound 3 (6.6 mg; tR = 14.4 min). Using the same CC and elution with 45% MeCN–H2O (with 0.05% TFA) at 4 mL/min, compound 4 (2.0 mg; tR = 12.3 min) was obtained from Fr.11.8 (7 mg).
4.3.1. Phaeochromycin I (1)
Colorless powder; UV (MeOH) λmax (log ε): 221 (4.68), 300 (4.37) nm; IR (KBr) νmax: 3424, 2927, 1685, 1644,1620, 1508, 1437, 1388, 1210, 1140, 1030, 841, 803, 724 cm–1; 1H and 13C NMR data are presented in Table 1; HRESIMS m/z 665.1660 [M + H]+ (calcd. for C37H29O12, 665.1654).
4.3.2. Phaeochromycin J (2)
Colorless powder; [α]D25 0 (c 0.1, MeOH); UV (MeOH) λmax (log ε): 215 (4.68), 252 (4.20), 280 (4.09), 309 (4.11) nm; IR (KBr) νmax: 3394, 2927, 1683, 1603,1577, 1473, 1439, 1385, 1320, 1209, 1140, 1028, 880, 841, 802, 724 cm–1; 1H and 13C NMR data are presented in Table 1; HRESIMS m/z 617.1654 [M + H]+ (calcd. for C33H29O12, 617.1654).
4.3.3. Phaeochromycin K (3)
Colorless powder; [α]D25 0 (c 0.1, MeOH); UV (MeOH) λmax (log ε): 215 (4.14), 248 (3.77), 303 (3.77) nm; IR (KBr) νmax: 3368, 2261, 2131, 1684, 1541, 1507, 1456, 1385, 1209, 1141, 1051, 1026, 1004, 829, 801, 768, 721 cm–1; 1H and 13C NMR data are presented in Table 1; HRESIMS m/z 599.1544 [M + H]+ (calcd. for C33H27O11, 599.1548).
Acknowledgments
This work was financially supported by the National Natural Science Foundation of China (NSFC, Nos. U1906213 and 41876172).
Supporting Information Available
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.2c07038.
NMR and HRESIMS spectra for compounds 1–3, physico and spectral data for compound 4, and a description of the bioassay protocol used (PDF)
Author Contributions
∥ Y.X., D.W., and Q.L. contributed equally.
The authors declare no competing financial interest.
Supplementary Material
References
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