Isarubrolones Containing a Pyridooxazinium Unit from Streptomyces

Article Cite This: J. Nat. Prod. XXXX, XXX, XXX−XXX

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Isarubrolones Containing a Pyridooxazinium Unit from Streptomyces as Autophagy Activators Linli Li,† Shufen Li,† Bingya Jiang,*,† Miaoqing Zhang,† Jingpu Zhang,† Beibei Yang,‡ Li Li,‡ Liyan Yu,† Hongyu Liu,† Xuefu You,† Xinxin Hu,† Zhen Wang,† Yuhuan Li,† and Linzhuan Wu*,†

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NHC Key Laboratory of Biotechnology of Antibiotics, Key Laboratory of Synthetic Biology for Drug Innovation, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People’s Republic of China ‡ Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People’s Republic of China S Supporting Information *

ABSTRACT: Isarubrolones are bioactive polycyclic tropoloalkaloids from Streptomyces. Three new isarubrolones (2− 4), together with the known isarubrolone C (1) and isatropolones A (5) and C (6, 3(R)-hydroxyisatropolone A), were identified from Streptomyces sp. CPCC 204095. The structures of these compounds were determined using a combination of mass spectrometry, 1D and 2D NMR spectroscopy, and ECD. Compounds 3 and 4 feature a pyridooxazinium unit, which is rarely seen in natural products. Compound 6 could conjugate with amino acids or amines to expand the structural diversity of isarubrolones with a pentacyclic or hexacyclic core. Importantly, 1 and 3−6 were found to induce complete autophagy.

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determined the configuration of C-3 as R for isarubrolone C (1) and isatropolone C (6, 3-hydroxyisatropolone A). We also synthesized new isarubrolones by in vitro incubation of isatropolone C (6) with amino acids and amines, which further expanded the structural diversity of isarubrolones, especially isarubrolones with a hexacyclic core. Data are presented in support of autophagic activation as a shared biological activity for the isarubrolones (1, 3, 4) and isatropolones (5, 6). Autophagy is a eukaryotic cell mechanism to degrade unnecessary or dysfunctional cellular organelles. Autophagy activation (or inhibition) may become a therapeutic strategy for treating human neurodegenerative diseases, immunological diseases, and pathogenic infections in the future.3−5

sarubrolones are bioactive tropoloalkaloids produced by Streptomyces Gö66. They feature a unique seven-membered tropolone in the pentacyclic core of each molecule. The pentacyclic core is biosynthetically assembled by biochemical reactions, followed by a final nonenzymatic reaction. The final nonenzymatic reaction, which results in the formation of the pyridine of the pentacyclic core, has been utilized to generate diverse isarubrolones, by in vitro incubation of isatropolone A (the immediate precursor of isarubrolone) with various amino acids or amines.1 We are interested in new secondary metabolites produced by Streptomyces. We found that Streptomyces sp. CPCC 204095, a soil isolate from the Miyun District of Beijing, China, was able to produce purple-red pigments. After sequencing its genome DNA by Illumina 454 and PacBio smart cell II, a 42.5 kb DNA fragment containing a set of genes for aromatic polyketide synthases and many other enzymes was located by AntiSMASH analysis.2 The DNA fragment was found to be nearly identical to the isarubrolone/isatropolone biosynthetic gene cluster from Streptomyces Gö66. The purple-red pigments produced by Streptomyces sp. CPCC 204095 were speculated to be isarubrolones, the conjugating products of isatropolones with amino acids or amines, and this was confirmed by the following microbial chemistry study. Herein, we reported the identification of three new isarubrolones (2−4) from Streptomyces sp. CPCC 204095, with 3 and 4 featuring a dihydro-1,4-oxazine heterocycle (F ring) fused to the pyridine (E ring) of the pentacyclic core of these molecules. We © XXXX American Chemical Society and American Society of Pharmacognosy

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RESULTS AND DISCUSSION Streptomyces sp. CPCC 204095 was cultured on ISP2 medium plates to produce isarubrolone and isatropolone. The cultures were pooled and extracted with EtOAc. The extract was fractionated by ODS column chromatography, followed by reverse-phase HPLC to yield 1−6. Compounds 1−4 were purple-red amorphous solids with UV−visible absorption profiles very similar to isarubrolone. Compounds 5 and 6 were yellow amorphous solids with UV− visible absorption profiles very similar to isatropolones.1 They Received: October 15, 2018

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DOI: 10.1021/acs.jnatprod.8b00857 J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products

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were expected to belong to isarubrolone or isatropolone. As described below, 1−6 displayed NMR signals for the unique pentacyclic core of isarubrolone or isatropolone.1 Compound 1 had the molecular formula C24H25NO9 according to HRESIMS (Figure S7), identical to the known isarubrolone C. The 1D and 2D NMR spectra demonstrated its identity as isarubrolone C (Figures S13−S18). Keto−enol tautomerization was observed for 1 in methanol (Figure S50). Besides, the configuration of C-3 in 1 was resolved by us as R by comparing its experimental CD spectrum with the spectra calculated for the isomer with 3R and 3S configuration (Figure S51). Compound 2 had the molecular formula C31H31N2O9+ according to HRESIMS (Figure S8), which was C7H6NO more than that of isarubrolone A. Compound 2 showed very similar NMR spectral features to isarubrolone A except the new signals for an ortho-substituted benzene [δH 7.70 (td, J = 7.2, 1.8 Hz, H-19), 7.80 (td, J = 7.2, 1.8 Hz, H-20), 7.82 (td, J = 7.2, 1.8 Hz, H-21), and 7.90 (dd, J = 7.2, 1.8 Hz, H-22)], an Scheme 1. (a) (Bio)synthetic Pathway of Isarubrolones E (3) and F (4); (b) Synthetic Pathway of 10 and 12 (Both Bearing a Pyridooxazinium Unit) Derived from 6 Reacting with Histidine and Lysine

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Journal of Natural Products Table 1. 1H and

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C NMR Data for Isarubrolones E and F (3 and 4) in DMSO-d6 isarubrolone E (3)

position

δC, type

1 2 3 4 5 6 7 8 9 10 11 11-OH 12 13 14 15 16 17 18 19 19-OH 20 1′ 2′ 2′-OH 3′ 3′-OH 4′ 5′ 6′ 7′

9.8, CH3 27.8, CH2 74.8, CH 143.5, C 119.1, C 192.4, C 117.4, CH 183.7, C 126.4, C 162.2, C 170.0, C 137.9, C 111.8, C 163.2, C 117.2, CH 156.9, C 20.8, CH3 48.5, CH2 163.3, C

106.5, CH 81.8, C

δH, mult, (J in Hz)

isarubrolone F (4) HMBC

δC, type

1.04, t (7.8) 1.91, m 6.24, dd (9.6,4.8)

C-2, C-3 C-1, C-3, C-4, C-11 C-1, C-2, C-4, C-5, C-19

6.4, d (3.0)

C-9, C-12, C-13

9.8, CH3 29.3, CH2 69.3, CH 151.8, C 118.8,C 192.4, C 117.0, CH 183.5, C 126.3, C 162.4, C 169.4, C

8.44, s

C-5, C-13, C-16, C-17

2.67, s 5.18,d (18.6); 5.21,d (18.6)

C-14, C-15, C-16 C-4, C-16, C-19

137.8, C 111.5, C 160.8, C 116.5, CH 157.5, C 20.9, CH3 55.8, CH2 92.3, C 25.6, CH3 106.5, CH 81.7, C

5.43, s

C-2′, C-3′, C-5′

67.6, CH

5.75, d (12.0) 4.12, m

C-1′, C-2′ C-1′, C-2′

67.8, CH

79.9, 66.3, 18.3, 57.0,

3.18, 3.89, 1.22, 3.29,

C-5′, C-6′, C-7′ C-2′ C-3′, C-4′, C-5′ C-4′

80.0, 66.5, 18.5, 57.1,

CH CH CH3 CH3

dd (8.4, 3.0) m d (6.0) d (3.0)

CH CH CH3 CH3

δH, mult, (J in Hz)

HMBC

0.95, t (7.2) 1.81, m 5.47, t (5.4)

C-2, C-3 C-1, C-3, C-4 C-1, C-2

6.38, s

C-6,C-9, C-12, C-13

8.47, s

C-5, C-16

2.67, brs 4.15, d (12.6); 4.35, d (13.8)

C-15, C-16 C-4, C-16, C-19

6.80,s 1.54, s 5.42, s

C-18, C-19 C-3, C-18, C-19 C-2′, C-3′, C-5′

5.78, 4.11, 5.67, 3.19, 3.86, 1.21, 3.29,

C-1′, C-2′ C-2′ C-3′ C-5′, C-6′, C-7′ C-2′ C-4′, C-5′ C-4′

s m brs dd (7.2, 3.0) m d (6.6) s

Figure 1. Key COSY, HMBC, and NOESY correlations of isarubrolones D−F (2−4).

C−N single bond bridging the benzamide and pyridine according to electronic circular dichroism (ECD) calculation (Figure S53). Compound 2 was designated as isarubrolone D, and its NMR data were assigned in Table S4. Compound 3 had the molecular formula C26H26NO10+ according to HRESIMS (Figure S9), which was C2HO more than that of 1. Compound 3 showed very similar NMR spectral features to 1 except the new signals for a methylene [δH 5.21 (d, J = 18.6 Hz) and δH 5.27 (d, J = 18.6 Hz), δC 48.5] and an oxygenated carbonyl (δC 163.3). HMBC correlations from H218 (δH 5.24) to C-4, C-16, and C-19 (δC 163.3), in combination with their chemical shift values, suggested an

amide carbonyl (δC 166.7), and two hydrogens (δH 8.22, s and 7.62, s) from an amino group. The benzene moiety had an amide substituent confirmed by HMBC correlations from NH2 (δH 8.22, s and 7.62, s) to C-24 (δC 166.7) and C-23 and from H-22 to C-24. Bridging of the benzene and pyridine via a C−N bond was supported by (1) the perturbed NMR chemical shift of C-1, C-2, C-3, C-4, C-16, and C-17; (2) NOESY correlations from H-19 to H3-17 and H2-3; and (3) the molecular formula given by HRESIMS. Thus, the structure of 2 was determined as isarubrolone A bonded with a benzamide. Keto−enol tautomerization was observed for 2 in methanol (Figure S52), but it had no axial configuration concerning the C



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who reported that molecules with a benzotropolone core displayed an autophagic inhibition effect,8 we assayed 1 and 3−6 for their autophagic effects on human liver cancer HepG2 cells (2 was not assayed due to lack of material). Autophagy flux proteins and ubiquitin-like enzymes involved in autophagosome formation of HepG2 cells were measured (Figure 2). Compounds 1 and 3−6 displayed inducing effects

acetyl bonded to the N of pyridine (E ring) through the methylene. The C-19 (δC 163.3) was connected to C-3 through oxygen, supported by the molecular formula requirement, the HMBC correlation from H-3 to C-19, and the shift change of C-3 from δC 69.6 (in 1) to δC 74.8 (3). Therefore, a heterocycle of dihydro-1,4-oxazine (2-oxo-3,6-dihydro-2H-1,4oxazine, F ring) fused with pyridine (E ring) was determined as part of 3. The structure of 3 was thus depicted as above. The NMR spectra of 3 suggested rapid keto−enol tautomerization (tautomerization of diketo form tropolone and dihydrogen pyridine was not observed).6,7 The configuration of C-3 should be assigned as R based on the synthetic pathway of 3 from 6 [Scheme 1, intramolecular esterification of C-19 carboxyl with C-3 (R) hydroxy in 6]. Compound 3 was designated as isarubrolone E. Its NMR data were assigned in Table 1. It is worthy to note that the pyridooxazinium unit (EF rings) in 3 is rarely seen in natural products. Compound 4 had the molecular formula C27H30NO10+ according to HRESIMS (Figure S10), which was CH4 more than that of 3. The NMR spectra of 4 (Table 1) were very similar to 3 except the new signals for a methyl [δC 25.6, δH 1.54 (s)], a hydroxy [δH 6.80 (s)], and a semiacetal carbon (δC 92.3) replacing the oxygenated carbonyl (δC 163.3) in 3. These signal differences revealed a 2-hydroxy-2-methyl-3,6-dihydro2H-1,4-oxazine (F ring) heterocycle fused with pyridine (E ring) in 4, which was supported by HMBC correlations of 19OH/C-19, H3-20/C-19, C-18, and H2-18/C-16, C-14 (Figure 1). Thus, a pyridooxazinium unit also appeared in 4. The configuration of C-3 should be assigned as R based on the (bio)synthetic pathway of 4 from 6 (Scheme 1). The configuration of C-19 was determined as R by NOESY correlation of H3-20 to H-3. Compound 4 was designated as isarubrolone F. Compound 5 had the molecular formula C 24 H 24 O 9 according to HRESIMS (Figure S11), identical to the known isatropolone A.1 Compound 6 had the molecular formula C24H24O10 according to HRESIMS (Figure S12), identical to the known isatropolone C (3-hydroxyisatropolone A).1 The 1D and 2D NMR spectra demonstrated the identity of 5 as isatropolone A and 6 as isatropolone C. The configuration of C-3 in 6 is assumed to be R, as 6 is the immediate precursor of 1. While the structure of 2 suggests it is the conjugate of 5 with 2-aminobenzamide (Figure S54), the structure of 3 and 4 suggests they are conjugates of 6 with either glycine or aminoacetone, respectively. In vitro incubation of 6 with glycine or aminoacetone at mild alkaline pH yielded the expected 3 and 4 (Scheme 1; Figure S55, together with new isarubrolones 7 and 8). Supplementation of glycine into the fermentation medium significantly increased the production of 3 by Streptomyces sp. CPCC 204095, and supplementation of threonine significantly increased the production of 4, as aminoacetone is formed by dehydrogenation and decarboxylation of threonine (Scheme 1, Figures S56 and S57). To expand the structural diversity of isarubrolones, we mixed 6 with amino acids or amines such as histidine, lysine, and 3-amino-2-methylbenzoic acid, which resulted in the detection of the expected new isarubrolones 9−13, bearing a pentacyclic or a hexacyclic core (Scheme 1, Figure S58 for LCMS analysis). Isarubrolone and isatropolone are structural analogues sharing the same tetracyclic unit, which led us to explore a common biological activity for them. Inspired by Kurdi et al.,

Figure 2. Autophagy-inducing effect of isarubrolone F (4). The levels of autophagy proteins P62, LC3B-II/I, ATG4a/b, ATG7, and ATG5 in HepG2 cells are displayed by Western blotting. GADPH (glyceraldehyde-3-phosphate dehydrogenase) was used as a loading control. Isarubrolone C (1), isarubrolone E (3), isatropolone A (5), and isatropolone C (6) showed the same or very similar effects on autophagy (Figure S59).

on autophagosome formation based on the increased LC3B II/ I ratio in HepG2 cells.9 Meanwhile, 1 and 3−6 significantly decreased the protein level of P62 in a concentrationdependent manner. These results indicated that 1 and 3−6 triggered complete autophagy. Compounds 1 and 3−6 promoted the complete autophagy process via enhancing autophagosome formation by decreasing the level of ATG4a and increasing the level of ubiquitin-like enzymes such as ATG7, ATG5, and ATG4b in HepG2 cells. As isarubrolone and isatropolone are very weakly cytotoxic to animal cells (IC50 of 1 at 770−1800 μM and 4 at 190−530 μM, for four tumor cell lines tested, Table S7), they may be close to ideal autophagy activators. Rubrolones and rubterolones are analogues of isarubrolones produced by Streptomyces echinoruber (and Streptomyces sp. KIB-H033) and Actinomadura sp. 5-2.6,10−13 It is interesting to speculate that these natural products may also be able to induce autophagy.

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EXPERIMENTAL SECTION

General Experimental Procedures. UV spectra were acquired with a Cary 300 spectrometer. IR spectra were obtained using a Nicolet 5700FTIR microscope spectrometer. ECD spectra were recorded at 25 °C using an Applied Photophysics Chirascan-Plus circular dichroism spectrometer and a 1 mm CD cell. Analytical HPLC was conducted on an Agilent system with a 1260 Quat-Pump and DAD detector. For analytical HPLC, a reverse-phase C18 column (Dikma Diamonsil C18 5 μ 250 × 4.6 mm) was used with a gradient solvent system from 15% to 70% CH3CN−H2O (0.1% HAc, v/v), 1.0 mL/min. For semipreparative HPLC, a reverse-phase C18 column (YMC-Pack ODS-A column: 250 mm × 10 mm, S-5 μm, 12 nm) was used with MeOH−H2O or CH3CN−H2O (0.1% HAc, v/v) as solvent system. NMR data were collected using a VNS-600 or Bruker-600/ 601 spectrometer, where chemical shifts (δ) were reported in ppm D



Article

and referenced to the DMSO-d6 solvent signal (δH 2.50 and δC 39.8) and the CD3OD solvent signal (δH 3.31 and δC 49.0). ESIMS, MS/ MS, and HRMS were analyzed by an LTQ Orbitrap XL from Thermo Fisher Scientific. Fermentation of Streptomyces sp. CPCC 204095. Frozen stock spores of Streptomyces sp. CPCC 204095 were thawed, inoculated on culture medium (soluble starch 1.0%, yeast extract 0.4%, malt extract 1.0%, glucose 0.4%, and agar 1.5%), and incubated at 28 °C for 7 days for sporulation. Fresh spores were collected and spread on ISP2 medium (yeast extract 0.4%, malt extract 1.0%, glucose 0.4%, and agar 1.5%) plates and incubated at 28 °C for 5−8 days (for isarubrolone production) or 2 or 3 days (for isatropolone production). Extraction and Isolation of Isarubrolones and Isatropolones. Isarubrolones (Compounds 1−4). ISP2 culture (45 L) of Streptomyces sp. CPCC 204095 was extracted three times with an equal volume of EtOAc. The EtOAc extract was concentrated under reduced pressure at room temperature to yield a dark purple residue (150 g). It was then loaded onto a preparative ODS column for fractionation with MeOH−H2O (10% MeOH−H2O, 30 min; 30% MeOH−H2O, 40 min; 60% MeOH−H2O, 40 min; 70% MeOH− H2O, 60 min; 90% MeOH−H2O, 60 min; and finally 100% MeOH, 30 min; H2O contained 0.1% HAc, v/v) at a constant flow rate of 25 mL/min, which yielded 20 fractions, F1−F20. Each fraction was analyzed by HPLC-MS. Compounds 1−4 were detected in fractions F9 (150 mg), F12 (7 mg), F10 (34 mg), and F11 (36 mg), respectively. Fraction F9 was further purified by semipreparative HPLC (50% MeOH−H2O, 2.0 mL/min, tR = 30 min), which yielded 53.8 mg of pure preparation of 1. Fraction F10 was further purified by semipreparative HPLC (51% MeOH−H2O, 1.5 mL/min, tR = 36 min), which yielded 9.5 mg of pure preparation of 4. Fraction F11 was further purified by semipreparative HPLC (27% MeCN−H2O, 1.0 mL/min, tR = 9 min), which yielded 10.7 mg of pure preparation of 3. Fraction F12 was further purified by semipreparative HPLC (27% MeCN−H2O, 1.5 mL/min, tR = 30 min), which yielded 2.2 mg of pure preparation of 2. Compound 2: purple-red solid; UV−visible (MeOH) λmax (log ε) 204 (2.94), 284 (2.76), 436 (2.67), 545 (2.622) nm; FTIR νmax 3393, 2920, 2850, 1735, 1646, 1568, 1467, 1419, 1364, 1321, 1076, 1031 cm−1; 1H and 13C NMR data, see Table S4; HRESIMS m/z 575.2028 [M]+ (calcd for C31H29NO10, 575.2024). Compound 3: purple-red solid; UV−visible (MeOH) λmax (log ε) 283 (2.68), 441 (2.89), 555 (2.95) nm; FTIR νmax 3351, 2937, 2851, 1766, 1716, 1646, 1600, 1554, 1472, 1322, 1182, 1123, 1095 cm−1; 1 13 C NMR data, see Table 1; [α]25 D 165 (c 0.0010 MeOH); H and + HRESIMS m/z 512.1551 [M] (calcd for C26H26NO10, 512.1551). Compound 4: purple-red solid; UV−visible (MeOH) λmax (log ε) 206 (2.93), 285 (2.85), 436 (2.62), 552 (2.72) nm; FTIR νmax 3358, 3275, 2919, 2851, 1714, 1635, 1595, 1564, 1317, 1180, 1123, 1094 cm−1; 1H and 13C NMR data, see Table 1; HRESIMS m/z 528.1870 [M]+ (calcd for C27H30NO10+, 528.1864). Isatropolones (Compounds 5 and 6). ISP2 culture (30 L) of Streptomyces sp. CPCC 204095 was extracted three times with an equal volume of EtOAc. The EtOAc extract was concentrated under reduced pressure at room temperature to yield a dark purple residue (15 g). It was then loaded onto a preparative ODS column for fractionation with MeOH−H2O (15−70% MeOH−H2O, 60 min; 70% MeOH−H2O, 60 min; and finally 70−100% MeOH−H2O, 60 min; H2O contained 0.1% HAc, v/v) at a flow rate of 15−20 mL/min, which yielded nine fractions, F1−F9. Each fraction was analyzed by HPLC-MS, and 5 and 6 were detected in fractions F8 (10.2 mg) and F4 (27.2 mg), respectively. Fraction F4 was further purified by semipreparative HPLC (32% MeCN−H2O, 2.0 mL/min, tR = 21 min), which yielded 8.5 mg of pure preparation of 6. Fraction F8 was further purified by semipreparative HPLC (39% MeCN−H2O, 2.0 mL/min, tR = 38 min), which yielded 3.4 mg of pure preparation of 5.

Compound 5: yellow, amorphous solid; 1H and 13C NMR data, see Table S5; HRESIMS m/z 457.1497 [M + H]+ (calcd for C24H25O9, 457.1420). Compound 6: yellow, amorphous solid; 1H and 13C NMR data, see Table S6; HRESIMS m/z 473.1451 [M + H]+ (calcd for C24H25O10, 473.1369). Autopahgic Activity Assay. HepG2 cells were cultured in minimum essential media (MEM) (Gibco) containing 10% fetal bovine serum (FBS) (Gibco) with penicillin (100 μg/mL) and streptomycin (100 μg/mL). They were treated with isarubrolone or isatropolone for 24 h at final concentrations of 1, 5, 10, or 20 μM. The cells were then lysed in RIPA cell lysis buffer with protease inhibitor cocktail. Proteins were separated by 12% SDS-PAGE and transferred onto nitrocellulose membranes. The membranes were incubated with anti-LC3B (M186-3, MBL), anti-P62 (PM045, MBL), anti-ATG5 (NB110-53818, Novus), anti-ATG7 (8558S, Cell Signaling Technology), anti-ATG4a (7613S, Cell Signaling Technology), and antiATG4b antibodies (13507S, Cell Signaling Technology) for quantification of autophagy marker proteins ATG4a/b, ATG5, ATG7, LC3B, and P62.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.8b00857. Experimental details, HRMS and 1D and 2D NMR spectra, and related computational data (PDF).

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (B. Jiang). *E-mail: [email protected] (L. Wu). ORCID

Bingya Jiang: 0000-0002-7415-3179 Liyan Yu: 0000-0002-8861-9806 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors would like to thank Prof. J. Dai (Institute of Materia Medica, CAMS & PUMC) for critical reading of the manuscript and Prof. Y. Wang (Institute of Medicinal Biotechnology, CAMS & PUMC) for advice in organic chemistry. The NMR and MS analyses were performed at Nuclear Magnetic Resonance Center of Institute of Materia Medica, CAMS & PUMC. This work was supported by CAMS Initiative for Innovative Medicine (CAMS-I2M-3-012), National Natural Science Foundation of China (81573328), and National Infrastructure of Microbial Resources (No. NIMR2018-3).

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Isarubrolones Containing a Pyridooxazinium Unit from Streptomyces

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