Prenylated Tryptophan-derived Alkaloids with Neurotrophic Effects

Article Cite This: J. Org. Chem. 2018, 83, 812−822

pubs.acs.org/joc

Asperorydines A−M: Prenylated Tryptophan-Derived Alkaloids with Neurotrophic Effects from Aspergillus oryzae Li Liu,†,‡,§ Li Bao,†,‡,§ Long Wang,†,§ Ke Ma,†,‡ Junjie Han,†,‡ Yanlong Yang,† Ruixing Liu,†,‡ Jinwei Ren,† Wenbing Yin,†,‡ Wenzhao Wang,† and Hongwei Liu*,†,‡ †

State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, People’s Republic of China ‡ Savaid Medical School, University of Chinese Academy of Sciences, Beijing, 100049, People’s Republic of China S Supporting Information *

ABSTRACT: As part of our program to discover new bioactive agents from fungi, 13 new alkaloids accompanying 13 known related alkaloids were isolated from a wild strain of Aspergillus oryzae L1020. Compounds 1 and 2 have unprecedented 6/6/5/7/5 and 6/6/6/5/5 chemical skeletons, representing new members of quinoline alkaloids. Compound 3 is a new macrolactam with an unusual 6/5/6/8 ring system. Compounds 4−13 are new α-cyclopiazonic acid-related alkaloids. The absolute configurations of 1−4, 8, and 9 were assigned by electronic circular dichroism calculations. Compounds 2, 5, 6, 11, 14, 22, and 26 exhibit pronounced neurite outgrowth-promoting effects on PC12 cells in the range of 25−100 μM.

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INTRODUCTION

alkaloids, asperorydines A−M (1−13), from the solid culture of A. oryzae L1020 fermented on rice.

With the extension of life expectancies, aging-related neurodegenerative diseases have become a major threat to the public health of aged people. Bioactive compounds with neurotrophic properties are in urgent need for the discovery and development of new drugs against neurodegenerative diseases. Natural products, such as jiadifenin from the plant Illicium jiadifengpi, huperzine A from Huperzia serrata, erinacines from medicinal mushroom Hericium erinacium, and paecilomycine A from the fruiting bodies of Paecilomyces tenuipes, have been demonstrated as a rich source for neurotrophic agents.1−5 Prenylated indole alkaloids have attracted much attention of chemists and biologists due to their complex structures and interesting bioactivities. Great efforts have been endeavored to synthesize and identify new prenylated indole alkaloids. Fungi belonging to the genus of Claviceps, Penicillium, and Aspergillus produced a wide array of indole alkaloids, including versicolamides, paraherquamides, fumitremorgins, α-cyclopiazonic acid, and the ergot alkaloids.6−10 With the aim of exploring new prenylated indole alkaloids, the solid culture extracts of different Aspergillus strains were screened by HPLC analysis of the secondary metabolites with the UV characteristics of indole alkaloids. The strains producing rich indole alkaloids were put into further chemical investigation. In our recent report, three highly modified dioxopiperazine alkaloids with novel skeletons were reported from A. tennesseensis.6 Herein, we report the isolation, structure elucidation, neuroprotective and neurotrophic activities of 13 new prenylated © 2017 American Chemical Society

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RESULTS AND DISCUSSION The fungus A. oryzae was isolated from the surface of an unidentified leaf collected in Tiantanshan Mountain (Shanxi, China) and identified on the basis of the morphological characteristics and ITS gene sequences. The fungus was fermented on rice medium and extracted with EtOAc. The EtOAc extract was subjected to silica gel, ODS, Sephadex LH20, and HPLC chromatography to afford new alkaloids 1−13 and known α-cyclopiazonic acid derivatives (Figure 1) including speradine D (14),11 α-cyclopiazonic acid (CPA) (15),9 3-OH-speradine A (16),12 speradine H (17),13 speradine A (18),14 cyclopiamide E (19),15 iso-α-cyclopiazonic acid (20),16 speradine B (21),11 speradine E (22),17 α-cyclopiazonic acid imine (23),18 cyclopiamide H (24),15 cyclopiamide (25),19 and bissecodehydrocyclopiazonic acid (26).18 Asperorydine A (1) has the molecular formula C20H20N2O3 with 12 unsaturation degrees, as determined from HRESIMS at m/z [M + H]+ 337.1551. The 1H, 13C, and HSQC NMR spectra (Tables 1 and 3) of 1 showed the presence of a 1, 2, 3trisubstituted benzene, three singlet methyls, two exchangeable hydrogens, a trisubstituted double bond, three carbonyl carbons, one methylene, three methines, and two quaternary carbons. The exchangeable hydrogens were deduced to be Received: November 5, 2017 Published: December 22, 2017 812

DOI: 10.1021/acs.joc.7b02802 J. Org. Chem. 2018, 83, 812−822

Article

The Journal of Organic Chemistry

Figure 1. Structures of 1−26 from Aspergillus oryzae.

and H3-22 with H-10β together with the larger coupling constant of 10.5 Hz between H-9 and H-17 supported the relative configurations of 1 as described in Figure 3. For the absolute configuration in 1 to be determined, the ECD calculation method by time-dependent density functional theory (TDDFT) at the B3LYP/6-311G(d,p) level was first applied. Unfortunately, the simulated ECD curves obtained by the B3LYP method did not match with the experimental ECD for 1. Next, we attempted the BP86 method that had been successfully used to determine the absolute configuration of bistramide C, bisnicalaterines, chisomicines, and eucophylline.20−23 A comparison of the experimental ECD spectrum for 1 with the calculated ECD spectra for the 1a and 1b enantiomers obtained by the BP86 method is shown in Figure 4. The overall ECD spectra for 1a obtained by the BP86 method matched well with the experimental ECD for 1 (Figure 4). Thus, the absolute configuration of 1 was determined to be 4S, 7S, 9S, 17S.

secondary amines in accordance with its molecular formula. 1 H−1H COSY correlations of H-1−H-2, H-12−H-13−H-14, and H2-10−H-9−H-17, as well as key HMBC correlations of H-2 with C-3, C-15, and C-17, H-9 with C-3, C-10, C-11, and C-17, H2-10 with C-9, C-11, C-12, C-16, and C-17, H-17 with C-2, C-3, C-9, C-10, and C-16, and NH-1 with C-2, C-3, C-15, and C-16 confirmed the presence of cyclopenta[de]quinoline moiety (Figure 2). The structural fragment of 3-acetylpyrrolidine-2,4-dione was deduced on the basis of 1H−1H COSY correlations of H-4 with NH-5 as well as HMBC correlations of H-4 with C-3, C-6, C-7, C-17, and C-18, NH-5 with C-4, C-6, C-7, and C-18, H3-20 with C-7 and C-19. HMBC correlations of H-21 (22) with C-7, C-8, and C-9 finally connected the moieties of cyclopenta[de]quinoline and 3-acetylpyrrolidine2,4-dione to form an unusual pentacyclic ring system of 6/6/5/ 7/5. The relative configuration of 1 was determined by ROESY experiments. The NOE correlations of H-4 with H-17 and H320, H3-21 with H-10α and H-17, H-9 with NH-5 and H-10β, 813


Article

The Journal of Organic Chemistry Table 1. 1H NMR Data of 1−7 δH mult (J in Hz)a position 1(N) 1N−CH3 2 3-OH 4 5 6

1

b

2A

b,d

2B

b,d

b

4c

3

10.76 s 3.71 s

3.37 s

3.45 s

1.82 td (10.5, 3.1)

10

2.82 dd (15.4, 10.5) 2.95 dd (15.4, 3.1)

14 15 16 17

6.74 d (7.0) 6.98 dd (8.1, 7.0)

9.33 brs

9.14 brs

3.66 o 4.01 d (11.0)

3.66 o 4.01 d (11.0)

4.12 d (7.9)

2.37 o 3.01 d (5.6) 3.17 o

2.35 o 2.98 d (5.6) 3.17 o

7.14 o

7.14 o

7.36 o 7.36 o

7.36 o 7.36 o

7.13 o

3.27 d (10.5)

3.38 s 7.15 o

5.44 s

6.62 s

6.54 s

2.20 d (15.9) 2.82 d (15.9)

4.43 m

4.61 m

2.61 dd (15.7, 10.4) 2.70 dd (15.7, 5.6)

2.40 dd (16.6, 5.6) 2.70 dd (16.6, 7.2)

8

9

7b

3.44 s

7.14 o 4.64 s 9.38 s

6c 8.09 s

3.70 s

7

11 12 13

5c

8.11 s

7.60 d (8.4) 7.53 dd (8.4, 7.0) 7.13 d (7.0)

7.84 s

7.84 s

7.55 d (8.5)

7.64 d (8.5)

7.50 dd (8.5, 6.9) 6.90 d (6.9)

7.49 dd (8.5, 6.9) 6.89 d (6.9)

2.70 m

2.95 dd (16.9, 6.0) 3.12 dd (16.9, 6.0)

8.52 s

6.90 d (6.8) 7.17 o 7.19 d (6.8)

7.68 o 7.68 o 7.19 d (7.5)

3.93 d (16.4)

3.11 dd (15.7, 5.7) 3.23 dd (15.7, 7.1) 4.17 m 4.64 d (5.3) 1.17 d (6.2) 1.82 s 1.82 s

4.02 d (16.4) 18 18-OH 19 20 21 22 23 24

2.03 s 1.13 s 1.33 s

8.95 2.33 1.51 1.49

s, 9.59s s s s

8.95 s, 9.72 s 2.35 s 1.51 s 1.49 s

1.91 s 1.49 s 1.92 s

1.83 s 1.93 s 1.57 d (6.2)

1.80 s 1.96 s 1.38 d (6.3)

2.24 s 1.25 s 1.69 s

a “m” means multiplet with other signals; “o” means overlapping with other signals. bRecorded in DMSO-d6. cRecorded in CDCl3. dA: ketamine form; B: enimine form.

methylene, three methines, and 14 quaternary carbons including three carbonyl groups, 10 olefinic carbons, and one sp3 hybridized carbon. The 1D NMR data of 2 showed similarity with those of cyclopiazonic acid imine (23)18 except that additional signals of N−CH3 and carbonyl group were present in 2. Compound 23 was reported as a pair of isomers with a ratio of 3:2 due to the existence of tautomeric forms of ketamine and enimine.18 Comparison of 1H NMR spectrum between 2 and 23 indicated that the exchangeable protons at δH 8.95 (two protons), 9.59, and 9.72 ppm in 2 were ascribed to hydrogens in the ketamine and enimine systems. Further interpretation of 1H−1H COSY and HMBC spectra confirmed a new type of quinoline alkaloid with an unusual ring system of 6/6/6/5/5 (Figure 2). A hydroxyl group (2A: δH 9.33; 2B: δH 9.14) was attached at C-3 on the basis of the HMBC correlation between OH-3 and C-4 and consideration of the chemical shift of C-3 (2A: δC 142.6; 2B: δC 142.5). In the

Figure 2. Key HMBC and 1H−1H COSY correlations of 1−3.

Asperorydine B (2) was obtained as a mixture of two interchangeable isomers. Its molecular formula was determined to be C22H23N3O4 on the basis of the HRESIMS. The 1H and 13 C NMR data (Tables 1 and 3) of 2 showed the presence of two sets of signals each containing three exchangeable hydrogens, four methyls (one attached to nitrogen), one 814


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Figure 3. Key NOE correlations of 1−3.

Figure 4. Experimental CD spectra of 1 and 2 and the calculated ECD spectra of 1a, 1b, 2a, and 2b.

ROESY spectrum of 2, the NOE correlations of H-12 with H-5 and H-13α, and H-6 with H-13β, assigned the relative configuration of 2 (Figure 3). The similar Cotton effects at 224 and 259 nm between 2 and 23 assigned the absolute configuration of 6S in 2 (Figure S11).9 The absolute configuration of 2 was further determined by ECD calculation. The calculation was conducted in methanol by using TDDFT at the B3LYP/6-311G(d,p) basis set level. Considering the relative configuration of 2, two possible stereoisomers 2a and 2b were deduced. The experimental ECD spectrum of 2 was similar to the calculated ECD spectrum of 2b (Figure 4). Accordingly, the absolute configuration of 2 was determined to be 5R, 6S, 12R.

The molecular formula of asperorydine C (3) was determined to be C20H20N2O3 with 12 degrees of unsaturation based on the HRESIMS at m/z 337.1547 for [M + H]+. The 1 H, 13C, and HSQC NMR spectra (Tables 1 and 3) of 3 revealed the presence of four methyl groups, one methylene, one oxygenated methine, two quaternary carbons, one of which is oxygenated carbon, one naphthalene system, and two carbonyl groups. A detailed comparison of the proton and carbon signals of 3 and 25 indicated the presence of a 4, 5disubstituted-1-methylbenzo[cd]indol-2(1H)-one moiety, which was further supported by HMBC experiments. The HMBC correlations of H-5 with C-2, C-3, C-4, C-11, and C-19, H2-7 with C-5, C-6, C-8, and C-19, H3-19 with C-5, C-6, C-7 and C-8 indicated the connection of 3-methylbutanoid acid815


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Figure 5. Experimental CD spectra of 3−5 and the calculated ECD spectra of 3a, 3b, 4a, and 4b.

the unsaturation degrees. The NOE cross peak between H-5 and H3-22 indicated that H3-22 and H-5 are orientated to the same side of 1,3-oxazinan-4-one ring in 4 (Figure S1). The absolute configuration of 4 was determined as 5S, 7S by the comparison of experimental and calculated ECD curves (Figure 5). Compound 5 was determined to possess the same planar structure as that of 4 by detailed analysis of its 2D NMR data. In the ROESY spectrum of 5, the NOE cross peak between H-5 and H-7 supported that these protons were on the same face of the 1,3-oxazinan-4-one ring (Figure S2). The CD spectrum of 5 was completely opposite to that of 4 (Figure 5), which helped us assign the 5R configuration in 5. With the relative configuration determined in 5, the absolute configuration of 5 was assigned as 5R and 7S. Asperorydine F (6) and G (7) were determined to have the molecular formulas C19H20N2O3 and C20H20N2O4 by HRESIMS, respectively. The 1H and 13C NMR data (Tables 1 and 3) comparison of 6 with 14 and 15 indicated that it shares the same perhydrobenzoindole moiety with 15 and the rest of the structure with 14. The NOE correlations of H3-21 with H-4 and H-8 supported the same orientation for H-4 and H-8 (Figure S3). The negative Cotton effect at 274 nm and the positive Cotton effect at 303 nm arising from the indole ring9 in the CD spectrum of 6 were in accordance with the corresponding Cotton effects of 15 (Figure S99), which speculated the 4R and 8R absolute configuration in 6. The 1D NMR data (Tables 1 and 3) of 7 show much similarity with those of 17 except for the absence of a ketone carbon in 17 and

related moiety to C-4 (Figure 2). The attachment of an isopropyl moiety to C-11 was confirmed by the HMBC correlations of H3-20 (21) with C-10 and C-11. Considering the molecular formula of 3, the unsaturation degree requirement, the chemical shifts of C-5, C-6, C-8, and C-10, an amide linkage between C-8 and C-10, and one oxirane ring incorporating with C-5 and C-6 were deduced. On the basis of the evidence, the planar structure of 3 was established. The NOE correlations of H-5 with H3-19 and H3-20 indicated that the H-5, CH3-19, and CH3-20 were on the same side of azocan2-one ring (Figure 3). Computer simulation of the ECD spectra for 3a and 3b was performed by using TDDFT at the B3LYP/ 6-31G(d) basis set level in methanol. The spectrum for 3a is in good accordance with the experimental spectrum of 3 (Figure 5). Therefore, the absolute configuration of 3 was assigned as 5R, 6S. Asperorydine D (4) and E (5) possess the same molecular formula of C20H20N2O3 as determined by HRESIMS (4: m/z 337.1546; 5: m/z 337.1547). The 1H and 13C NMR spectra (Tables 1 and 3) of 4 and 5 resembled those of 3 and 25, suggesting the presence of the same substituted N-Me benzoindolone moiety as in 3 and 25. The 1H−1H COSY correlations of H2-8−H-7−H3-22 as well as the HMBC correlations of H-5 with C-7, H-7 with C-5, C-8, and C-22, H-8 with C-7, C-9, and C-22, and H3-22 with C-7 and C-8 confirmed the linkage of a butanoic acid moiety at C-5 via an ether bond in 4 (Figure S1). Finally, the connection between C-9 and N-10 was proposed to satisfy its molecular formula and 816


Article

The Journal of Organic Chemistry Table 2. 1H NMR Data of 8−12 δH mult (J in Hz)a position

8

c

b

9

1(N) 1N−CH3 5 6 9 10

9.32 2.91 3.16 4.34

12 13

2.70 m 2.64 m 2.96 d (5.1)

14 15 16

m d (4.6) dd (9.9, 7.0) d (9.9)

6.40 d (7.3) 7.30 t (8.0)

17 18 19

6.55 d (8.6)

20 21 22

1.42 s 1.60 s

2.45 s

10

c

9.00 q (5.1) 2.87 d (5.1) 3.96 d (2.5)

2.92 d (5.0) 3.75 d (6.8)

2.65 2.64 2.93 6.47 7.34

2.64 2.79 2.95 6.39 7.30

m m dd (10.6, 2.5) d (7.1) dd (8.6, 7.2)

11Ab,d 9.15 2.86 2.97 4.16

m m m d (7.2) dd (8.6, 7.2)

6.61 d (8.6)

6.56 d (8.6)

3.83 d (16.8) 3.98 d (16.8)

3.80 d (16.8) 4.02 d (16.8)

2.11 s 1.44 s

3.68 s 1.54 s

1.52 s

1.65 s

11Bb,d

q (5.0) d (6.4) dd (10.0, 6.4) d (10.0)

9.15 2.86 2.97 4.24

12Ab,d

q (5.0) d (6.4) dd (10.0, 6.4) d (10.0)

12Bb,d

9.32 brs 2.86 s

9.32 brs 2.86 s

2.59 o 2.90 o 3.07 m

2.59 o 2.90 o 3.07 o

3.44 d (5.4) 2.86 m 2.92 t (14.0)

3.47 d (5.4) 2.86 m 2.92 t (14.0)

6.46 d (8.5) 7.32 t (8.5)

6.47 d (8.5) 7.32 t (8.5)

6.45 d (7.1) 7.28 t (8.5, 7.1)

6.45 d (7.1) 7.28 t (8.5, 7.1)

6.57 d (8.5)

6.57 d (8.5)

6.59 d (8.5)

6.59 d (8.5)

8.84 9.50 2.32 1.44 1.28

8.94 9.74 2.34 1.41 1.31

9.03 9.75 2.36 1.36 1.61

9.00 9.13 2.36 1.38 1.61

d (5.0) d (5.0) s s s

d (5.0) d (5.0) s s s

brs brs s s s

brs brs s s s

“m” means multiplet with other signals; “o” means overlapping with other signals. bRecorded in DMSO-d6. cRecorded in CDCl3. dA: ketamine form; B: enimine form. a

Table 3. 13C NMR Data of 1−12 δC position 1N-CH3 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 a

1a 118.1 111.7 62.0 169.6 74.5 45.1 46.3 27.3 130.3 115.2 122.1 108.7 133.8 127.0 41.3 205.6 200.2 30.0 16.6 21.6

2Aa,c

2Ba,c

3a

4b

5b

6b

7a

8b

9a

10b

11Aa,c

11Ba,c

12Aa,c

12Ba,c

29.9 157.7 142.6 117.4 35.9 70.1 194.3 97.8 174.9

29.9 157.6 142.5 116.8 36.0 68.9 196.0 99.2 172.2

26.2 166.4 121.3 134.1 74.5 78.2 51.2 172.7

26.5 166.5 122.6 131.8 83.5

26.5 166.4 122.7 132.0 87.1

120.0 106.6 40.6 176.4

26.5 164.0 124.2 125.7 164.2

29.1 152.1 114.6 190.6 53.6 170.6

29.5 153.1 113.8 190.4 54.0 170.8

69.0 41.8 169.1

71.1 40.1 167.9

29.6 153.0 116.4 184.5 117.3 117.7 176.0 99.3 168.8

62.4 50.7 28.0 144.1 114.5 135.5 108.9 167.9

62.1 51.0 28.1 144.2 114.5 135.5 108.9 168.2

62.7 56.3 31.4 143.5 115.1 135.2 110.0 166.5

62.4 56.4 31.5 143.5 115.1 135.2 110.0 166.5

18.7 24.7 24.7

17.8 24.7 24.8

66.6 149.9 123.7 130.3 120.5 129.5 105.0 140.7 125.8 28.7 28.1 22.9

64.0 43.9 29.2 143.2 114.7 136.4 109.9 167.7 45.8 168.1 52.5 24.4 23.1

29.6 153.0 116.4 184.6 117.3 117.7 178.1 100.8 168.6

66.7 150.4 123.6 130.3 120.6 129.5 105.0 140.8 125.7 28.4 28.4 21.8

63.1 42.7 28.3 143.4 113.2 136.1 109.6 168.2 53.8 202.1 29.9 23.7 22.8

29.1 152.3 113.3 196.7 49.1 65.4 195.9 98.9 172.4

61.5 49.0 27.4 133.7 122.6 126.6 112.4 134.1 117.0 168.1

65.3 152.4 124.3 131.7 120.2 131.5 105.6 140.9 125.5 172.4 47.6 62.9 23.7 26.4 26.4

29.1 152.2 113.4 196.8 49.1 66.5 193.5 97.3 175.2

61.7 49.0 27.5 133.7 122.5 126.6 112.4 134.2 117.0 168.2

66.2 43.2 25.3 128.4 116.7 123.5 108.7 133.5 126.2 168.6 54.4 201.7 30.3 22.2 26.7

29.5 153.3 113.8 195.8 48.8 68.1 193.3 105.0 175.6

18.6 24.2 24.7

17.8 24.2 24.8

18.5 20.2 28.1

19.4 20.3 28.1

62.6 153.3 123.9 128.7 120.0 128.7 104.9 139.3 124.4 25.3 29.7 26.0

64.2 51.3 28.8 143.3 114.4 136.1 109.6 185.4 19.8 24.1 25.2

Recorded in DMSO-d6. bRecorded in CDCl3. cA: ketamine form; B: enimine form.

and C-18 (Figure S4). Further analysis of 2D NMR data assigned the structure of 7. The configuration of C-18 was left unsolved due to the small quantity of 7. Asperorydine H (8) was assigned the molecular formula C20H22N2O4 by the HRESIMS at m/z 355.1656 for [M + H]+.

the presence of an oxygenated methine in 7. The hydroxyl group was assigned at C-18 by the 1H−1H COSY correlations of H2-17−H-18−H3-19 and OH-18−H-18 as well as the HMBC correlations of H2-17 with C-16, C-18, and C-19, H-18 and HO-18 with C-16, C-17, and C-19, and H3-19 with C-17 817


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Figure 6. Experimental CD spectra of 8−10 and calculated ECD spectra of 8a, 8b, 9a, and 9b.

The 1H and 13C NMR spectra (Tables 2 and 3) of 8 were similar to those of 16 except for the loss of an oxygenated quaternary carbon. Detailed analysis of 1H−1H COSY and HMBC spectral data completed the planar structure of 8 (Figure S5). Compound 8 possesses a new skeleton of 5,5a,6,11,11a,11b-hexahydro-1H-benzo[f ]pyrrolo[2,1-a]isoindole-1,3(2H)-dione. The α configurations of H-5 and H12 and the β configuration of H-6 were determined from the NOE cross peaks of H3-21 with H-5 and H-12, and H3-20 with H-6 (Figure S5). The experimental ECD spectrum of 8 was almost consistent with the calculated ECD spectrum for (5S, 6S, 12R)-8b (Figure 6). Thus, the absolute configuration of 8 was assigned as 5S, 6S, 12R. The HRESIMS spectra of asperorydine I (9) and J (10) indicated molecular formulas of C19H22N2O4 and C19H22N2O5, respectively. A detailed comparison of NMR data of 9 with those of 6 and 8 revealed the presence of a naphthalen-1(2H)one-derived moiety and a 1-(2,2-dimethyl-5-oxopyrrolidin-1yl)butane-1,3-dione moiety. Further HMBC spectrum analysis established the structure of 9 (Figure S6). The 1D NMR data of 10 were similar to those of 9 except for the replacement of the methyl keton of 9 with a carbomethoxy moiety in 10. HMBC correlation of the methoxyl group with C-17 indicated the attachment of a methoxyl group at C-17 in 10 (Figure S7). In the ROESY spectrum of 9, the NOE correlation of H3-19 with H-5 and H-9 confirmed the same orientation of H-5 and

H-9 (Figure S6). Computer simulations of the ECD spectra for 5S, 9S- and 5R, 9R-9 were conducted. The absolute configurations at C-5 and C-9 were assigned as 5R and 9R by comparison of the experimental and simulated ECD curves (Figure 6). The absolute configuration of 10 was determined to be the same as that of 9 by similar Cotton effects in the CD spectrum between 9 and 10 (Figure 6). Asperorydines K−M (11−13) were isolated as an interchangeable isomer mixture similar to 2 and 23. The structural assignments of 11−13 were achieved by careful interpretation of their 2D NMR spectra (Figures S8−S10). Compound 8 can be transformed into 11 with the addition of ammonia, which further confirmed the presence of the imine moiety in 11. As described for 23,18 compounds 2 and 11−13 could be derived from the reaction between the CPA-related metabolites and ammonia produced in the growth of fungi. Accordingly, the absolute configurations of 11−13 were determined to be 5S, 6S, 12R-11, 12R-12, and 3R, 4S, 5S, 11R-13, respectively. In this study, we reported two new quinoline alkaloids with unusual skeletons, 11 new CPA derivatives, and 13 known CPA analogues from a strain of A. oryzae. Compounds 1−13 are structurally related to each other and composed of a tryptophan residue, a prenyl moiety, and one polyketide unit. After the first report of CPA in 1968,9 a total of 30 CPA-type alkaloids have been discovered from species of Aspergillus and Penicillium. 818


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Figure 7. Effect of compounds 1−26 on H2O2-induced PC12 cell death. Numbers 1−26: compounds 1−26 at 100 μM; N: 400 μM H2O2 as negative control; P: 100 μM luteolin as positive control.

Figure 8. Neurite outgrowth of PC12 cells after 24 h treatment with NGF (B: 20 ng/mL) or 2 (C: 50 μμM). Cells with one or more neurites whose lengths were at least twice the diameter of the cell body were scored as positive. The percentage of positive neurite-bearing cells was determined from at least three different regions of interest in three independent experiments (D). Values were considered significant at ***P < 0.001 versus control group.

more beneficial to the neuroprotective and neurotrophic activities than the formation of a tetramic acid moiety. In conclusion, we isolated 26 prenylated alkaloids including 13 new compounds from the solid culture of A. oryzae. Compounds 2, 5, 6, 14, 22, and 26 showed both neuroprotective and neurotrophic activities in vitro. The discovery of structurally new and unique tryptophan-derived alkaloids from a strain of A. oryzae here indicates the incomparable tailoring effects on secondary metabolites produced by a gene cluster. A. oryzae is classified as a safe fungus used for the food industry. The current research greatly extends the chemical space of prenylated tryptophane-derived alkaloids and enriches our knowledge about the secondary metabolites from A. oryzae. Although new strategies including genome mining, epigenetics, heteroexpression of cryptic gene clusters, and coculturing method have been continuously put into use in the field of fungal natural product research, the potential of fungi as a reservoir of natural products is still far beyond our estimation.

CPA and its analogues show interesting bioactivities, such as inhibitory activity against Ca2+-ATPase,14,24 histone deacetylase,14 antitobacco mosaic virus,25 and toxicity against brine shrimp.15 The CPA biosynthesis gene cluster composed of 7 genes, cpaR, cpaA, cpaD, cpaO, cpaH, cpaM, and cpaT, has been described in A. oryzae.26 The functions of cpaA, cpaD, cpaO, cpaH, and cpaM were demonstrated in the biosynthesis of CPA, 2-oxo CPA, and speradine A.26 These genes are supposed to be partly involved in the biosynthesis of new compounds 1−13. We evaluated the neuroprotective effect and neuritepromoting activity of CPA analogues using PC12 cells. Compound 15 that showed cytotoxicity toward PC12 cells at 100 μM was not tested. The cytoprotective activities of compounds 1−14 and 16−26 against H2O2-induced oxidative stress were evaluated using PC12 cells. After incubation with 400 μM H2O2 for 24 h, only 47.29% of cultured cells survived. Compounds 4, 5, 6, 9, 10, 14, 17, 22, and 26 showed protective capabilities with survival rates from 70.16 to 90.85% at 100 μM (Figure 7). Luteolin is used as positive control with a survival rate of 91.61% at 100 μM. The effects of compounds 1−26 on the neurite outgrowth of undifferentiated PC12 cells were further evaluated by morphological observations and a quantitative analysis of neurite-bearing cells and neurite length. Compounds 2, 5, 6, 11, 14, 22, and 26 showed significant neurotrophic effects in the range of 25−100 μM (Figure 8, Figures S13−S18) as compared with the control group. The percentage of neurite-bearing cells for cells treated with compounds 2, 5, 6, 11, 14, 22, and 26 at 100 μM reached 18.58 ± 1.77, 18.62 ± 1.87, 20.07 ± 1.05, 26.85 ± 1.31, 18.64 ± 1.47, 20.14 ± 1.34, and 15.2 ± 1.35%, respectively. NGF is used as positive control with neurite-bearing cells of 22.06 ± 1.24% at a concentration of 20 ng/mL. The percentage of neuritebearing cells in the negative group was 4.83 ± 0.65%. Compounds 6 and 14 showed stronger neuroprotective and neurotrophic activities than those of 15 and 16, respectively, indicating that the substitution of a butanoic acid side chain is

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EXPERIMENTAL SECTION

General Experimental Procedures. Mass spectra were recorded on an Agilent Accurate-Mass-Q-TOF LC/MS 6520 spectrometer. NMR spectra were measured on a Bruker Avance-500 spectrometer using solvent signals (DMSO-d6, δH 2.50/δC 39.5; CDCl3, δH 7.26/ δC 77.2) as references. UV and IR spectra were recorded on a Thermo Genesys-10S UV−vis spectrophotometer and a Nicolet IS5FT-IR spectrophotometer, respectively. Optical rotations were obtained on a polarimeter with sodium light (589 nm) by using a PerkinElmer 241 polarimeter. HPLC separation was conducted on an Agilent 1200 HPLC system equipped with an Agilent G1315D DAD detector using a YMC-Pack ODS-A column (5 μm; 9.4 × 250 mm). Fungal Materials. The fungal strain A. oryzae (numbered as L1020) was isolated from the surface of an unidentified leaf collected in Tiantanshan Mountain (Shanxi, China) and identified on the basis of the morphological characteristics and the ITS gene sequences (Table S2). 819


Article


cm−1; positive HRESIMS m/z [M + H]+ 394.1763 (calcd for C22H24N3O4, 394.1761). 1H and 13C NMR data can be seen in Tables 1 and 3. Asperorydine C (3). Yellow powder; [α]25 D +113.8 (c 0.09 MeOH); UV (MeOH) λmax (log ε) 220 (4.1), 265 (3.8), 302 (3.8), 338 (3.9) nm; CD (c 8.9 × 10−4 M, MeOH) λmax (Δε) 227 (+20.7), 264 (−2.7), 283 (+7.8), 307 (−2.6), 378 (+4.1); IR(neat) vmax 3392, 1684, and 1612 cm−1; positive HRESIMS m/z [M + H]+ 337.1547 (calcd for C20H21N2O3, 337.1547). 1H and 13C NMR data can be seen in Tables 1 and 3. Asperorydine D (4). Yellow powder; [α]25 D −71.4 (c 0.06 MeOH); UV (MeOH) λmax (log ε) 211 (4.2), 252 (3.9), 328 (3.6), 334 (3.6) nm; CD (c 8.9 × 10−4 M, MeOH) λmax (Δε) 208 (+1.8), 228 (−0.8), 253 (−0.2); IR(neat) vmax 3447, 1701, and 1620 cm−1; positive HRESIMS m/z [M + H]+ 337.1546 (calcd for C20H21N2O3, 337.1547). 1H and 13C NMR data can be seen in Tables 1 and 3. Asperorydine E (5). Yellow powder; [α]25 D +133.1 (c 0.16 MeOH); UV (MeOH) λmax (log ε) 211 (4.2), 252 (3.9), 328 (3.6), 334 (3.6) nm; CD (c 1.2 × 10−3 M, MeOH) λmax (Δε) 208 (−2.6), 230 (+3.3), 254 (+1.5); IR(neat) vmax 3440, 1708, and 1624, cm−1; positive HRESIMS m/z [M + H]+ 337.1547 (calcd for C20H21N2O3, 337.1547). 1H and 13C NMR data can be seen in Tables 1 and 3. Asperorydine F (6). Yellow powder; [α]25 D +25.9 (c 0.1 MeOH); UV (MeOH) λmax (log ε) 221 (4.3), 273 (3.8) nm; CD (c 7.7 × 10−4 M, MeOH) λmax (Δε) 213 (−3.1), 228 (+10.1), 274 (−0.4), 303 (+0.67); IR(neat) vmax 3392, 1725, and 1617 cm−1; positive HRESIMS m/z [M + H]+ 325.1551 (calcd for C19H21N2O3, 325.1547). 1H and 13C NMR data can be seen in Tables 1 and 3. Asperorydine G (7). Light yellow powder; [α]25 D +3.3 (c 0.2 MeOH); UV (MeOH) λmax (log ε) 221(4.3), 273 (3.8) nm; IR(neat) vmax 3503, 1734, and 1636 cm−1; positive HRESIMS m/z [M + H]+ 353.1492 (calcd for C20H21N2O4, 353.1496). 1H and 13C NMR data can be seen in Tables 1 and 3. Asperorydine H (8). Yellow powder; [α]25 D −47.1 (c 0.06 MeOH); UV (MeOH) λmax (log ε) 220 (3.2), 238 (2.7) nm, 269 (1.9), 398 (0.8) nm; CD (c 8.5 × 10−4 M, MeOH) λmax (Δε) 202 (+9.1), 224 (−9.1), 250 (−5.0), 297 (+2.6), 390 (−0.9); IR(neat) vmax 3308, 1714, and 1624 cm−1; positive HRESIMS m/z [M + H]+ 355.1656 (calcd for C20H23N2O4, 355.1652). 1H and 13C NMR data can be seen in Tables 2 and 3. Asperorydine I (9). Yellow powder; [α]25 D −129.9 (c 0.04 CDCl3); UV (MeOH) λmax (log ε) 221(3.1), 240 (2.6) nm, 267 (1.7), 398 (0.9); CD (c 8.8 × 10−4 M, MeOH) λmax (Δε) 218 (+0.76), 236 (−0.64), 249 (+1.13), 264 (−0.23), 279 (+1.63), 337 (−0.72), 399 (−0.39); IR(neat) vmax 3317, 1726, and 1625 cm−1; positive HRESIMS m/z [M + H]+ 343.1654 (calcd for C19H23N2O4, 343.1652). 1H and 13 C NMR data can be seen in Tables 2 and 3. Asperorydine J (10). Yellow powder; [α]25 D −112.3 (c 0.04 CDCl3); UV (MeOH) λmax (log ε) 223(3.1), 242 (2.7) nm, 273 (1.8), 398 (0.9); CD (c 8.4 × 10−4 M, MeOH) λmax (Δε) 213 (+1.8), 235 (−1.6), 249 (+1.4), 263 (−0.5), 279 (+2.0), 320 (−0.7), 397 (−0.5); IR(neat) vmax 3316, 1700, and 1626 cm−1; positive HRESIMS m/z [M + Na]+ 381.1426 (calcd for C19H22N2O5Na, 381.1421). 1H and 13C NMR data can be seen in Tables 2 and 3. Asperorydine K (11). Yellow powder; [α]25 D −155.5 (c 0.18 MeOH); UV (MeOH) λmax (log ε) 215 (3.3), 238 (2.5) nm, 272 (1.6), 398 (0.7) nm; CD (c 1.1 × 10−3 M, MeOH) λmax (Δε) 220 (−19.3), 258 (+2.0), 272 (−4.2), 305 (+3.6); IR(neat) vmax 3306, 1713, and 1621 cm−1; positive HRESIMS m/z [M + H]+ 354.1813 (calcd for C20H24N3O3, 354.1812). 1H and 13C NMR data can be seen in Tables 2 and 3. Asperorydine L (12). Red powder; [α]25 D +68.7 (c 0.03 MeOH); UV (MeOH) λmax (log ε) 238 (3.9), 289 (3.8), 397 (3.3) nm; CD (c 9.5 × 10−4 M, MeOH) λmax (Δε) 214 (−2.0), 226 (+0.86), 259 (−3.5), 300 (+1.70), 355 (−0.35), 392 (+0.33); IR (neat) vmax 3303, 1682, and 1606 cm−1; positive HRESIMS m/z [M + H]+ 352.1656 (calcd for C20H22N3O3, 352.1654). 1H and 13C NMR data can be seen in Tables 2 and 3. Asperorydine M (13). Light yellow powder; [α]25 D +79.0 (c 0.1 MeOH); UV (MeOH) λmax (log ε) 209 (4.0), 242 (4.1), 314(3.2) nm;

Fermentation and Extraction. A. oryzae was cultured on PDA plates at 25 °C for 7 days. Agar plugs were inoculated into a 250 mL Erlenmeyer flask containing 100 mL of PDB medium cultured at 25 °C for 7 days on a rotary shaker at 180 rpm. Mass scale fermentation was carried out in 200 × 500 mL Fernbach culture flasks each containing 80 g of rice and 100 mL of distilled water. Each flask was inoculated with 5 mL of culture medium and incubated at 25 °C for 40 days in the dark. The fermented rice substrate was extracted repeatedly with ethyl acetate (3 × 25 L) at room temperature, and 80 g of crude extract was obtained by evaporating solvent under vacuum. Isolation and Characterization of Compounds 1−26. The crude extract was fractionated by silica gel column chromatography (CC) with 20:1 n-hexane−EtOAc (Fr. A), 80:1 CH2Cl2−MeOH (Fr. B), 50:1 CH2Cl2−MeOH (Fr. C), and 30:1 CH2Cl2−MeOH (Fr. D). Fr. A (3.0 g) was subjected to ODS CC with 40% MeOH−H2O (Fr. A1), 55% MeOH−H2O (Fr. A2). Fr. A1 was purified by recrystallization in MeOH to afford 21 (28 mg). Fr. A2 was purified by reversed-phase (RP) HPLC separation with 45% MeCN in H2O (0.1% TFA) to afford 22 (4.5 mg, tR = 33.8 min). Fr. B (9.4 g) was separated by silica gel CC eluting with CH2Cl2 (Fr. B1) and 50:1 CH2Cl2−MeOH (Fr. B2). Fr. B1 (1.8 g) was further subjected to ODS CC with 50% MeOH−H2O (Fr. B1-1, Fr. B1-2) and 60% MeOH−H2O (Fr. B1-3). Fr. B1-1 was purified by Sephadex LH-20 CC with CH2Cl2−MeOH (1:1) to obtain 17 (32 mg). Fr. B1-2 was further purified by Sephadex LH-20 CC with CH2Cl2−MeOH (1:1) followed by RP HPLC with 52% MeCN in H2O (0.1% TFA) to afford 9 (3.0 mg, tR = 21.1 min) and 6 (2.2 mg, tR = 32.5 min). Fr. B13 was subjected to Sephadex LH-20 CC with CH2Cl2−MeOH (1:1) to yield subfractions Fr. B1-3-1−Fr. B1-3-5. Fr. B1-3-2 was purified by RP HPLC to afford 26 (8.0 mg, tR = 35.3 min) and 8 (15 mg, tR = 37.5 min) with an eluent of 52% MeCN in H2O (0.1% TFA). Compounds 10 (3.8 mg, tR = 43.7 min), 20 (22 mg, tR = 45.2 min), and 15 (37 mg, tR = 68.0 min) were obtained by HPLC with an eluent of 48% MeCN in H2O (0.1% TFA). Fr. B2 (3.2 g) was subjected to ODS CC with 45% MeOH−H2O (Fr. B2-1, Fr. B2-2) and 50% MeOH−H2O (Fr. B2-3). Fr. B2-1 was purified by RP HPLC with 50% MeCN in H2O (0.1% TFA) to afford 7 (1.2 mg, tR = 16.8 min). Fr. B2-2 was subjected to RP HPLC with 37% MeCN in H2O (0.1% TFA) to obtain 19 (12.3 mg, tR = 29.4 min), 5 (3.7 mg, tR = 37.5 min), and 4 (6.2 mg, tR = 42.7 min). Fr. B2-3 was purified by RP HPLC with 55% MeCN in H2O (0.1% TFA) to afford 1 (7.4 mg, tR = 18.0 min). Fr. C (8.6 g) was separated by ODS CC with 45% MeOH−H2O (Fr. C1), 55% MeOH−H2O (Fr. C2), and 60% MeOH−H2O (Fr. C3). Fr. C1 was further purified by silica gel CC with 50:1 CH2Cl2− MeOH followed by RP HPLC with 38% MeCN in H2O (0.1% TFA) to afford 14 (6.3 mg, tR = 12.8 min), 9 (4.3 mg, tR = 19.5 min), and 16 (48.6 mg, tR = 24.5 min). Fr. C2 was subjected to Sephadex LH-20 CC with MeOH and then purified by RP HPLC with 45% MeCN in H2O (0.1% TFA) to give 11 (7.7 mg, tR = 19.2 min). Fr. C3 was further purified by Sephadex LH-20 CC with MeOH to afford 23 (5.5 mg). Fr. D (4.0 g) was subjected to ODS CC eluting with 30% MeOH− H2O (Fr. D1), 40% MeOH−H2O (Fr. D2), 50% MeOH−H2O (Fr. D3), and 60% MeOH−H2O (Fr. D4). Fr. D1 was further separated by Sephadex LH-20 CC with 80% MeOH−H2O followed by RP HPLC with 35% MeCN in H2O to obtain 24 (9.1 mg, tR = 13.5 min) and 25 (15.0 mg, tR = 18.6 min). Fr. D2 was further separated by RP HPLC with 32% MeCN in H2O (0.1% TFA) to afford 13 (5.2 mg, tR = 32.0 min). Compounds 2 (2.2 mg, 65% MeOH−H2O, tR = 22.4 min) and 12 (7.0 mg, 45% MeCN−H2O, tR = 22.1 min) were obtained from Fr. D3 and Fr. D4, respectively. Asperorydine A (1). Light yellow powder; [α]25 D −38.0 (c 0.05, MeOH); UV (MeOH) λmax (log ε) 210 (4.1), 273 (3.3) nm; CD (c 8.9 × 10−4 M, MeOH) λmax (Δε) 204 (+4.1), 219 (+1.9), 293 (−1.0); IR (neat) vmax 3401, 1697, and 1609 cm−1; positive HRESIMS m/z [M + H]+ 337.1551 (calcd for C20H21N2O3, 337.1547). 1H and 13C NMR data can be seen in Tables 1 and 3. Asperorydine B (2). Light yellow powder; [α]25 D −185.0 (c 0.02, MeOH); UV (MeOH) λmax (log ε) 224 (4.2), 293 (3.9) nm; CD (c 1.8 × 10−4 M, MeOH) λmax (Δε) 224 (−11.2), 259 (+0.4), 284 (−3.0), 310 (+0.2), 330 (−1.5); IR (neat) vmax 3306, 1682, and 1616 820



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CD (c 6.5 × 10−4 M, MeOH) λmax (Δε) 219 (−7.4), 237 (−5.0), 259 (+7.1), 295 (−3.5); IR (neat) vmax 3309, 1717, and 1612 cm−1; positive HRESIMS m/z [M + H]+ 382.176 (calcd for C21H24N3O4, 382.1761). 1H and 13C NMR data can be seen in Table S3. Computation Section. Systematic conformational analyses of 1a, 2b, 3a, 4a, 8b, and 9b were carried out using the MMFF94 molecular mechanics force field. All MMFF minima were optimized with PM6 using semiempirical theory method and then optimized at the B3LYP/ 6-311G(d,p) or B3LYP/6-31G(d) level in MeOH using the PCM polarizable conductor calculation model by the Gaussian09 program. The geometry was optimized starting from various initial conformations with vibrational frequency calculations confirming the presence of minima. The 30 excited states were calculated using time-dependent density-functional theory (TDDFT) methodology at the BP86/6311G(d,p) level for 1a, B3LYP/6-311G(d,p) level for 2b, 4a, and 9b, B3LYP/6-31G(d) level for 3a, and CAM-B3LYP/6-311G(d,p) level for 8b. ECD spectra were stimulated using a Gaussian function with bandwidth of 0.24, 0.40, 0.35, 0.36, 0.16, and 0.18 eV for 1a, 2b, 3a, 4a, 8b, and 9b, respectively. The overall ECD spectra were then generated according to Boltzmann weighting of each conformer. Neuroprotective and Neurotrophic Effects Assay. Cell Materials. The PC12 (rat adrenal pheochromocytoma) cell line was purchased from National Infrastructure of Cell Line Resource (Beijing, China). DMEM and PBS were purchased from hyclone (Greeley, CO, USA). Horse serum and fetal bovine serum were purchased from Gibco (Life Technologies, Carlsbad, CA, USA). DMSO was obtained from Applichem Co. (Darmstadt, Germany). Hydrogen peroxide was purchased from Sinopharm (Beijing, China). NGF was purchased from Wuan Hitech Biological Pharma Co., Ltd., China. Cytoprotective Effects of Compounds 1−26 in PC12 Cells. Rat PC12 cells were sustained in DMEM medium supplemented with 10% horse serum, 5% fetal bovine calf serum, and 100 U/mL penicillin-streptomycin in a humidified atmosphere containing 5% CO2 at 37 °C. Before treatment, 100 μL of PC12 cells were seeded on a 96-well plate at the density of 1 × 104 cells/well and cultured for 24 h. The medium was changed, and the cells were treated with compounds 1−26 and then exposed to 400 μm H2O2 for 24 h. Twenty microliters of 5 mg/mL MTT solution was added to each well, and the cells were incubated for 4 h. The resultant formazan product was dissolved by the addition of 150 μL of DMSO. The absorbance was measured at a wavelength of 570 nm using a Thermo Scientific Multiskan MK3 microplate reader. Neuritogenic Effects of Compounds 1−26 in PC12 Cells. Rat PC12 cells were sustained in DMEM medium supplemented with 10% horse serum, 5% fetal bovine calf serum, and 100 U/mL penicillinstreptomycin in a humidified atmosphere containing 5% CO2 at 37 °C for 72 h, and then single-cell PC12 suspensions were cultured in serum-free medium for the next 12 h. Each test compound and 20 ng/ mL of NGF were dissolved in DMSO. The final volume of DMSO for all assays in each well was less than 0.1%. Single-cell PC12 suspensions were plated at a density of 4 × 104 cells/well in 24-well plates with serum-free culture medium and then treated with tested compounds or NGF, respectively. After 24 h incubation, the percentage of cells showing neurite outgrowth was determined by light microscopy. Cells with one or more neurites whose lengths were at least twice the diameter of the cell body were scored as positive. Neurite outgrowth was determined from at least three different regions of interest in three independent experiments.

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Article

AUTHOR INFORMATION

Corresponding Author

*Tel: +86 10 64806074; e-mail: [email protected]. ORCID

Wenbing Yin: 0000-0002-9184-3198 Hongwei Liu: 0000-0001-6471-131X Author Contributions §

L.L., L.B., and L.W. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported in part by the National Natural Science Foundation of China (21472233) and the Youth Innovation Promotion Association of CAS (2014074). The calculated ECD performed by Guangzhou Yinfo Information Technology Co. Ltd. is gratefully acknowledged.

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REFERENCES

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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.joc.7b02802. NMR spectra for compounds 1−13, CD data, and computational details (PDF) 821


Article

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Prenylated Tryptophan-derived Alkaloids with Neurotrophic Effects

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