Heterocyclic Compounds from the Mushroom Albatrellus confluens

Article Cite This: J. Org. Chem. 2018, 83, 10158−10165

pubs.acs.org/joc

Heterocyclic Compounds from the Mushroom Albatrellus confluens and Their Inhibitions against Lipopolysaccharides-Induced B Lymphocyte Cell Proliferation Shuaibing Zhang,†,‡,§ Ying Huang,†,‡,§ Shijun He,∥ Heping Chen,† Bin Wu,† Shanyong Li,‡,§ Zhenzhu Zhao,‡,§ Zhenghui Li,† Xian Wang,† Jianping Zuo,*,∥ Tao Feng,*,† and Jikai Liu*,† †

School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan 430074, China State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Kunming 650201, China § University of Chinese Academy of Sciences, Beijing 100049, China ∥ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

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‡

S Supporting Information *

ABSTRACT: Eight hetereocyclic compounds conflamides B−I with an unprecedented skeleton and their precursor conflamide A were isolated from the mushroom Albatrellus conf luens. Their structures and absolute configurations were determined by use of NMR studies, total synthesis, and calculated ECD spectra. Conflamides D and E were found to exhibit potent inhibition against LPS-induced B lymphocyte cell proliferation with IC50 values 1.48 and 5.71 μM, respectively.

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INTRODUCTION

N-containing compounds in the widespread higher fungi are characteristic chemical constituents and exert a broad spectrum of biological activities.1 To date, more than 14 classes of Ncontaining compounds from macromycetes have been reported.2 For example, bionectins A and B were indole alkaloid isolated from mycelium of liquid fermentation cultures Bionectra byssicola, which showed anti-MRSA activities.3 Suillumide and its diacetyl derivative were two phytosphingosine-type ceramides with an unusual tetrahydrofuranyl ring, remarkable cyctoxicities, derived from fruiting bodies of basidiomycete Suillus luteus.4 Relatively speaking, due to the high prevalence and abundance of heteroatoms in these molecules, mushroom-derived N-containing molecules were often considered as valuable products. Our previous screening for natural products from higher fungi (mushrooms), the edible mushroom Albatrellus conf luens has been demonstrated to be rich in novel and bioactive metabolites.5 A further investigation on this mushroom has found that the lower-polarity fraction of the extract contained totally different metabolites to those reported previously. After careful studies on this fraction, eight novel nitrogen-containing heterocyclic compounds, namely conflamides B−I (2−9), together with a parent compound conflamide A (1) (Figure 1) were isolated and elucidated. Conflamides B−I (2−9) possessed a novel six-membered 1,2,5-oxadiazinan-4-one (ketal of α-oxime-acid) or a six-membered 1,3,4-oxadiazinan6-one (ketal of α-hydrazone-amide) heterocyclic moiety with © 2018 American Chemical Society

Figure 1. Compounds 1−9 isolated from the mushroom Albatrellus confluens.

multiple chiral centers, which are unprecedented in nature. Because these compounds are amorphous, our initial attempt to cultivate single crystals of these compounds with different conditions was unsuccessful. This made the determination of their planar structures and absolute configurations substantially complicated. However, the absolute configurations of these compounds were finally determined by ECD calculations and syntheses of certain structural fragments. The connectivity of the heteroatoms was confirmed by 13C NMR calculation.6 These compounds were evaluated for their in vitro inhibition Received: June 6, 2018 Published: July 26, 2018 10158

DOI: 10.1021/acs.joc.8b01420 J. Org. Chem. 2018, 83, 10158−10165

Article

The Journal of Organic Chemistry Table 1. 1H NMR (600 MHz) and 13C NMR (150 MHz) Data of 1 1 no. 1 2 3 4 5 6 7 9

δH a

δC a

δHb

δC b

δHc

6.60 (s), 5.53 (s)

3.07−3.45 (m) 1.74−2.04 (m) 1.49−1.65 (m) 0.88 (t, 7.5) 1.21 (d, 7.1)

168.9 157.3 33.4 27.2 12.8 17.0

3.26−3.30 (m) 1.84−1.89 (m) 1.59−1.64 (m) 0.87 (t, 7.5) 1.23 (d, 7.1)

7.22 (s), 7.06 (s) 166.1 157.7 32.5 26.2

2.92−3.22 (m) 1.62−1.88 (m) 1.35−1.59 (m) 0.78 (t, 7.5) 1.10 (d, 7.1) 11.37 (s)

12.6 16.6

a

Measured in methanol-d4. bMeasured in CDCl3. cMeasured in DMSO-d6.

activity on concanavalin A (ConA) induced T cell proliferation and lipopolysaccharide (LPS) induced B cell proliferation. Among them, conflamides D and E exhibited potent inhibition specifically against the LPS-induced proliferation of B lymphocyte cells.

Scheme 1. Beckmann Rearrangement of 1

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RESULTS AND DISCUSSION Conflamide A (1) was obtained as white powder. It had a molecular formula of C6H12N2O2 as determined by the [M + Na]+ ion peak at m/z 167.0792 in its HRESIMS data. This formula suggested that 1 had two degrees of unsaturation. The 1 H and 13C NMR spectra of 1 showed noticeable similarities to the spectra of L-isoleucine, indicating that the compound had this α-amino acid core structure. The 1H NMR spectrum of 1 (Table 1) in CD3OD showed a primary methyl group at δH 0.88 (t, J = 7.5 Hz, H3-6), a secondary methyl group at δH 1.21 (d, J = 7.1 Hz, H3-7), a methylene group at δH 2.04−1.74 (m, H1-5a) and 1.65−1.49 (m, H1-5b), and a methine group at δH 3.45−3.07 (m, H1-4). In the 13C NMR spectrum, there were signals corresponding to two quaternary carbons at δC 157.3 (C-3) and 168.9 (C-2), respectively. The aliphatic side chain was established as a sec-butyl group by 1H−1H COSY correlations of H1 -4−H2 -5−H 3-6 and H 1-4−H3 -7 and HMBC correlations from H3-7 and H3-6 to C-4 and C-5, which were located at C-3 by the HMBC correlations between H1-4 and H3-7 and C-3. The key HMBC correlations from −NH2 to C-2 and C-3 revealed the basic skeleton (Figure 2).

prepared the target molecules (LB-3, DB-3 and LDB-3) in good yields over three steps8 (Scheme 2). NMR spectra and Scheme 2. Syntheses of Compound 1

separation by chiral column chromatography on amylose carbamate (isopropanol:hexane 20:80) (Figure 3) revealed identical retention times for 1 and LB-3 which confirms an S configuration at C-4. Conflamide B (2), obtained as a yellow oil, had a molecular formula of C14H24N2O4 based on its ion peak for [M + Na]+ at m/z 307.1630 in its HRESIMS data. 1 H− 1 H COSY

Figure 2. Key correlations in 2D NMR spectra of the compounds.

The configuration of the oxime in 1 was determined by the analysis of its ROESY spectrum. The key ROESY correlation between H-4 and N−OH suggested that 1 had a trans-oxime (Figure S33 of the Supporting Information, SI), it was further confirmed by its product (A-1) of a Beckmann rearrangement7 (Scheme 1). Compound 1, which was isolated from every subfraction and accounted for 10% of the total extracted compounds in mass, could be a precursor to 2−9. Thus, compound 1 was synthesized to conduct further experiments. L-isoleucine, D-isoleucine and DL-isoleucine were used as starting materials for the synthesis, and we successfully

Figure 3. Chiral analysis of 1, LB-3, LDB-3, and DB-3 on amylose carbamate (isopropanol:hexane = 20:80). 10159


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The Journal of Organic Chemistry

respectively. Therefore, it could be inferred that compounds 6−9 owned the same skeleton. Meanwhile, The NMR data (Tables 2, 3) of 8 were in good agreement with those of 6, except that H-9 was substituted by a hydroxy group, which was supported by the value of C-2′ shifting to downfield. Thus, the basic scaffold of this pair of epimers was ascertained. Compounds 2−9 are on an extremely narrow range of polarities and had to be purified by different separation methods. Finally, we obtained the series of pure compounds by the separation on a chiral analytical column (Figure 5). The compounds showed very interesting chromatographic patterns. For each pair of epimers, the first peak to elute from the chiral column was the S-2′ compound, and the ECD curves of 2 and 7 were the same as 4 and 9, respectively. The ECD curves of 2, 4, 6, and 8 were also impressively consistent (Figure 6). Given that conflamide B (2) harbored an unusual carbon skeleton, the calculations of 13C NMR chemical shifts of 2 at the mPW1PW91/6-311++g(2d,2p) level with PCM model in CHCl3 based on predominant mPW1PW91/6-311++g(2d,2p) optimized geometries were performed. The results revealed that the correlation coefficient (R2) between the experimental and calculated data from linear regression analysis was 0.9994, and the root-mean-square deviation (RMSD) was 1.37 ppm, which further provided powerful evidence for the structural rationality of 2.6,10 (Figure 7) Therefore, the connectivities of the heteroatoms in compounds 1−9 were validated by comparing their experimental and theoretical 13C NMR shifts using their coefficient of determination (R2) and root-mean-square deviation (RMSD) as the evaluation criteria, which provided additional evidence for structure assignments of compounds 1−9. In other words, compounds 2−5 possessed an α-oxime-amide ketal, and compounds 6−9 possessed an α-hydrazone-acid ketal (Table 4). Unfortunately, due to the limited amount of isolated 9, we were not able to obtain its 13C NMR spectrum, but it did not affect its structure assignment. We also tried to totally synthesize these heterocyclic compounds, however, the result was not ideal. (Scheme S1) Conflamides B−I represented nor-cyclopeptide with novel heterocyclic scaffolds, which aroused great interest in their possible biogenesis. Biosynthetically, four pairs of epimers together with the parent compound might possibly be derived from the L-isoleucine or D-alloisoleucine since they possessed the same side chain. The presumptive biogenetic pathways for 1−9 were proposed (Scheme 3). This pathway made α carbon of isoleucine epimerized since it underwent a planar aromatic intermediate (D and E), which was in conformity to the fact that conflamides 2 to 9 coming in pairs.

correlations and HMBC correlations, similar to those of compound 1, indicated the presence of two sec-butyl side chains. Similarly, the HMBC correlations from H1-4 (H1-3′) to C-2 (C-1′), H2-5 (H2-4′) to C-3 (C-2′), H3-7 (H3-6′) to C-3 (C-2′), and H2-1″ to C-1′ placed the isobutyl group at C-3 (C2′) and an ethoxycarbonyl group at C-2′. Additionally, the key HMBC correlations from N−H to C-3 and C-2′ revealed the basic skeleton (Figure 2). The absolute configuration of the ketal moiety was determined to be S by using ECD.9 (Figure 4)

Figure 4. Experimental (MeOH) and calculated ECDs (gas phase) for compounds 2 and 3.

Conflamide C (3) was isolated as yellow oil. Its molecular formula was determined to be C14H24N2O4 based on its HRESIMS data, which was the same as that of 2. The UV and IR spectra were remarkably similar to those of 2. In addition, the experimental ECD spectra of 2 and 3 were mirror images of each other. The above-mentioned data indicated that 2 and 3 were a pair of epimers. Conflamide D (4) and conflamide E (5), a pair of epimers, were both obtained as white powders. On the basis of their HRESIMS data, they share the same molecular formula, C14H24N2O5, which contains one more oxygen atom than 2 and 3. By comparing their experimental ECD curves, we discovered that the ECD curves of 4 and 5 were very consistent with those of 2 and 3, respectively, which meant that these two pairs of epimers shared the same skeletal structure. Correspondingly, in the 13C NMR spectrum, a downfield shift of C-3 (Δδ = 1.9 and 1.7 ppm, respectively) and an upfield shift of C-2′ (Δδ = 5.3 and 5.5 ppm, respectively) were shown, which suggested that the additional hydroxyl group was connected to N-1. Thus, the basic scaffold of this pair of epimers could be easily identified. The molecular formula C14H24N2O4 of 6 and 7, namely, Conflamide F and Conflamide G, were assigned by HRESIMS, which were the isomers of 2 and 3. Analysis of NMR data revealed that the chemical shift of C-3 in 6 and 7 shifted to a higher field (δC 140.4; 140.8) as well as that of C-2 shifted to a lower field (δC 167.2; 166.6), compared to compounds 2 and 3, respectively, which demonstrated the fragment of αhydrozone acid in these compounds. Simultaneously, the mirror symmetry of their ECD spectra showed that 6 and 7 were a pair of epimers, and the absolute configurations of them were also confirmed by calculated ECD. Conflamides H (8) and I (9) were isolated as minor constituents, which possessed the same molecular formula C14H24N2O5, one more oxygen atom than 6 and 7, as supported by the HRESIMS data. The experimental ECD curves of 8 and 9 were almost coinciding with those of 6 and 7,

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CONCLUSIONS In summary, a series of novel natural products with sixmembered 1,2,5-oxadiazinan-4-one and 1,3,4-oxadiazinan-6one heterocyclic ring were isolated. They occurred as pairs of epimers which could be separated on a chiral analytical HPLC column. Their structures and absolute configurations were elucidated and determined by ECD calculations, syntheses of certain structural fragments and 13C NMR calculation. All the compounds were investigated for their in vitro immunomodulatory effect on BALB/c mice T and B lymphocyte proliferation. 11 Compounds 4 and 5 exhibited potent inhibition activity against the LPS-induced proliferation of B lymphocyte cell with IC50 values as 1.48, 5.71 μM, respectively (Table 5). Others displayed poor inhibition. The results 10160


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(m) (m), 1.63 (m) (t, 7.0) (d, 7.0) (m) (m), 1.48 (m) (t, 7.0) (d, 7.1) (m) (t, 7.2)

Table 3. 13C NMR (150 MHz) Data in CDCl3 of 2-8

(m) (m), 1.62 (m) (t, 7.0) (d, 7.0) (m) (m), 1.34 (m) (t, 7.0) (d, 7.1) (m) (t, 7.2) 7.05(s) 3.03 (m) 1.88 (m), 1.66 (m) 0.88 (t, 7.3) 1.25 (d, 6.9) 2.68 (m) 1.24 (m), 1.03 (m) 0.93 (t, 7.3) 1.01 (d, 6.8) 4.43−4.08 (m) 1.30 (t, 7.0) 7.62 (s) 3.03−2.90 (m) 2.00−1.88 (m), 1.67−1.56 (m) 0.86 (t, 7.5) 1.24 (d, 7.1) 2.68 (m) 1.51 (m), 1.15−1.05 (m) 1.01 (t, 7.4) 0.78 (d, 6.7) 4.39−4.20 (m) 1.29 (t, 7.1)

no.

2

3

4

5

6

7

8

2 3 4 5 6 7 1′ 2′ 3′ 4′ 5′ 6′ 1″ 2″

154.5 161.3 35.2 29.5 11.7 18.8 169.2 92.4 39.9 22.9 11.8 12.1 62.7 14.2

154.2 161.1 34.5 27.7 11.1 16.0 169.3 92.3 40.0 22.7 12.4 11.9 62.7 14.1

153.0 159.4 35.6 26.0 11.8 18.7 167.9 97.7 39.0 22.8 12.1 13.3 62.8 14.1

152.8 159.4 34.8 27.7 11.0 16.2 167.8 97.8 38.9 23.9 12.3 12.5 62.8 14.1

167.2 140.4 30.9 25.0 12.3 15.1 164.8 91.3 38.0 24.0 12.1 10.7 63.6 13.9

166.6 140.8 31.1 25.5 12.4 15.5 164.8 91.4 37.9 21.1 11.3 13.2 63.8 14.1

166.2 141.4 31.2 24.9 12.3 15.3 162.7 94.5 37.1 23.6 12.7 11.3 63.9 13.9

Figure 5. Chiral separation of conflamides B−I on amylose carbamate. Eluent: i-propanol/hexane; 2-3 and 6-7 (15:85); 4-5 (10:90); and 8-9 (16:84).

(m) (m), 1.51 (m) (t, 7.9) (d, 7.8) (m) (m), 1.43 (m) (t, 7.9) (d, 7.9) (m) (t, 7.0) 2.90 1.77 0.91 1.12 2.38 1.81 0.99 1.16 4.28 1.30 (s) (m) (m), 1.37 (m) (t, 7.5) (d, 7.8) (m) (m), 1.15 (m) (d, 7.6) (t, 7.6) (m) (t, 7.0)

Figure 6. Experimental ECD spectra of compounds 1−9.

indicated that the presence of the oxidized α-oxime-amide ketal was crucial for the immunosuppressive activity of this class of compounds. Heterocyclic molecules are well-known as bioactive compounds. Heterocyclic moieties provide extra binding sites to interact with a variety of enzymes and receptors in biological systems.12 The discovery of this new type of natural hetereocyclic compounds provides new possibilities to explore new immunsuppresants by inhibiting B cell proliferation from natural sources.

(s) (m) (m), 1.48 (m) (t, 7.5) (d, 7.8) (m) (m), 1.16 (m) (d, 7.6) (t, 7.6) (m) (t, 7.1)

7.05 3.00 1.66 0.86 1.16 2.15 1.49 1.07 0.97 4.26 1.30

3

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7.27 2.91 1.77 0.91 1.10 2.15 1.80 0.98 0.97 4.25 1.29

2

EXPERIMENTAL SECTION

General Experimental Procedures. UV−vis spectra were tested using a Shimadzu UV2401PC spectrometer (Shimadzu, Kyoto, Japan). Optical rotations (OR) were obtained on a JASCO P-1020

1 4 5 6 7 3′ 4′ 5′ 6′ 1″ 2″

no.

Table 2. 1H NMR (600 MHz) Data in CDCl3 of 2-8

4

3.00 1.65 0.85 1.19 2.34 1.64 0.98 1.16 4.28 1.30

(m) (m), 1.40 (m) (t, 7.9) (d, 7.8) (m) (m), 1.48 (m) (t, 7.9) (d, 7.9) (q, 7.4) (t, 7.2)

7 5

6

3.02 1.90 0.85 1.23 2.67 1.83 1.05 0.83 4.32 1.30

8

3.01 2.01 0.87 1.26 2.70 1.90 1.03 0.83 4.33 1.32

9


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Figure 7. (A) Regression analysis of calculated versus experimental 13C NMR chemical shifts of 2; linear fitting was drawn as a line; and (B) relative chemical shift errors between experimental and scaled 13C NMR for 2.

Table 4. Fitting Degree between Calculated

13

C NMR Chemical Shifts and Corresponding Experimental Chemical Shifts

[a]

Calculated 13C NMR chemical shifts of the compounds. [b]Experimental 13C NMR chemical shifts of the corresponding compound. [c] Coefficient of determination between the calculated 13C NMR chemical shifts and the corresponding experimental shifts. [d]Root-mean-square deviation between the calculated 13C NMR chemical shifts and the corresponding experimental shifts; the close R2 is to 1, and the closer RMSD is to 0, the more consistent the structure of the compound.

Scheme 3. Proposed Biosynthetic Pathway of 1−9

digital polarimeter (Horiba, Kyoto, Japan). CD spectra were recorded on an Applied Photophysics Chirascan Circular Dichroism Spectrometer (Applied Photophysics Limited, Leatherhead, Surrey, U.K.). IR spectra were obtained using a Bruker Tensor 27 FT-IR spectrometer (Bruker Optics, Inc., Billerica, MA) with KBr pellets. HR ESI-MS were recorded on an Agilent 6200 Q-TOF MS system (Agilent Technologies, Santa Clara, CA, U.S.A.). NMR spectra were measured on a Bruker AvanceIII 600 MHz spectrometer and DPX400 MHz (Bruker Biospin GmbH, Karlsruhe, Germany). Microwave irradiation reactions were carried out in a CEM Discover SP system. Sephadex LH-20 (Amersham Biosciences, Sweden) and Silica gel (200−300 mesh, Qingdao Haiyang Chemical Co., Ltd., P. R. China) were used for column chromatography (CC). Medium-pressure liquid chromatography (MPLC) was conducted on a Büchi Sepacore

System equipped with pump manager C-615, pump modules C-605 and fraction collector C-660 (Büchi Labortechnik AG, Switzerland), and columns packed with Chromatorex C-18 (40−75 μm, Fuji Silysia Chemical Ltd., Japan). Chiral phase HPLC analysis/preparation were conducted on liquid chromatography (an Agilent 1100) system equipped with a Diacel CHIRAL-PAK AS-H column (particle size 5 μm, dimensions 250 × 4.6 mm2). Preparative HPLC was performed on an Agilent 1260 liquid chromatography system equipped with two types of Zorbax SB-C18 columns (150 × 21.2 mm2 and 150 × 9.4 mm2, particle size 5 μm). Concanavalin A (Con A), lipopolysaccharide (LPS, Escherichia coli 055:B5), CCK-8: WST-8 [2-(2-methoxy-4nitrophenyl)-3-(4nitrophenyl)-5-(2, 4-disulfophenyl)-2H-tetrazolium, monosodium salt], and RPMI 1640 medium were purchased from GibcoBRL, Life Technologies (U.S.A.). Fetal bovine serum (FBS) 10162


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(MeOH) λmax (logε) 209 (3.70); IR (KBr) νmax 3473, 3332, 1666, 1459, 988 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C6H12N2O2Na: 167.0791; found 167.0792. Conflamide B (2). Yellow oil; [α]20D + 90.3 (c 0.01, MeOH); 1H and 13C NMR (600 MHz, CDCl3) see Tables 2 and 3; UV (MeOH) λmax (logε) 205 (3.71); CD (MeOH, Δε) λmax 207 (−45.26), 243 (+29.93); IR (KBr) νmax 3200, 2971, 1742, 1696, 1461, 1261 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ m/z calcd for C14H24N2O4Na, 307.1628; found 307.1630. Conflamide C (3). Yellow oil; [α]20D − 74.3 (c 0.005, MeOH); 1H and 13C NMR (600 MHz, CDCl3) see Tables 2 and 3; UV (MeOH) λmax (logε) 205 (3.57); CD (MeOH, Δε) λmax 207 (+48.73), 242 (−29.36); IR (KBr) νmax 3200, 2971, 1742, 1696, 1461, 1261 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ m/z calcd for C14H24N2O4Na, 307.1628; found 307.1636. Conflamide D (4). Yellow oil; [α]20D + 48.9 (c 0.058, MeOH); 1H and 13C NMR (600 MHz, CDCl3) see Tables 2 and 3; UV (MeOH) λmax (logε) 209 (3.60); CD (MeOH, Δε) λmax 207 (−45.28), 246 (+30.68); IR (KBr) νmax 3440, 2970, 1740, 1632, 575 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ m/z calcd for C14H24N2O5Na, 323.1577; found 323.1579. Conflamide E (5). Yellow oil; [α]20D − 29.4 (c 0.035, MeOH); 1H and 13C NMR (600 MHz, CDCl3) see Tables 2 and 3; UV (MeOH) λmax (logε) 209 (3.56); CD (MeOH, Δε) λmax 206 (+43.71), 241 (−29.06); IR (KBr) νmax 3440, 2970, 1740, 1632, 575 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C14H24N2O5Na, 323.1577; found 323.1579. Conflamide F (6). Yellow oil; [α]20D + 2.3 (c 0.17, MeOH); 1H and 13C NMR (600 MHz, CDCl3) see Tables 2 and 3; UV (MeOH) λmax (logε) 252 nm (3.17); CD (MeOH, Δε) λmax 224 (−18.99), 251 (+19.08); IR (KBr) νmax 3430, 2929, 1717, 1570, 1386, 1262 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ m/z calcd for C14H24N2O4Na, 307.1628; found 307.1632. Conflamide G (7). Yellow oil; [α]20D − 92.0 (c 0.08, MeOH); 1H and 13C NMR (600 MHz, CDCl3) see Tables 2 and 3; UV (MeOH) λmax (logε) 251 nm (4.00); CD (MeOH, Δε) λmax 225 (+27.74), 248 (−23.87); IR (KBr) νmax 3219, 2968, 1753, 1717, 1570, 1386, 1250 cm −1; HRMS (ESI-TOF) m/z [M + Na]+ m/z calcd for C14H24N2O4Na, 307.1628; found 307.1630. Conflamide H (8). Yellow oil; [α]20D + 54.0 (c 0.05, MeOH); 1H and 13C NMR (600 MHz, CDCl3) see Tables 2 and 3; UV (MeOH) λmax (logε) 255 (3.65); CD (MeOH, Δε) λmax 224 (−12.85), 250 (+27.30); IR (KBr) νmax 3129, 2971, 1746, 1679, 1259 cm−1; HRMS (ESI-TOF) m/z [M − H]− calcd [C14H23N2O5]−, 299.1607; found 299.1600. Conflamide I (9). Yellow oil; [α]20D − 19.3 (c 0.008, MeOH); UV (MeOH) λmax (logε) 255 (3.70); CD (MeOH, Δε) λmax 226 (+16.32), 252 (−31.77); IR (KBr) νmax 3126, 2971, 1748, 1678, 1262 cm −1 ; HRMS (ESI-TOF) m/z [M − H] − m/z calcd for [C14H23N2O5]−, 299.1607; found 299.1612. General Procedure for the Rearrangement Reaction of Conflamide A. Preparation of Silica Sulfate. Chlorosulfonic acid (5.83 g, 0.05 mol) was added dropwise to the mixture of silica gel/ CH2Cl2 (10g/50 mL) over a period of 30 min, and stirred at room temperature. HCl gas was evolved from flask immediately. The mixture was stirred for 30 min at room temperature after the addition was completed. Then the solvent was evaporated off under reduced pressure to give the white solid, which was stored in a desiccator until use. To a round-bottomed flask (10 mL) containing 1 (14.4 mg, 0.1 mmol) and acetone (4 mL), the right amounts of silica sulfate was added. Then the flask was transferred into the modified microwave oven fitted with a condenser. The mixture was subjected to microwave irradiation at 80 °C and last for 6 min then filtered, and concentrated under reduced pressure to provide A-1 as yellow oil, yield 100%. 1H NMR (400 MHz, CD3OD) δ = 2.97 (m, 1H), 1.92 (m, 1H), 1.64 (m, 1H), 1.57 (s, 3H), 1.26 (d, J = 7.10 Hz, 3H), 0.87 (t, J = 7.5 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ = 165.3, 141.4, 85.8, 32.3, 26.6, 26.3, 26.2, 15.7, 12.7. HRMS (ESI-TOF) m/z [M + H]+calcd C9H16N2O2Na, 207.1109; found 207.1114.

Table 5. Immunosuppressive Tests of the Compounds ConA-induced T-cell proliferation

LPS-induced B-cell proliferation

compd

CC50 (μM)

IC50 (μM)

SIa

IC50 (μM)

SIa

1 2 3 4 5 6 7 8 CsA

>160 97.16 176.10 65.51 136.80 530.70 >400 414.20 4.63

>200 115.80 149.40 6.61 10.67 >200 >200 >200 0.02

0.84 1.18 9.91 12.82 − − − 189.43

>200 24.36 46.97 1.48 5.71 443.70 212.20 47.28 0.77

3.99 3.75 44.26 23.97 1.20 − 8.76 5.99

a

SI (the selectivity index) is determined as the ratio of the concentration of the compound that reduced cell viability to 50% (CC50) to the concentration of the compound needed to inhibit the proliferation by 50% relative to the control value (IC50). “−” stands for inactive. was bought from HyClone Laboratories (Utah, U.S.A.). [3H]Thymidine (10 μ Ci mL−1) was acquired from the Shanghai Institute of Atomic Energy (SIAE). Female BALB/c mice (18−20g) were provided from Shanghai Experimental Animal Center and they were housed in specific conditions (12 h dark/12 h light photoperiod, 55% ± 5% relative humidity, 22 ± 1 °C). All experimental contact and husbandry were made with the mice maintained specific pathogen-free conditions. All experiments were performed following the NIH Guidelines for Care and Use of Laboratory Animals and authorized by the Bioethics Committee of Shanghai Institute of Materia Medica. Fungal Materials. The fresh fruiting bodies of Albatrellus confluens were obtained from Hutiao Gorge in southwestern China, Yunnan province, in August 2012 and identified by Mr. Li Zhenghui, South-Central University for Natioanalities. A voucher specimen (No. 20120815A) was deposited at the KUN, the Chinese Academy of Sciences. Extraction and Isolation. The air-dried and powdered fruiting bodies of Albatrellus confluens (2.5 kg) were soaked with 95% ethanol for three years. The extract was evaporated under reduced pressure and partitioned between water and ethyl acetate for four times to give a crude extract of ethyl acetate (25.0 g). The crude extract was performed to normal CC with a stepwise gradient of CHCl3/MeOH [v/v 100:0 (600 mL) → 95:5 (400 mL) → 90:10 (300 mL) → 85:15 (300 mL) → 80:20 (200 mL) → 70:30 (200 mL) → 60:40 (100 mL) → 50:50 (100 mL) → 30:70 (100 mL) → 0:100 (150 mL)] to afford 16 fractions (A−P). Fraction C (2.2 g) was subject to mediumpressure liquid chromatography (MPLC) with a gradient solvent system of MeOH/H2O (v/v 20:80−100:0, 25 mL·min−1, 9 h) to obtain 20 subfractions (C1−C20). Subfraction C9 (150 mg) was followed by Sephadex LH-20 (MeOH) to give 12 subfractions (C9−1 to C9−12). C9−4 was further purified by prep-HPLC to yield compound 1 (5.5 mg, MeCN−H2O: 20%, 16 min, 10 mL·min−1), compounds 2/3 (8.4 mg, MeCN−H2O: 22%, 20 min, 10 mL·min−1), 4/5 (6.5 mg, MeCN−H2O: 30%, 10 mL·min−1), 6/7 (9.9 mg, MeCN−H2O: 25%, 10 mL·min−1), and 8/9 (3.6 mg, MeCN−H2O: 32%, 10 mL·min−1). Compounds 2−9 were further purified by chiral column (2, 3.9 mg, yield 0.156‰, tR = 7 min; 3, 3.2 mg, yield 0.128‰, tR = 14 min, n-hexane-isopropanol: 85:15, 1 mL·min−1); (4, 2.2 mg, yield 0.088‰, tR = 8 min; 5, 3.1 mg, yield 0.124‰, tR = 20 min, n-hexane-isopropanol: 90:10, 1 mL·min−1); (7, 2.9 mg, yield 0.116‰, tR = 5 min; 6, 6.1 mg, yield 0.244‰, tR = 21 min, n-hexaneisopropanol: 85:15, 1 mL·min−1); (9, 0.3 mg, yield 0.012‰, tR = 10 min; 8, 2.5 mg, yield 0.1‰, tR = 15 min, n-hexane-isopropanol: 84:16, 1 mL·min−1). Additionally, compound 1 (2.5 g, yield 10%) was obtained from every subfraction. Conflamide A (1). White powder; [α]20D + 0.3 (c 0.17, MeOH); 1 H and 13C NMR (600 MHz, methanol-d4) see Table 1; UV 10163


Article

The Journal of Organic Chemistry We also tried to have other solvents like methanol, ethyl acetate, tetrahydrofuran to complete this reaction but we didn’t get a satisfied result, which indicated that acetone seemed to be the optimal solvent. General Procedure for the Synthesis of LB-1.8a To a roundbottom flask containing anhydrous methanol (14 mL), SOCl2 (2.8 mL) was added in −15 °C and kept in 0 °C for 1 h then put Lisoleucine (1.645g, 12.56 mmol) into the solvent and refluxed for 3 h. The mixture was concentrated under reduced pressure to provide LB1 as a yellow oil; 100% yield. LB-1: 1H NMR (400 MHz, CD3OD) δ = 4.02 (m, 1H), 3.80 (s, 3H), 2.07 (m, 1H), 1.54 (m, 1H), 1.35 (m, 1H), 1.01 (d, J = 7.2 Hz, 3H), 0.94 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ = 170.1, 57.0, 53.7, 37.5, 26.9, 15.6, 12.2. HRMS (ESI-TOF) m/z [M + Na]+ m/z calcd for C7H15NO2Na, 168.1000; found 168.1002. General Procedure for the Synthesis of LB-2.8b To a roundbottom flask containing L-isoleucine methyl ester LB-1 (14.5 mg, 0.1 mmol) and NaHCO3 (130 mg, 1.5 mmol) in H2O (10 mL), oxone (310 mg, 0.5 mmol) was added. After stirring at 25 °C for 1 h, the reaction mixture was extracted with CH2Cl2 (15 mL × 3). The combined organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (30−40% EtOAc/n-hexane) to provide LB-2 as a yellow oil; 90% yield. 1H NMR (400 MHz, CD3OD) δ = 3.77 (s, 3H), 1.73 (m, 1H), 1.54 (m, 1H), 1.30 (m, 1H), 1.16 (d, J = 7.18 Hz, 3H), 0.85 (t, J = 7.11 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ = 165.9, 156.7, 52.5, 33.7, 27.3, 17.0, 12.8. HRMS (ESITOF) m/z [M + Na]+ m/z calcd for C7H13NO3Na, 182.0793; found 182.0794. General Procedure for the Synthesis of LB-3.8c To a roundbottom flask containing LB-2 (15.9 mg, 0.1 mmol), NH4Cl (5.35 mg, 0.1 mmol), and NH4OH (10 mL) were added. After stirring at 25 °C for 24 h, the reaction mixture was extracted with EtOAc (15 mL × 3). The combined organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by HPLC (15−20% acetonitrile/H2O, 6 min) to provide LB3 as a white powder; 90% yield. (yield), [α]20D + 3.1 (c 0.19, MeOH); 1 H NMR (400 MHz, CD3OD) δ = 3.24 (m, 1H), 1.86 (m, 1H), 1.55 (m, 1H), 1.19 (d, J = 7.1 Hz, 3H), 0.85 (t, J = 7.5 Hz, 3H);13C NMR (100 MHz, CD3OD) δ = 169.1, 157.4, 33.5, 27.3, 17.1, 12.9. HRMS (ESI-TOF) m/z [M - H]− m/z calcd for [C6H11N2O2]−, 143.0826; found 143.0825. DB-3 (yellow oil, three steps 39% yield), [α]20D − 2.0 (c 0.19, MeOH); 1H NMR (400 MHz, CD3OD) δ = 3.24 (m, 1H), 1.86 (m, 1H), 1.55 (m, 1H), 1.19 (d, J = 7.1 Hz, 3H), 0.85 (t, J = 7.5 Hz, 3H);13C NMR (100 MHz, CD3OD) δ = 169.1, 157.4, 33.5, 27.3, 17.1, 12.9. HRMS (ESI-TOF) m/z [M - H]− m/z calcd for [C6H11N2O2]−, 143.0826; found 143.0825. LDB-3 (yellow oil, three steps 62% yield), [α]20D +1.3 (c 0.19, MeOH); 1H NMR (400 MHz, CD3OD) δ = 3.24 (m, 1H), 1.86 (m, 1H), 1.55 (m, 1H), 1.19 (d, J = 7.1 Hz, 3H), 0.85 (t, J = 7.5 Hz, 3H);13C NMR (100 MHz, CD3OD) δ = 169.1, 157.4, 33.5, 27.3, 17.1, 12.9. HRMS (ESI-TOF) m/z [M − H]− m/z calcd for [C6H11N2O2]−, 143.0826; found 143.0825. Immunosuppressive Activities Assay. Preparation of Spleen Cells from Mice. Female BALB/c mice were sacrificed by cervical dislocation, and the spleens were removed aseptically. Mononuclear cell suspensions were prepared after cell debris, and clumps were removed. Erythrocytes were depleted with ammonium chloride buffer solution. Lymphocytes were washed and resuspended in RPMI 1640 medium supplemented with 10% FBS, penicillin (100 U mL−1), and streptomycin (100 mg mL−1). Cytotoxicity Assay. Cytotoxicity was tested with Cell Counting Kit-8 (CCK-8) assay. Briefly, fresh spleen cells were gained from female BALB/c mice (18−20g). Spleen cells (1 × 106 cells) were seeded in triplicate in 96-well flat plates and cultured at 37 °C for 48 h in 96-well flat plates, in the presence or absence of various concentrations of compounds, in a humidified and 5% CO2containing incubator. A certain amount of CCK-8 was added to each well at the final 8−10 h of culture. To the end of the culture, we measured the OD values with microplate reader (Bio Rad 650) at 450 nm. Cyclosporin A (CsA) an immunosuppressive agent, was used as positive compound with definite activity, and the OD values from

medium only culture were used as background. The cytotoxicity of each compound was expressed as the concentration of compound that reduced cell viability to 50% (CC50). T cell and B Cell Function Assay. Fresh spleen cells were obtained from female BALB/c mice (18−20g). The 5 × 105 spleen cells were cultured at the same conditions as those mentioned above. The cultures, in the presence or absence of various concentrations of compounds, were stimulated with 5 μg mL−1 of ConA or 10 μg mL−1 of LPS to induce T cells or B cells proliferative responses, respectively. Proliferation was assessed in terms of uptake of [3H]-thymidine during 8 h of pulsing with 25 μL/well of [3H]-thymidine, and then cells will be harvested onto glass fiber filters. The incorporated radioactivity was counted using a Beta scintillation counter (MicroBeta Trilux, PerkinElmer Life Sciences). Cells treated without any stimuli were used as negative control. The immunosuppressive activity of each compound was expressed as the concentration of compound that inhibited ConA-induced T cell proliferation or LPS-induced B cell proliferation to 50% (IC50) of the control value. Both the cytotoxicity and proliferation assessment repeated twice. Computation Methods. ECD Calculation. Conformation search based on molecular mechanics with MMFF94S force fields were performed for all isomers and gave corresponding stable conformers with distributions higher than 1%, respectively.9b,c All these conformers were further optimized by the density functional theory method at the B3LYP/6-31G (d,p) level by Gaussian 09 program package.9d The ECDs were calculated using CAM-B3LYP/6-311+G (d,p) level in gas phase on B3LYP/6-31G (d,p). The calculated ECD curves and weighted ECD were all generated using SpecDis 1.60, respectively.9e,f 13 C NMR Calculation. All the conformers were further optimized by the density functional theory method at the mPW1PW91/6-311+ +g (2d,2p) level in CHCl3 with PCM model in Gaussian 09 program package, led to predominant conformers within a 2.5 kcal/mol energy threshold from global minimum. Gauge-Independent Atomic Orbital (GIAO) calculations of 13C NMR of the conformers were accomplished by density functional theory (DFT) at mPW1PW91/ 6-311++g (2d,2p) level in CHCl3 with PCM model. The 13C NMR chemical shift of TMS was calculated in the same level and used as reference. The calculated NMR data of these conformers were averaged according to the Boltzmann distribution theory and their relative Gibbs free energy. Compared to the experimental data, linear correlation coefficients (R2) and root-mean-square deviation (RMSD) were calculated for evaluation of the results.6

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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.8b01420.

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Spectroscopic data including 1D et al., spectroscopic data including 1D and 2D NMR, HRMS, and computational details of 1−9 (PDF) Optimized at the B3LYP/6-31g(d,p) level in gas phase (ECD); optimized at the mPW1PW91/6-311++g(2d,2p) level in CHCl3 with PCM model (NMR) (PDF)

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (J.-P.Z.) *E-mail: [email protected] (T.F.) *E-mail: [email protected] (J.-K.L.) ORCID

Heping Chen: 0000-0003-0416-9535 Zhenghui Li: 0000-0003-1284-0288 Tao Feng: 0000-0002-1977-9857 10164


Article

The Journal of Organic Chemistry Notes

E.; De Cesare, L.; Fattorusso, C.; Giannini, G.; Persico, M.; Petrella, A.; Rondinelli, F.; Rodriquez, M.; Russo, A.; Taddei, M. Oxime Amides as a Novel Zinc Binding Group in Histone Deacetylase Inhibitors: Synthesis, Biological Activity, and Computational Evaluation. J. Med. Chem. 2011, 54, 2165−2182. (d) Fiedler, W.; Faust, G.; Carstens, E.; Fü rst, H. Zur Darstellung tetraquaternärer BisThioäther. J. Prakt. Chem. 1963, 21, 140−146. (e) Igarashi, M.; Midorikawa, H. Syntheses of α-Keto Amides and Acids from Ethyl Alkylidenecyanoacetates. J. Org. Chem. 1963, 28, 3088−3092. (9) (a) Zhang, S. B.; Li, Z. H.; Stadler, M.; Chen, H. P.; Huang, Y.; Gan, X. Q.; Feng, T.; Liu, J. K. Lanostane triterpenoids from Tricholoma pardinum with NO production Inhibitory and Cytotoxic Activities. Phytochemistry 2018, 152, 105−112. (b) Goto, H.; Osawa, E. Corner Flapping: a Simple and Fast Algorithm for Exhaustive Generation of Ring Conformations. J. Am. Chem. Soc. 1989, 111, 8950−8951. (c) Goto, H.; Osawa, E. An Efficient Algorithm for Searching Low-energy Conformers of Cyclic and Acyclic Molecules. J. Chem. Soc., Perkin Trans. 2 1993, 2, 187−198. (d) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Keith, T.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J.. Gaussian 09, revision D. 01: Gaussian, Inc., Wallingford CT. 2010. (e) Bruhn, T.; Schaumlöffel, A.; Hemberger, Y.; Bringmann, G. S. University of Wuerzburg, (Germany) Version 1.60, 2012. (f) Zhang, S. B.; Huang, Y.; He, S. J.; Chen, H. P.; Li, Z. H.; Wu, B.; Zuo, J. P.; Feng, T.; Liu, J. K. Albatredine A and B, a pair of epimers with Unusual Natrural Hererocylic Skeletons from Edible Mushroom Albatrellus confluens. RSC Adv. 2018, 8, 23914−23918. (10) Wolinski, K.; Hinton, J. F.; Pulay, P. Efficient Implementation of the Gauge-Independent Atomic Orbital Method for NMR Chemical Shift Calculations. J. Am. Chem. Soc. 1990, 112, 8251−8260. (11) Fan, Y. Y.; Gan, L. S.; Liu, H. C.; Li, H.; Xu, C. H.; Zuo, J. P.; Ding, J.; Yue, J. M. Phainanolide A, Highly Modified and Oxygenated Triterpenoid from Phyllanthus hainanensis. Org. Lett. 2017, 19, 4580− 4583. (12) (a) Zhou, C.-H.; Wang, Y. Recent Researches in Triazole Compounds as Medicinal Drugs. Curr. Med. Chem. 2012, 19, 239− 280. (b) Majeed, R.; Sangwan, P. L.; Chinthakindi, P. K.; Khan, I.; Dangroo, N. A.; Thota, N.; Hamid, A.; Sharma, P. R.; Saxena, A. K.; Koul, S. Synthesis of 3-O-Propargylated Detulinic Acid and Its 1, 2, 3triazoles as Potential Apoptotic Agents. Eur. J. Med. Chem. 2013, 63, 782−792.

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by the National Key Research and Development Program of China (2017YFC1704007), National Natural Science Foundation of China (81773590, 81561148013), Thailand Research Fund (grant No. DBG5980002), the Key Projects of Technological Innovation of Hubei Province (No. 2016ACA138), and the Fundamental Research Funds for the Central University, South-Central University for Nationalities (CZP18005, CZQ17010, CZQ17008, CZT18014, and CZT18013). Computational resources used in this work were supported in part by the HPC Center, Kunming Institute of Botany, CAS, China and the Supercomputing Environment of Chinese Academy of Science (ScGrid).

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Heterocyclic Compounds from the Mushroom Albatrellus confluens

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