Asperversiamides, Linearly Fused Prenylated Indole Alkaloids from

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Asperversiamides, Linearly Fused Prenylated Indole Alkaloids from the Marine-Derived Fungus Aspergillus versicolor Huaqiang Li, Weiguang Sun, Mengyi Deng, Qun Zhou, Jianping Wang, Junjun Liu, Chunmei Chen, Changxing Qi, Zengwei Luo, Yongbo Xue, Hucheng Zhu, and Yonghui Zhang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01087 • Publication Date (Web): 17 Jul 2018 Downloaded from http://pubs.acs.org on July 17, 2018

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Asperversiamides, Linearly Fused Prenylated Indole Alkaloids from the Marine-Derived Fungus Aspergillus versicolor Huaqiang Li,§ Weiguang Sun,§ Mengyi Deng,§ Qun Zhou, Jianping Wang, Junjun Liu, Chunmei Chen, Changxing Qi, Zengwei Luo, Yongbo Xue,* Hucheng Zhu,* and Yonghui Zhang* Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China


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ABSTRACT: Asperversiamides A−H (1−8), eight linearly fused prenylated indole alkaloids featuring an unusual pyrano[3,2-f]indole unit, were isolated from the marine-derived fungus Aspergillus versicolor. The structures and absolute configurations of these compounds were elucidated by extensive spectroscopic analyses, single-crystal X-ray diffraction, electronic circular dichroism (ECD) calculations and optical rotation (OR) calculations. The relative configuration of C-21 of iso-notoamide B was herein revised, and a new methodology for preliminarily determining if the relative configuration of the bicyclo[2.2.2]diazaoctane moiety of a spiro-bicyclo[2.2.2]diazaoctane-type indole alkaloid is syn or anti was developed. The anti-inflammatory activities of the isolated compounds were all tested, and of these compounds, 7 exhibited a potent inhibitory effect against iNOS with an IC50 value of 5.39 µM.



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Introduction Prenylated indole alkaloids, such as stephacidins,1 paraherquamides,2 notoamides,3 and brevianamides,4 which comprise one or two isoprenyl units in addition to tryptophan and proline moieties, are mostly produced by fungi from the genera Aspergillus and Penicillium. Due to their intriguing structures and appreciable biological activities,1,5 prenylated indole alkaloids have attracted considerable attention from natural product and organic chemists.6 Normally, the isoprenyl group is located at C-7 and is cyclized to form a dimethyldihydropyran ring with the hydroxy group

at

C-6,

and

we

define

these

prenylated

indole

alkaloids

with

pyrano[2,3-g]indole moieties as angularly fused alkaloids (Figure 1). To date, more than 100 compounds of this class have been reported.5,7 In contrast, compounds with the isoprenyl substituent located at C-5, which forms a pyrano[3,2-f]indole moiety, are uncommon, and we call these compounds linearly fused prenylated indole alkaloids (Figure 1). Linearly fused indole alkaloids are quite rare, and only five examples, namely, carneamides A–C, dihydrocarneamide A, and iso-notoamide B, have been previously reported.8

Figure 1. Two different fusion patterns of pyrane and indole rings. 1


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Figure 2. Structures of compounds 1−10. As part of our ongoing commitment to discover novel, structurally intriguing, and biologically active metabolites from fungi,9 Aspergillus versicolor, a fungus isolated from the mud of the South China Sea, was chemically investigated. A series of linearly fused prenylated indole alkaloids were isolated (Figure 2), and of these compounds, asperversiamides A–C and E (1–3 and 5) each contains a rare anti bicyclo[2.2.2]diazaoctane ring, and asperversiamide D (4) contains the analogous syn 2



ring (when the C21−C22 and C17−N13 bonds are cofacial, the ring is defined as “syn”, and when the C21−C22 and C17−N13 bonds are on opposite faces, the ring is considered “anti” (Figure S1)).3c,10 Asperversiamide A (1) is the first linearly fused indole alkaloid found to have a rare fused-imine-containing pyrrole ring system. In addition, compounds 2 and 3 and compounds 4 and 5 are pairs of C-3 and C-21 epimers, respectively. Asperversiamide F (6) is the C-17 epimer of dihydrocarneamide A (9),11 and asperversiamide G (7) possesses an unusual Z-geometry of the double bond between C-10 and C-11. Based on the biosynthesis pathway, compound 8, possessing an isoprenyl unit at C-3, is a pivotal precursor of spiro-bicyclo[2.2.2]diazaoctane type indole alkaloids (2 and 3). Co-isolated deoxybrevianamide E (10)12 could serve as a precursor to a series of structurally related prenylated indole alkaloids by further modification (Scheme S1). Herein, the isolation, structural elucidation, and plausible biosynthetic pathway as well as biological evaluations of new compounds 1–8 are presented. Results and discussion Asperversiamide A (1), a white amorphous powder, was established to have a molecular formula of C26H29N3O4 by HRESITOFMS from the [M + H]+ ion at m/z 448.2232 (calcd for C26H30N3O4+, 448.2231). The IR absorption bands at 1703 and 1659 cm−1 indicated the presence of amide groups. The 1H NMR data of 1 (Table 1) included resonances of four olefinic protons (δH 7.17, s; 6.83, s; 6.43, d, J = 9.8 Hz; and 5.71, d, J = 9.8 Hz), two exchangeable protons (δH 7.11, s; and 8.75, s), and four methyl groups (δH 1.16, s; 1.18, s; 1.37, s; and 1.38, s) as well as signals attributable 3


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to five methylene moities and a methine group. The

13

C NMR data (Table 2)

displayed 26 carbon resonances, namely, four methyl carbons, five methylene carbons, an sp3 and four sp2 methine carbons, and twelve quaternary sp3 carbons including two oxygenated carbons, two in amide groups, and a resonance of unknown origin at δC 189.9. Taken together, the aforementioned data suggested that compound 1 is an indole diketopiperazine alkaloid.1,3a Further analyses of the 1H–1H COSY and HMBC spectra of 1 confirmed the presence of a bicyclo[2.2.2]diazaoctane core including a proline (E/F/G ring system, Figure 2). In view of the uncertainty of the origin of the carbon signal at δC 189.9 (carbonyl or double bond) and δC 80.1 (oxygenated or N-substituted), two possible substructures (1a and 1b, Figure 3) were deduced on the basis of the HMBC correlations from H-10 to C-2, C-3, and C-9; from H-21 to C-11, C-22 and C-23; and from H3-23 and H3-24 to C-2 and C-21. The proposed substructure (1a) included a unique azetidine unit that was found in the initial structure of taichunamide A.10c Recently,

the

structure

of

taichunamide

A

was

revised

to

have

a

fused-imine-containing pyrrole ring (1b) based on calculated 13C NMR and ECD data, and the revised structure was further confirmed by X-ray crystallographic analysis of taichunamide H, a diastereomer of taichunamide A.13 Given the 1H and 13C NMR data of 1 were similar to those of taichunamides A and H (Table S1), the presence of rings C and D in 1 was further refined based on the structures of taichunamides A and H. Thus, compound 1 was proposed to have a fused-imine-containing pyrrole ring (1b).

4



Figure 3. Two possible substructures (1a) and (1b) of compound 1. Interestingly, the singlet protons at δH 7.17 (H-4) and 6.83 (H-7) of 1 indicated the presence of a 1,2,4,5-tetrasubstituted benzene ring with two para-protons. The HMBC correlations from H3-28 and H3-29 to C-26 and C-27; from H-25 to C-4, C-5 (δC 118.7), C-6 (δC 153.5), and C-27; from H-26 to C-5; from H-4 to C-25; and from H-7 to C-5 and C-9 confirmed the presence of rings A and B and the linear fusion pattern in 1 (Figure 4). Furthermore, the crucial HMBC correlations from H-4 to C-3 and H-10 to C-9 established the connectivity of rings B and D through C-3, resembled taichunamides A and H.13 Thus, the planar structure of 1 was elucidated as shown.

Figure 4. Key 2D NMR correlations of compound 1.

5


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Exptl. for 1 Calcd. for 1 Calcd. for ent-1

20

∆ε (M-1cm-1)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


0

-20

200 225 250 275 300 325 350 375 400

Wavelength [nm]

Figure 5. Experimental and calculated ECD spectra of 1. The relative configuration of 1 was confirmed by the examination of its NOESY spectrum (Figure 4). The NOESY correlations of H-21/H-10a and H-21/H3-23 revealed these protons were cofacial and α-oriented. Accordingly, the NOESY correlations of H3-24/3-OH, 3-OH/H-10b, and H-10b/19-NH indicated that the 3-OH, 19-NH, and H3-24 groups were β-oriented. Thus, the relative configuration of 1 was determined. To determine the absolute configuration of 1, the calculated ECD were performed using time-dependent density functional theory (TD-DFT) at the B3LYP/6-31+g (d, p) level for 3R,11R,17R,21S (1) and 3S,11S,17S,21R (ent-1). The calculated curve of 1 fitted well with its experimental ECD spectrum (Figure 5), which confirmed the absolute configuration of 1 as 3R,11R,17R,21S. Asperversiamide B (2), isolated as colorless crystals, was found to have the chemical formula C26H29N3O4, which indicates 14 degrees of unsaturation, by a positive HRESITOFMS experiment. The 1H NMR data of 2 (Table 1) indicated two singlet aromatic protons (δH 7.09, H-4; and 6.19, H-7) and typical signals of a 6



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Z-configured double bond (δH 6.30, J = 9.8 Hz, H-25; 5.58, J = 9.8 Hz, H-26) that closely resembled those of 1, suggesting that 2 and 1 have the same benzopyran motif. The

1

H–1H

COSY

and

HMBC

spectra

confirmed

the

presence

of

a

bicyclo[2.2.2]diazaoctane ring. In the HMBC spectrum of 2, H3-23 and H3-24 showed correlations with C-3 rather than C-2, which suggested that 2 and notoamide B have the same fusion pattern, bearing a spiro[4.4]nonane ring system.3a Thus, the planar structure of 2 was established.

Figure 6. Key 2D NMR correlations of compounds 2 and 4. The NOESY correlations (Figure 6) of 19-NH/ H3-23 and H-4/H3-23 along with the interaction between H-21 and H3-24 indicated the α-orientation of 19-NH and β-orientation of H-21. According to the reports by Williams and co-workers, the Cotton effects (CEs) at 200−250 nm are due to the n−π* transition of the 7


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diketopiperazine amide bonds, which is diagnostic the absolute configuration of the bicyclo[2.2.2]diazaoctane ring system.4,14 In the case of compound 2, the characteristic positive CE at 223 nm (+25.9) and negative CE at 242 nm (−28.6) in the experimental ECD spectrum (Figure S3) suggested the absolute configuration of 2 was 3S,11S,17S,21R. The single-crystal X-ray diffraction analysis of 2 unambiguously confirmed its structure and absolute configuration (Figure 7).

Figure 7. ORTEP drawing of the X-ray crystal structures of compounds 2, 4, 8, and 9 (Displacement ellipsoids are drawn at the 30% probability level). A search using SciFinder indicated the elucidated structure of 2 was identical to that of iso-notoamide B.11 However, the NMR data of 2 and iso-notoamide B were substantially different, which suggested there was a mistake in the structural assignment of iso-notoamide B. After careful analysis of the NOESY spectrum of iso-notoamide B, the H-21 (δH 3.20)/19-NH (δH 9.08) cross-peak was observed, 8



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indicating that H-21 and 19-NH are cofacial and that the bicyclo[2.2.2]diazaoctane core was in a syn configuration. Therefore, iso-notoamide B was the C-21 epimer of 2, and its structure should be revised (Figure 8).

Figure 8. Structure of 2 and revised structure of iso-notoamide B.

To

identify

patterns

in

bicyclo[2.2.2]diazaoctanes, the

the

syn

or

anti

configurations

of

the

13

C NMR data of previously reported prenylated

indole alkaloids with spiro-bicyclo[2.2.2]diazaoctane core were thoroughly analyzed and summarized in Table S4 and Figures S4 and S5.15 We found that for the compounds in the anti-configuration, the ∆δ│C11-C21│ values (the deviation in chemical shifts of C-11 and C-21) are normally >14 ppm and the ∆δ│C21-C22│ values are 100 2 25.09 ± 2.21 16.58 ± 0.57 >100 3 23.72 ± 1.89 13.86 ± 1.22 >100 6 11.17 ± 0.54 5.39 ± 0.27 >100 7 MG132b 0.24 ± 0.01 0.17 ± 0.02 2.95 ± 0.15 a Data are reported as the mean ± SD, n = 3. bPositive control.

Figure 10. Low-energy binding conformations of compound 7 bound to iNOS generated by virtual ligand docking. Black and red balls indicate the hydrogen bonding and π-π interactions, respectively. Molecular docking studies between compound 7 and iNOS were performed to better understand their interaction.22 As shown in Figure 10, compound 7 adopted an extended conformation and fit well into the ligand binding site of mutant iNOS. In addition, hydrogen bonds were predicted between the carbonyl (C-12) and Asn115 and the carbonyl (C-18) and Gln257. Moreover, a possible π-π stacking interaction between the diketopiperazine or the ∆10 double bond and the HEME was also observed. The inhibitory activities and molecular docking results revealed that the planarity of the molecule is important for its binding capacity, as this conformation provides enough space for the two carbonyls to form strong hydrogen bonds with the HEME.

Conclusions 16



In summary, asperversiamides A–H (1–8), eight rare linearly fused prenylated indole alkaloids, were isolated from the marine-derived fungus A. versicolor. Asperversiamide A (1) represents the first linearly fused indole alkaloid bearing a rarely fused-imine-containing pyrrole ring system. Based on the structural revision of iso-notoamide B, an auxiliary methodology was developed as a tool to effectively distinguish the syn/anti configuration of the bicyclo-[2.2.2]diazaoctane moiety of prenylated indole alkaloids containing a spiro-bicyclo[2.2.2]diazaoctane carbon skeleton. Compound 7 exhibited considerable iNOS inhibitory activity, making this compound potentially relevant in the development of novel anti-inflammatory agents for the treatment of various inflammatory diseases and other related disorders. Because of the rarity of linearly fused prenylated indole alkaloids, the discovery of a series of this type enriches the chemical diversity of the family. Further investigations on the mode of action and biosynthesis of these prenylated indole alkaloids are in progress.

Experimental section General experimental procedures The NMR spectra were recorded on Bruker AM-400, 600, and 800 spectrometers (Bruker, Karlsruhe, Germany). The 1H and 13C NMR chemical shifts were referenced to the solvent or solvent impurity peaks for methanol-d4 (δH 3.31 and δC 49.0), CDCl3 (δH 7.26 and δC 77.0) and DMSO-d6 (δH 2.50 and δC 39.5). The UV, ECD, and FT-IR spectra were measured using a Perkin Elmer Lambda 35 UV spectrophotometer (PerkinElmer, Inc., Fremont, CA, USA), a JASCO-810 ECD spectrometer (JASCO Co., Ltd., Tokyo, Japan), and a Bruker Vertex 70 instrument (Bruker, Karlsruhe, Germany), respectively. Optical rotations were determined with an AUTOPOL IV-T 17


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Automatic polarimeter (Rudolph Research Analytical, Hackettstown, NJ, USA). HRESITOFMS data were obtained in the positive ion mode on a Thermo Fisher LTQ XL spectrometer (Thermo Fisher, Palo Alto, CA, USA). Crystal X-ray diffraction data were measured on a Rigaku XtaLAB PRO MM007HF (Rigaku, Tokyo, Japan). Semipreparative HPLC was carried out using an Agilent 1200 quaternary system with a UV detector, using a reversed-phase C18 column (5 µm, 10 × 250 mm, Welch Ultimate XB-C18). Column chromatography (CC) was performed using silica gel (100-200 and 200-300 mesh; Qingdao Marine Chemical Inc., China), ODS (50 µm, YMC, Kyoto, Japan), and Sephadex LH-20 (GE Healthcare Bio-Sciences AB, Sweden). Thin-layer chromatography (TLC) was performed on silica gel 60 F254 (Yantai Chemical Industry Research Institute, Yantai, China) and RP-C18 F254 plates (Merck, Germany). Fungal Material. The fungus Aspergillus versicolor was isolated from the mud of the South China Sea. The sequence data for this strain have been submitted to DDBJ/EMBL/GenBank under accession no. 2081031. A voucher sample has been deposited in the culture collection of Tongji Medical College, Huazhong University of Science and Technology, P. R. China. Fermentation and Isolation. The A. versicolor strain was cultured on potato dextrose agar (PDA) at 28°C for 7 days to prepare the seed culture. Then, the agar plugs were cut into small pieces and inoculated into 250 Erlenmeyer flasks (1 L), previously sterilized by autoclaving, each containing 200.0 g of rice and 160.0 mL of distilled water. All flasks were incubated at 28°C for 28 days. Following incubation, the growth of cells was stopped by adding 300 mL of 95% EtOH to each flask, and collected the culture with the rice in buckets. Then, soaked with 95% EtOH many times until the solvent was near colorless at room temperature. The culture was 18



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removed under reduced pressure to yield a brown extract and suspended in water (2 L) and then extracted with EtOAc (1:1) for three times. The EtOAc was removed under reduced pressure. The extracts (170.0 g) were subjected to a silica gel chromatography column (CC) eluting with PE/EtOAc (20:1–0:1) progressively to obtain six fractions (Fr. 1–Fr. 6). Fr.3 was further separated with by silica gel CC to yield four subfractions (Fr. 3.1–Fr. 3.4). The subfraction Fr. 3.2 was subjected to a Sephadex LH-20 (MeOH) to afford three parts (Fr. 3.2a–Fr. 3.2c). The second part (Fr. 3.2b) was chromatographed on ODS (MeOH–H2O, 30:70–100:0, v/v) to yield a mixture (1, 4, 9). The mixture was purified by repeated semi-preparative HPLC (MeCN–H2O, 40:60–60:40, v/v, 1h, 2 ml/min) to yield 1 (7.6 mg, tR 25.5 min, 45:55, v/v, 2 ml/min), 4 (48.9 mg, tR 27.2 min, 45:55, v/v, 2 ml/min), and 9 (400 mg, tR 21.0 min, 40:60, v/v, 2 ml/min). Fr.4 was further separated by repeated silica gel CC to yield four subfractions (Fr. 4.1–Fr. 4.4). Fr. 4.2 and Fr. 4.3 was subjected by Sephadex LH-20 (MeOH), medium-pressure ODS, and silica gel chromatography columns alternately before purified by semi-preparative HPLC (MeCN-H2O, 40%–60%, t = 1 h, 2 ml/min). Then, six compounds were isolated: 2 (12.5 mg, tR 26.5 min, 48:52, v/v, 2 ml/min), 3 (1.1 mg, tR 21.5 min, 40:60, v/v, 2 ml/min), 5 (3.4 mg, tR 22.0 min, 40:60, v/v, 2 ml/min), 6 (18.7 mg, tR 23.0 min, 50:50, v/v, 2 ml/min), 7 (3.2 mg, tR 32.0 min, 50:50, v/v, 2 ml/min), 8 (20.5 mg, tR 13.4 min, 57:43, v/v, 2 ml/min), and 10 (5.1 mg, tR 30.0 min, 50:50, v/v, 2 ml/min). Asperversiamide A (1): C26H29N3O4; white amorphous powder; [α]25D –95.3 (c 0.28, MeOH); UV (MeOH) λmax (log ε) = 243 (4.46) and 338 (3.68) nm; IR (KBr) νmax 3419, 3260, 1702, 1659, 1461, 1261, 1161, 1111 cm-1; ECD (MeOH) λmax (∆ε) = 221 (+13.1), 246 (+15.5), and 268 (–22.7) nm; For 1H NMR (600 MHz) and

13

C NMR

(150 MHz) data, see Tables 1 and 2; HRESITOFMS [M + H]+ m/z 448.2232 (calcd. 19


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for C26H30N3O4+, 448.2231). Asperversiamide B (2): C26H29N3O4; colorless crystals; m.p. 198−199 °C; [α]25D – 10.9 (c 0.73, MeOH); UV (MeOH) λmax (log ε) 236 (4.54) and 315 (3.89) nm; IR (KBr) νmax 3434, 1693, 1400, 1274, 1202, 1139 cm−1; ECD (MeOH) λmax (∆ε) = 223 (+25.9), 243 (–28.7), and 266 (+0.6) nm; For 1H NMR (600 MHz) and 13C NMR (150 MHz) data, see Tables 1 and 2; HRESITOFMS [M + Na]+ m/z 470.2074 (calcd. for C26H29N3O4Na+, 470.2050). Asperversiamide C (3): C26H29N3O4; white amorphous powder; [α]25D +15.8 (c 0.10, MeOH); UV (MeOH) λmax (log ε) 236 (4.40) and 317 (3.77) nm; IR (KBr) νmax 3427, 1678, 1468, 1388, 1275, 1209, 1142, 1026 cm−1; ECD (MeOH) λmax (∆ε) = 223 (+11.5), 244 (–13.5), and 311 (+2.36) nm; For 1H NMR (800 MHz) and

13

C NMR

(200 MHz) data, see Tables 1 and 2; HRESITOFMS [M + Na]+ m/z 470.2064 (calcd. for C26H29N3O4Na+, 470.2050). Asperversiamide D (4): C26H29N3O3; colorless crystals; m.p. 198−199 °C; [α]25D +104.1 (c 0.34, MeOH); UV (MeOH) λmax (log ε) 236 (4.36) and 317 (3.79) nm; IR (KBr) νmax 3363, 1668, 1462, 1426, 1378, 1255, 1216, 1153, 1114 cm−1; ECD (MeOH) λmax (∆ε) = 203 (–4.58), 278 (+10.41), 239 (–2.15), and 257 (+2.45) nm; For 1H NMR (400 MHz) and 13C NMR (100 MHz) data, see Tables 1 and 2; HRESITOFMS [M + Na]+ m/z 454.2092 (calcd. for C26H29N3NaO3+, 454.2101). Asperversiamide E (5): C26H29N3O3; white amorphous powder; [α]25D +27.5 (c 0.20, MeOH); UV (MeOH) λmax (log ε) 232 (4.20) and 281 (3.93) nm; IR (KBr) νmax 3421, 1688, 1469, 1443, 1385, 1258, 1217, 1148, 1127 cm−1; ECD (MeOH) λmax (∆ε) = 207 (+0.81), 222 (+17.30), 240 (–4.78), and 256 (+10.71) nm; For 1H NMR (400 MHz) and

13

C NMR (100 MHz) data, see Tables 1 and 2; HRESITOFMS [M + H]+ m/z

432.2296 (calcd. for C26H30N3O3+, 432.2282). 20



Asperversiamide F (6): C26H31N3O3; white amorphous powder; [α]25D +91.2 (c 0.22, MeOH); UV (MeOH) λmax (log ε) 257 (4.77) and 330 (3.82) nm; IR (KBr) νmax 3434, 1693, 1628, 1490, 1400, 1333, 1274, 1202, 1139 cm−1; ECD (MeOH) λmax (∆ε) = 200 (+24.32), 215 (–19.44) and 259 (+37.38) nm; For 1H NMR (400 MHz) and 13C NMR (100 MHz) data, see Tables 1 and 2; HRESITOFMS [M + Na]+ m/z 456.2254 (calcd. for C26H31N3NaO3+, 456.2258). Asperversiamide G (7): C26H29N3O3; light yellow power; [α]25D –1.23 (c 0.24, MeOH); UV (MeOH) λmax (log ε) 253 (4.41) and 334 (3.98) nm; IR (KBr) νmax 3364, 1690, 1664, 1629, 1431, 1384, 1256, 1116 cm−1; ECD (MeOH) λmax (∆ε) = 221 (+33.28), 251 (–17.05), 297 (+3.97) and 356 (+5.71) nm; For 1H NMR (600 MHz) and

13

C NMR (150 MHz) data, see Tables 1 and 2; HRESITOFMS [M + H]+ m/z

432.2277 (calcd. for C26H30N3O3+, 432.2282). Asperversiamide H (8): C26H31N3O4; colorless cubic crystals; m.p. 201−202 °C; [α]25D +83.4 (c 0.55, MeOH); UV (MeOH) λmax (log ε) 237 (4.51), 316 (3.93); IR (KBr) νmax 3363, 3196, 2972, 2925, 2880, 1703, 1664, 1626, 1444, 1331, 1213, 1138 cm−1; ECD (MeOH) λmax (∆ε) = 200 (–37.46) and 232 (+38.70) nm; For 1H NMR (400 MHz) and 13C NMR (100 MHz) data, see Tables 1 and 2; HRESITOFMS [M + Na]+ m/z 472.2208 (calcd. for C26H31N3NaO4+, 472.2207). Dihydrocarneamide A (9): C26H31N3O3; colorless crystals; m.p. 201−202 °C; [α]25D –39.9 (c 0.38, MeOH); For 1H NMR (400 MHz) and 13C NMR (100 MHz) data, see Tables S3; HRESITOFMS [M + Na]+ m/z 456.2227 (calcd. for C26H31N3NaO3+, 456.2258). Deoxybrevianamide E (10): C21H25N3O2; white amorphous powder; [α]25D –45.9 (c 0.44, MeOH); 1H NMR (600 MHz, CDCl3) data: δH 8.06 (s, 1H, 19-NH), 7.48 (d, J = 7.9 Hz, 1H, H-4), 7.33 (d, J = 8.1 Hz, 1H, H-7), 7.17 (t, J = 7.6 Hz, 1H, H-6), 7.11 (t, 21


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J = 7.5 Hz, 1H, H-5), 6.14 (dd, J = 17.4, 10.6 Hz, 1H, H-21), 5.70 (s, 1H, 1-NH), 5.20 (brs, 1H, H-20b), 5.18 (d, J = 6.7 Hz, 1H, H-20a), 4.44 (dd, J = 11.9, 4.0 Hz, 1H, H-11), 4.07 (dd, J = 9.0, 6.9 Hz, 1H, H-17), 3.75 (dd, J = 15.3, 4.0 Hz, 1H, H-10b), 3.69 (dt, J = 11.9, 8.0 Hz, 1H, H-14b), 3.60 (ddd, J = 12.1, 9.0, 2.9 Hz, 1H, H-14a), 3.18 (dd, J = 15.3, 11.7 Hz, 1H, H-10a), 2.35 (m, 1H, H-16b), 2.12–2.02 (m, 2.5 Hz, 2H, H-15b and H-16a), 1.96–1.87 (m, 1H, H-15a), 1.56 (s, 6H, H3-23 and H3-24). HRESITOFMS [M + H]+ m/z 352.2025 (calcd. for C21H26N3O2+, 352.2020). X-ray Crystal Structure Analysis. Compounds 2, 4, 8, and 9 were crystallized by using the solvent vapor diffusion method. A suitable crystal was selected on a SuperNova, Dual, Cu at zero, AtlasS2 diffractometer. The crystal was kept at 100.01(10) K during data collection. Using Olex2, the structure was solved with the ShelXT. Structure solution program using Intrinsic Phasing refined with the ShelXL. Refinement package was measured by Least Squares minimisation.

The

crystallographic data for 2 (deposition no. CCDC 1812291), 4 (deposition no. CCDC 1813412), 8 (deposition no. CCDC 1585402), and 9 (deposition no. CCDC 1585404) have been deposited in the Cambridge Crystallographic Data Centre. Copies of the data can be obtained free of charge from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB21EZ, UK (fax: + 44-1223-336-033; or e-mail: [email protected]). Crystal Data for Asperversiamide B (2): C26H29N3O4·CH3OH, M = 479.56, a = 7.01728(18) Å, b = 8.2752(2) Å, c = 10.7566(3) Å, α = 93.959(2)°, β = 106.285(2)°, γ = 95.686(2)°, V = 593.55(3) Å3, T = 100.00(10) K, space group P1 (no. 1), Z = 1, µ (Cu Kα) = 0.756 mm-1, Dcalc = 1.342 g/cm3, 11144 reflections measured (8.608 ≤ 2Θ ≤ 147.014), 4395 unique (Rint = 0.0161, Rsigma = 0.0150) which were used in all calculations. The final R1 values were 0.0266 and wR2 values were 0.0711 (I > 2σ (I)). 22



The final R1 values were 0.0267 and wR(F2) values were 0.0711. The goodness of fit on F2 was 1.038. Flack parameter = 0.09(7). Crystal Data for Asperversiamide D (4): C26H29N3O3, M = 431.52, a = 11.02750(10) Å, b = 11.02750(10) Å, c = 38.1512(5) Å, α = 90°, β = 90°, γ = 90°, V = 4639.41(10) Å3, T = 100.00(10) K, space group P43212, Z = 8, µ (Cu Kα) = 0.653 mm−1, Dcalc = 1.236 g/cm3, 29747 reflections measured, (Rint = 0.0622, Rsigma = 0.0316). The final R1 values were 0.0420 and wR2 values were 0.1071 (I > 2σ (I)). The final R1 values were 0.0435 and wR(F2) values were 0.1083. The goodness of fit on F2 was 1.054. Flack parameter = -0.09(11). Crystal Data for Asperversiamide H (8): C26H31N3O4, M = 449.54, a = 8.14900 (10) Å, b = 9.85930 (10) Å, c = 28.6560 (2) Å, α = 90°, β = 90°, γ = 90°, V = 2302.32(4) Å3, T = 100.01(10) K, space group P212121, Z = 4, µ (Cu Kα) = 0.711 mm−1, Dcalc = 1.297 g/cm3,10122 reflections measured, and 4507 independent reflections (Rint = 0.0208, Rsigma = 0.0219). The final R1 values were 0.0738 and wR2 values were 0.1731 (I > 2σ (I)). The final R1 values were 0.0756 and wR(F2) values were 0.1749. The goodness of fit on F2 was 1.034. Flack parameter = 0.07(7). Crystal Data for Dihydrocarneamide A (9): C26H31N3O3, M = 433.54, a = 21.9246(7) Å, b = 15.7608(5) Å, c = 6.6049(2) Å, α = 90°, β = 90°, γ = 90°, V = 2282.32(13) Å3, T = 100.00(10) K, space group P212121, Z = 4, µ (Cu Kα) = 0.664 mm−1, Dcalc = 1.262 g/cm3, 14262 reflections measured, and 4495 independent reflections (Rint = 0.0403, Rsigma = 0.0371). The final R1 values were 0.0530 and wR2 values were 0.1627 (I > 2σ (I)). The final R1 values were 0.0556 and wR(F2) values were 0.1646. The goodness of fit on F2 was 1.033. Flack parameter = 0.06(15). Quantum mechanical calculation ECD Calculations of compound 1. The preliminary conformational distribution 23


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search was performed by Spartan'10 software (Wavefunction, Inc., Irvine, CA, USA) using the MMFF94S force field. The corresponding minimum geometries were further fully optimized with the Gaussian 03 (Gaussian, Wallingford, CT, USA) program package at the B3LYP/6-31G (d) computational level as frequency calculations. The obtained stable conformers were submitted to CD calculation by the TDDFT B3LYP/6-311+G(d) method. ECD spectra were generated using the program SpecDis 1.6 (University of Würzburg, Würzburg, Germany) and OriginPro 8.5 (OriginLab, Ltd., Northampton, MA, USA) from dipole-length rotational strengths by applying Gaussian band shapes with sigma = 0.19 eV. Optical rotation calculations of compound 6. Monte Carlo conformational searches were carried out by means of the Spartan’s 10 software using Merck Molecular Force Field (MMFF). The conformers with Boltzmann-population of over 5% were chosen for OR calculations, and then the conformers were initially optimized at B3LYP/6-31+g (d, p) level in MeOH using the CPCM polarizable conductor calculation model. The theoretical calculation of OR was conducted in MeOH using Time-dependent Density functional theory (TD-DFT) at the B3LYP/6-31+g (d, p) level for all conformers of compound 6a (11S,17R). ECD Calculations of compound 7. The conformations generated by BALLOON were subjected to semiempirical PM3 quantum mechanical geometry optimizations using the Gaussian 09 program. Duplicate conformations were identified and removed when the root-mean-square (RMS) distance was less than 0.5 Å for any two geometry-optimized conformations. The remaining conformations were further optimized at the B3LYP/6-31G(d) level in MeOH with the IEFPCM solvation model using Gaussian 09, and the duplicate conformations emerging after these calculations were removed according to the same RMS criteria above. The harmonic vibrational frequencies were calculated to confirm the stability of the final conformers. The electronic circular dichroism (ECD) spectrum were calculated for each conformer using the TDDFT methodology at the B3LYP/6-311++G(d,p)//B3LYP/6-31G(d) level with MeOH as solvent by the IEFPCM solvation model implemented in Gaussian 09 program. The ECD spectra for each conformer were simulated using a Gaussian function with a bandwidth σ of 0.3 eV. The spectra were combined after Boltzmann weighting according to their population contributions and UV correction was applied. 24



Biological Assays Cell cultures and cell survival assay. Mouse macrophage Raw264.7 cells were obtained from ATCC. The cells were cultured at 37 oC in DMEM supplemented with 10% (v/v) heat-inactivated FBS (Invitrogen) and 100 U/ml penicillin/streptomycin under a water-saturated atmosphere of 95% air and 5% CO2. The cell survival assay was performed using the MTT method. Briefly, after incubated with serious concentrations of compounds for 24 h, culture supernatants were removed and exchanged with medium containing 0.5 mg/mL MTT. Then, the cells were incubated for 4 h at 37 oC in darkness, followed by the removal of the medium and adding 100 µL dimethyl sulfoxide. The absorbance at 570 nm was detected and the data were expressed as the mean percentage of absorbance in treated vs. control cells. The value of the control was set at 100%. Bioassay for LPS-Induced NO production.22 Raw264.7 cells were seeded in 96-well culture plates (5×104 cells/well) and allowed to adhere for 24 h at 37 oC. After a 24 h preincubation, the seeded cells were treated with gradient dilutions of compounds with a maxium concentration of 100 µM, followed by stimulation with LPS (1 µg/mL) for 2 h. The nitrite concentrations were measured by the Griess reaction using the supernatant. Briefly, 50 µL of the cell culture supernatant were reacted with 50 µL of Griess reagent for 5 min and the absorbance was read with a microplate reader (Thermo Fisher Scientific Inc. America) at 570 nm. The experiment was performed three times, and the IC50 values for the inhibition of NO production were determined on the basis of linear or nonlinear regression analysis of the concentration–response data curves. iNOS enzymatic inhibitory activity.23 After treated as described above, the culture supernatant was removed and 100 µL of NOS assay buffer (50% NOS assay buffer, 25


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39.8% MilliQ water, 5% L-Arginine solution, 5% 0.1 mM NADPH, 0.2% DAF-FMDA) were added to each well. After incubated for 2 h at 37 oC, fluorescence was measured with a fluorescence plate reader (Biotek) at excitation of 495 nm and emission of 515 nm. Molecular docking studies.20-21 Molecular docking simulations were performed using the software AutoDockVina along with AutoDock Tools (ADT 1.5.6) using the hybrid Lamarckian Genetic Algorithm (LGA). The crystal structure of iNOS (PDB code 3E6T) was obtained from the RCSB Protein Data Bank.19 Molecules were built with Chemdraw and optimized at molecular mechanical and semiempirical level by using Open Babel GUI.7. The crystallographic ligands were extracted from the active site and the designed ligands were modelled. All hydrogen atoms were added to define the correct ionization and tautomeric states, and the carboxylate, phosphonate and sulphonate groups were considered in their charged form. In the docking calculation, the default FlexX scoring function was used for exhaustive searching, solid body optimizing and interaction scoring. The pose with the most favorable score was remained. ASSOCIATED CONTENT Supporting Information Spectroscopic data including NMR, HRESITOFMS, UV, and IR spectra of 1−8, and X-ray crystallographic data of 2, 4, 8 and 9 (CIF). The materials are available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] (Y.X.). *E-mail: [email protected] (H. Z.). 26



*E-mail: [email protected] (Y.Z.). Author Contributions §

H. Li., W. Sun. and M. Deng. contributed equally to this work.

Notes The authors declare no competing financial interest. ACKNOWLEDGMENT This work was financially supported by the Program for the Changjiang Scholars of Ministry of Education of the People's Republic of China (No. T2016088); the National Science Fund for Distinguished Young Scholars (No. 8172500151); the National Natural Science Foundation of China (Nos. 81573316, 31770379, and 31670354); the Academic Frontier Youth Team of HUST; the Integrated Innovative Team for Major Human Diseases Program of Tongji Medical College (HUST); Innovative Research Groups of the National Natural Science Foundation of China (NO. 81721005). We thank the Analytical and Testing Center at Huazhong University of Science and Technology for assistance in testing of ECD, UV, and IR spectra.

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