(±)-Uncarilins A and B, Dimeric Isoechinulin-Type Alkaloids from

Feb 22, 2017 - (±)-Uncarilins A and B (1a/1b and 2a/2b), two pairs of unusual dimeric isoechinulin-type enantiomers with a symmetric four-membered co...
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(±)-Uncarilins A and B, Dimeric Isoechinulin-Type Alkaloids from Uncaria rhynchophylla Chang-An Geng, Xiao-Yan Huang, Yun-Bao Ma, Bo Hou, Tian-Ze Li, Xue-Mei Zhang, and Ji-Jun Chen* State Key Laboratory of Phytochemistry and Plant Resources in West China; Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, People’s Republic of China S Supporting Information *

ABSTRACT: (±)-Uncarilins A and B (1a/1b and 2a/2b), two pairs of unusual dimeric isoechinulin-type enantiomers with a symmetric four-membered core, were isolated from Uncaria rhynchophylla driven by LCMS-IT-TOF analyses. Their structures were elucidated by extensive 1D and 2D NMR spectra, X-ray diffraction, and ECD spectroscopic data. (−)-Uncarilin B (2a) showed activities on MT1 and MT2 receptors with agonistic rates of 11.26% and 52.44% at a concentration of 0.25 mM.

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The traditional Chinese medicine Gou-Teng is widely applied for treating neurological disorders, e.g., convulsions, eclampsia, epilepsy, cerebral diseases, and hypertension.12,13 According to the latest Chinese Pharmacopoeia (2015), five Uncaria species, namely, U. rhynchophylla, U. macrophylla, U. hirsute, U. sinensis, and U. sessilif ructus, are officially documented as the original plants for Gou-Teng. The main chemical constituents of Gou-Teng are indole alkaloids, flavonoids, triterpenoids, and organic acids, of which indole alkaloids are characteristic constituents responsible for the hypotensive effect.14−17 However, the cause of the sedative and hypnotic constituents of Gou-Teng is still unclear. As a continuous search for novel MT receptor agonists from natural sources,18,19 the LCMS-guided investigation of U. rhynchophylla resulted in two pairs of dimeric isoechinulin-type enantiomers, (±)-uncarilin A (1) and (±)-uncarilin B (2). This paper describes their isolation, structural characterization, and agonistic activities on MT1, MT2, 5-HT1A, and 5-HT2C receptors.

elatonin (5-methoxy-N-acetyltryptamine, MT), as an endogenous hormone released by the pineal gland, is important for circadian rhythms and neuroendocrine processes, which takes effect via activating two G-protein-coupled receptors, dubbed MT1 and MT2. The MT1 and MT2 receptors, widely distributed in the central nervous system and peripheral tissues, are promising targets for drug discovery. Several MT receptor-mediated drugs, e.g., circadin (slow-release melatonin), ramelteon, tasimelteon, and agomelatine, have been clinically used to treat insomnia, depression, and sleep disorders.1−3 Nevertheless, it is challenging to assess the function of MT1 and MT2 receptors because of their low binding site densities in tissues and high amino acid homology. MT1 and MT2 receptors can form heterodimers with the serotonin (5-HT) receptors, which further complicates this issue.4,5 Previous investigations indicate that activation of the MT1 receptor will inhibit cyclic adenosine monophosphate (cAMP) formation and protein kinase A (PKA) activity, which is closely related to promoting sleep and vasoconstriction. In contrast, the MT2 receptor shows a close relationship with circadian rhythms and angiectasis.6,7 With the aid of cloned MT1 and MT2 receptors, researchers have achieved considerable success in discovering high-affinity and selective ligands; however, most of the reported ligands are synthesized compounds showing a high similarity with melatonin.8−11 Therefore, there is a need to explore novel types of natural agonists for MT receptors. © 2017 American Chemical Society and American Society of Pharmacognosy

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RESULTS AND DISCUSSION

Uncarilin A (1), colorless needles (MeCN−H2O, 9:1), showed a positive response to Dragendorff’s reagent. The positive HRESIMS spectrum displayed a protonated molecular ion at Received: October 13, 2016 Published: February 22, 2017 959

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an indole moiety was deduced when eight characteristic carbon signals resonating from δC 106.7 to 144.9 were taken into consideration.21 This deduction was further corroborated by the cross-peaks of H-4/H-5/H-6/H-7 in the 1H−1H COSY spectrum and cross-peaks from H-1 to C-3 and C-3a, from H-4 to C-3 and C-7a, and from H-7 to C-3a in the HMBC spectrum. The HMBC cross-peaks from H-16/17 to C-15 and from H-19/20 to C-15 and C-16 allowed the establishment of a 2-methylbut-3-en-2-yl group, which was linked to C-2 of the indole moiety. Similarly, the HMBC cross-peaks from H-11 to C-9, C-10, C-12, and C-13, from H-14 to C-9, C-10, C-12, and C-13, and from H-12 and H-18 to C-13 confirmed the presence of a 2,5-diketopiperazine unit. In addition to the aforementioned structural features, the C-8 methine group was deduced to be linked with C-3 and C-9 to connect the 2,5diketopiperazine and indole moieties based on the crosspeaks from H-8 to C-2, C-3, C-3a, C-9, and C-10 in the HMBC spectrum (Figure 2). Collectively these data represent half of

m/z 647.3341 ([M + H]+, +0.1 mDa), corresponding to a molecular formula of C38H42N6O4, suggesting 21 indices of hydrogen deficiency. The UV absorptions at 283 and 226 nm suggested the presence of an indole chromophore in the structure (Figure 1).20 The 13C NMR (DEPT) spectrum showed a total of 19 signals that could be assigned as 12 sp2hybridized carbons including two amide carbonyls (δC 171.0 and 168.0), one terminal double bond (δC 145.9 and 112.9), one quaternary carbon (δC 39.2), one nitrogenated tertiary carbon (δC 67.3), two methines, and three methyls, indicating a symmetric structure. In the deshielded region of the 1H NMR spectrum, three singlets at δH 11.51, 10.52, and 10.16 were discerned as three amido protons, which showed no cross-peak with any carbons in the HSQC experiment. The presence of an ortho-disubstituted phenyl ring was evident from the proton signals at δH 9.38 (1H, d, J = 8.1 Hz, H-4/4′), 7.43 (1H, t, J = 8.1 Hz, H-5/5′), 7.20 (1H, t, J = 8.1 Hz, H-6/6′), and 7.38 (1H, d, J = 8.1 Hz, H-7/7′). On the basis of the above analysis,

Figure 2. Key 2D NMR correlations for 1.

the structure occupying 10 of the 21 indices of hydrogen deficiency. Therefore, one additional four-membered ring was empirically determined to link the two identical structural moieties via C-8(8′) and C-9(9′). The relative configuration of 1 could not be determined with confidence due to the densely substituted four-membered core with contiguous stereocenters. Therefore, an X-ray diffraction

Figure 1. UFLCMS-IT-TOF chromatogram (A), HRMS (B), and chiral separation (C) of compounds 1 and 2. 960

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Figure 3. X-ray ORTEP drawings of 1 and 2.

Table 1. 1H (600 MHz) and 13C NMR (150 MHz) Data of 1 and 2 in Pyridine-d5 uncarilin A no. 1/1′ 2/2′ 3/3′ 3a/3a′ 4/4′ 5/5′ 6/6′ 7/7′ 7a/7a′ 8/8′ 9/9′ 10/10′ 11/11′ 12/12′ 13/13′ 14/14′ 15/15′ 16/16′ 17/17′ 18/18′ 19/19′ 20/20′

uncarilin B

δH (J, Hz)

δC

δH (J, Hz)

11.51, s

9.38, 7.43, 7.20, 7.38,

d (8.1) t (8.1) t (8.1) d (8.1)

6.38, s

10.16, s 4.15, q (7.0)

144.9, 106.7, 129.3, 122.6, 120.1, 121.2, 111.7, 136.2, 46.2, 67.3, 171.0,

s s s d d d d s d s s

49.9, d 168.0, s

10.52, s 6.37, 5.30, 5.12, d (10.5) 1.45, 1.56, 1.33,

dd (17.3, 10.5) d (17.3)

δC

11.54, s

9.93, 7.46, 7.22, 7.43,

d (8.1) t (8.1) t (8.1) d (8.1)

6.79, s

10.02, s 4.52, q (6.8)

146.1, 105.6, 129.6, 121.3, 120.6, 121.4, 112.0, 136.1, 41.3, 71.1, 167.0,

s s s d d d d s d s s

50.8, d 168.7, s

8.21, s 39.2, s 145.9, d 112.9, t

d (7.0) s s

18.6, q 29.2, q 28.5, q

6.30, 5.10, 4.87, d (10.5) 1.51, 1.63, 1.54,

dd (17.3, 10.5) d (17.3) d (6.8) s s

39.1, s 146.3, d 113.0, t 19.1, q 29.3, q 29.2, q

Uncarilin B (2) was assigned a molecular formula of C38H42N6O4 from the [M + H]+ ion at m/z 647.3345 (+0.5 mDa) in the positive HRESIMS. Similar to 1, only 19 carbons ascribed to three methyls, one olefinic methylene, seven methines (four aromatic and one olefinic), and eight nonprotonated carbons (two carbonyls and four aromatic carbons) were resolved in the 13C NMR (DEPT) spectrum, indicating a symmetric skeleton. Detailed comparison of their 1H and 13C NMR data showed that uncarilins A and B (1 and 2) were a pair of diastereoisomers, and the major difference involved the chemical shifts of H-8 (δH 6.38 vs 6.79), H-12 (δH 4.15 vs 4.52), H-14 (δH 10.52 vs 8.21), and H-17 (δH 5.30, 5.32 vs 5.10, 4.87) in the 1H NMR spectrum and C-8 (δC 46.2 vs 41.3), C-9 (δC 67.3 vs 71.1), and C-10 (δC 171.0 vs 167.0) in the 13C NMR spectrum (Table 1). Analysis of their 2D NMR (1H 1H

analysis using Cu Kα radiation was performed, from which the structure of uncarilin A (1) was defined. The crystal of 1 had a P1̅ space group, indicative of a pair of enantiomers. Chiral separation was performed on a Kromasil 5-CelluCoat RP column to yield a pair of enantiomers, (−)-uncarilin A (1a) and (+)-uncarilin A (1b). Their absolute configurations were determined by comparison of its experimental and quantum chemical ECD spectra, the latter calculated at the b3lyp/631+G(d) level using the conductor polarizable continuum model in MeCN. On the basis of the matching of the experimental and computed ECD spectra, the absolute configurations of 1a and 1b were defined as (8R,9S,12S,8′R,9′S,12′S) and (8S,9R,12R,8′S,9′R,12′R), respectively (Figure 3). 961

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Figure 4. Experimental and calculated ECD spectra for 1a, 1b, 2a, and 2b.

(12S,12′S) or (12R,12′R) configurations, and whether heterogeneous dimers (12S,12′R or 12R,12′S) are present in this plant is an intriguing question. This is the first report of isoechinulin-tpye alkaloid dimers with an unusual fourmembered core, which further enriches the structural types of natural agonists for MT receptors.

COSY and HMBC) spectra showed that compounds 1 and 2 shared the same 2D structures. Therefore, the differences between their NMR data should be derived from configurational variations. An X-ray diffraction analysis (Cu Kα) was performed to verify the structure of uncarilin B (2). Similar to 1, the detected C2/c space group indicated that 2 was a pair of enantiomers, and subsequent chiral separation afforded (−)-uncarilin B (2a) and (+)-uncarilin B (2b). Their absolute configurations were determined as (8R,9S,12S,8′R,9′S,12′S) for 2a and (8S,9R,12R,8′S,9′R,12′R) for 2b by comparison of experimental and TDDFT-calculated ECD data (Figure 4). Compounds 1a, 1b, 2a, and 2b were evaluated for their agonistic activities on MT1 and MT2 receptors and 5-HT1A and 5-HT2C receptors of the HEK293 cell line in vitro, i.e., receptors that are always involved in the etiology and pathology of many mental diseases such as depression and sleep disorders. All compounds showed activities on the MT1 and MT2 receptors, but no activity on the 5-HT1A and 5-HT2C receptors, at the tested concentration of 0.25 mM. Of the four enantiomers, compound 2a possessed the most potent activities on MT1 and MT2 receptors, with the agonistic rates of 11.26% and 52.44%. Compounds 1a/1b and 2a/2b, as two pairs of unusual dimeric isoechinulin-type enantiomers, were isolated from U. rhynchophylla driven by LCMS analyses.22 Structurally, uncarilins A and B contained three characteristic units: indole, 2-methylbut-3-en-2-yl, and diketopiperazine. From a biosynthesis point of view, the diketopiperazine core (cyclic dipeptide) was condensed by “head to tail” cyclization of tryptophan (Trp) and alanine (Ala). Subsequent incorporation of mevalonic acid afforded the intermediate, neoechinulin A, which was transformed via intermolecular [2 + 2] cycloaddition to yield 1 and 2. The isoechinulin-type alkaloids always contained the (12S)-diketopiperazine cores, which were derived from the common L-amino acids.20,23 In this investigation, the (12R)-enantiomers (1b and 2b) were obtained in addition to the “normal” (12S)-enantiomers (1a and 2a), indicating an unusual biosynthesis pathway, in which the D-amino acids (DTrp and D-Ala) should be involved. Most of the natural diketopiperazines were isolated from microorganisms, mainly fungi (including endophytic fungi) and bacteria, and only a few analogues were obtained from the plant kingdom, e.g., cristatin A from Lepidagathis cristata.24−28 Therefore, the isolation of uncarilins A and B (1 and 2) is interesting from a biosynthesis point of view, which might be related with the endophytic fungus in U. rhynchophylla. It is worth noting that both uncarilins A (1) and B (2) belong to homologous dimers with

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EXPERIMENTAL SECTION

General Experimental Procedures. The melting points were recorded on a SGW X-4B microscopic melting point instrument. Optical rotations were measured on a Jasco model 1020 digital polarimeter. UV spectra were performed on a Shimadzu UV2401PC spectrophotometer. Electronic circular dichroism (ECD) data were recorded on an Agilent Chirascan spectropolarimeter. IR spectra were recorded on a Bio-Rad FTS-135 infrared spectrometer. 1D and 2D NMR spectra were measured on a Bruker AVANCE III-600 spectrometer. Mass spectra were acquired on a Shimadzu LCMS-ITTOF mass spectrometer. MPLC separations were done on a Dr-Flash II apparatus using a CHP20P MCI gel column. HPLC purifications were performed on a Chuangxin Tongheng LC3000 system with an Agilent Eclipse XDB-C18 column. The chiral resolutions were performed on an Agilent Technologies 1200 Series instrument equipped with a Kromasil 5-CelluCoat RP column. X-ray crystallographic analysis was performed on a Bruker APEX DUO diffractometer (Cu Kα). LCMS Analyses. A Shimadzu UFLCMS-IT-TOF apparatus with an Agilent Eclipse Plus C18 column (1.8 μm, 2.1 × 100 mm) was used for LCMS analyses. The mobile phase comprised H2O with 0.05% formic acid (A) and MeCN with 0.05% formic acid (B). A binary gradient elution with a flow rate of 0.2 mL/min was performed as follows: linear gradient 5−100% B from 0 to 12.0 min, followed by isocratic elution of 100% B from 12.0 to 16.0 min, then 5% B (18.0 min), and maintained until 20.0 min for column equilibration. Highresolution masses were calibrated by CF3CO2Na clusters. The firststage MS data (positive and negative ion modes) were acquired in automatic scan modes over a range of m/z 200−2000. Plant Material. The hook-bearing stems of U. rhynchophylla were purchased from Jvhuacun medicinal market, Kunming, Yunnan Province, China, in July 2012, and the plant was authenticated by Dr. Li-Gong Lei. A voucher specimen (No. 201207001) was deposited in the Laboratory of Antivirus and Natural Medicinal Chemistry, Kunming Institute of Botany, CAS. Extraction and Isolation. The air-dried sample (4.2 kg) was powdered and extracted with 90% aqueous EtOH (3 × 15 L) under reflux. The combined EtOH extracts were evaporated under reduced pressure and partitioned between H2O and EtOAc. The EtOAc part (190 g) was fractionated by silica gel column using a CHCl3−MeOH gradient system to give seven fractions, Frs. 1−7. Fr. 3 (4.7 g) was separated by MPLC on a CHP20P MCI gel column eluted with MeOH−H2O to provide five subfractions, Fr. 3-1 to Fr. 3-5. Fr. 3-4 (0.8 g) was further chromatographed on a silica gel column using petroleum ether−acetone (1:1) to give three fractions, Fr. 3-4-1 to Fr. 962

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3-4-3, of which Fr. 3-4-2 (20 mg) displayed one main spot on TLC after spraying with Dragendorff’s reagent. UFLC-MS-IT-TOF analysis of this fraction revealed two adjacent peaks with an identical molecular formula of C38H42N6O4 from their positive and negative HRMS data. Consequently, Fr. 3-4-2 was purified by semipreparative HPLC (MeCN−H2O, 35:75, v/v, 3 mL/min) over a C18 column (9.4 × 250 mm, 5 μm) to afford compounds 1 (3.0 mg) and 2 (2.1 mg). The chiral resolutions of compounds 1 and 2 were performed on a Kromasil 5-CelluCoat RP column (4.6 × 250 mm, 5 μm) using MeCN−H2O (40:60 for 1; 50:50 for 2, v/v, 1 mL/min) as the eluent, to yield the enantiomers 1a (0.63 mg), 1b (0.60 mg), 2a (0.55 mg), and 2b (0.51 mg). Compound 1: colorless crystals (MeOH−H2O, 9:1); mp 236−237 °C; UV λmax (MeCN) (log ε) 197 (4.43), 226 (4.45), 283 (3.81) nm; IR (KBr) νmax 3449, 2971, 2931, 1660, 1487, 1427, 1387, 1309, 920, 751 cm−1; 1H and 13C NMR data, see Table 1; (+) HRESIMS m/z 647.3341 (calcd for C38H42N6O4, + 0.1 mDa). Compound 1a: [α]25D −53 (c 0.1, MeCN); ECD (c 0.1, MeCN) λmax (Δε) 201 (+15.7), 216 (−3.5), 229 (+14.7), 295 (−7.6) nm. Compound 1b: [α]25D +24 (c 0.1, MeCN); ECD (c 0.2, MeCN) λmax (Δε) 202 (−19.3), 215 (+5.5), 231 (−16.3), 295 (+10.2) nm. Compound 2: colorless crystals (MeOH−H2O, 9:1); mp 234−235 °C; UV λmax (MeCN) (log ε) 199 (4.02), 226 (4.05), 283(3.38) nm; IR (KBr) νmax 3334, 2967, 2933, 1683, 1491, 1420, 1385, 1302, 1247, 909, 750, 580 cm−1; 1H and 13C NMR data, see Table 1; (+) HRESIMS m/z 647.3345 (calcd for C38H42N6O4, + 0.5 mDa). Compound 2a: [α]D25 −11 (c 0.1, MeCN); ECD (c 0.2, MeCN) λmax (Δε) 200 (+10.3), 211 (−4.8), 227 (+11.8), 296 (−3.5) nm. Compound 2b: [α]D25 +6 (c 0.1, MeCN); ECD (c 0.2, MeCN) λmax (Δε) 200 (−10.9), 213 (+5.6), 225 (−11.8), 297 (+4.2) nm. Crystal data for 1: 2(C38H42N6O4)·C2H3N·H2O, M = 1352.62, a = 10.7266(2) Å, b = 15.3359(3) Å, c = 22.6051(4) Å, α = 77.6050(10)°, β = 80.4720(10)°, γ = 76.4160(10)°, V = 3504.26(12) Å3, T = 100(2) K, space group P1̅, Z = 2, μ(Cu Kα) = 0.688 mm−1, 53 555 reflections measured, 12 491 independent reflections (Rint = 0.0683). The final R1 values were 0.0835 (I > 2σ(I)). The final wR(F2) values were 0.2290 (I > 2σ(I)). The final R1 values were 0.0898 (all data). The final wR(F2) values were 0.2386 (all data). The goodness of fit on F2 was 0.979. Crystal data for 2: C38H42N6O4, M = 646.78, monoclinic, a = 22.1604(8) Å, b = 15.5985(6) Å, c = 11.4109(4) Å, α = 90.00°, β = 120.9440(10)°, γ = 90.00°, V = 3383.0(2) Å3, T = 100(2) K, space group C2/c, Z = 4, μ(Cu Kα) = 0.674 mm−1, 15 000 reflections measured, 2858 independent reflections (Rint = 0.0484). The final R1 values were 0.0459 (I > 2σ(I)). The final wR(F2) values were 0.1217 (I > 2σ(I)). The final R1 values were 0.0480 (all data). The final wR(F2) values were 0.1252 (all data). The goodness of fit on F2 was 1.032. Crystallographic data have been deposited in the Cambridge Crystallographic Data Centre (CCDC 1502283 for 1 and CCDC 1502284 for 2). Bioassay for Agonistic Activities on MT1/2 and 5-HT1A/2C Receptors. HEK293 cells stably expressing human MT1/2 and 5HT1A/2C receptors were maintained in Dulbecco’s modified Eagle medium containing 10% fetal bovine serum, which were purchased from HD Biosciences Co. Ltd. (Shanghai, China). Cells were seeded in Matrigel-coated black wall/clear bottom 96-well plates at a density of 4 × 104 cells/well. After an overnight incubation (5% CO2, 37 °C), the medium was removed, and 100 μL of loading solution (HDB Wash Free Fluo-8 calcium assay kit) was added into each well. The plate was incubated at 37 °C for 1 h and then transferred to the FlexStation3 benchtop multi-mode microplate reader. The tested samples were dissolved in Hank’s balanced salt solution buffer (50 μL) and transferred to the sample plate in the microplate reader to perform the bioassay. The raw data from time sequence recording were normalized as percentage responses to melatonin and 5-hydroxytryptamine (positive controls) and analyzed to fit the four-parameter logistic equation to assess the agonistic rates.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.6b00938. Crystallographic data of compound 1 (CIF) Crystallographic data of compound 2 (CIF) 1D and 2D NMR, IR, UV, [α]D, and ECD spectra of compounds 1 and 2 (PDF) (PDF) (PDF)

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AUTHOR INFORMATION

Corresponding Author

*Tel (J.-J. Chen): + 86 871 65223265. Fax: + 86 871 65227197. E-mail: [email protected]. ORCID

Chang-An Geng: 0000-0001-9834-0756 Ji-Jun Chen: 0000-0001-5781-7511 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This project was financially supported by the National Natural Science Foundation of China (81573322), the Youth Innovation Promotion Association, CAS, the Hundred Talents Program of CAS, the West Light Foundation of CAS (Western Youth Scholars “A”), and the Program of Yunling Scholarship.

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REFERENCES

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DOI: 10.1021/acs.jnatprod.6b00938 J. Nat. Prod. 2017, 80, 959−964