Piperidine Alkaloids with Diverse Skeletons from Anacyclus

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Cite This: J. Nat. Prod. 2018, 81, 1474−1482

Piperidine Alkaloids with Diverse Skeletons from Anacyclus pyrethrum Qi-Bin Chen, Jie Gao, Guo-An Zou, Xue-Lei Xin, and Haji Akber Aisa* Key Laboratory of Plant Resources and Chemistry in Arid Zone and State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, People’s Republic of China

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S Supporting Information *

ABSTRACT: Fifteen new piperidine derivatives, pyracyclumines A−J (1−10), including five pairs of enantiomers, (+)-1/ (−)-1 to (+)-5/(−)-5, together with three known compounds, agrocybenine (11), 4,6,6-trimethyl-5,6-dihydro-2(1H)-pyridone (12), and 3,5,5-trimethyl-1,5-dihydro-2H-pyrrol-2-one (13), were isolated from the roots of Anacyclus pyrethrum. Pyracyclumines A, B, and H (1, 2, and 8) possess a novel 6/5/ 6/6 dimeric piperidine skeleton, a unique 6/5/6 dimeric piperidine skeleton, and a 1,4,6-triazaindan skeleton, respectively. Pyracyclumine C (3) is based on a rare cyclopentane− piperidine framework. The structures of the isolated compounds were established by analysis of their NMR and HRESIMS data. The racemic pyracyclumines A−E (1−5) were further separated by chiral HPLC to give the enantiomers (+)-1/ (−)-1 to (+)-5/(−)-5, for which the absolute configurations were determined by comparison of their experimental and calculated ECD spectra. The plausible biogenetic pathways of these piperidine alkaloids were proposed starting from the basic units of compounds 12 and 13. All of the isolated compounds were tested for their inhibitory effects on menin−mixed lineage leukemia 1 protein−protein interaction.

P

(1−10), together with one pyrrolidine alkaloid (13) (Chart 1), were obtained from the roots of A. pyrethrum. These alkaloids belong to six subtypes of the piperidine family. Herein, we present the isolation, structure elucidation, plausible biosynthesis pathways, and the biological activities of these alkaloids.

iperidine alkaloids, a major group of plant constituents, have been found to display a variety of structural frameworks and diverse bioactivities.1 There are numerous pharmaceuticals and lead compounds, whether synthesized or naturally occurring, that contain one or more piperidine units.1,2 The various bioactivities associated with piperidine alkaloids have led to the development of new chemosynthetic as well as biomimetic synthetic methods.3 To discover more naturally occurring piperidine alkaloids with novel structures and significant bioactivities, an investigation was carried out of alkaloids from the roots of Anacyclus pyrethrum (L.) DC. This species belongs to the family Asteraceae.4 The roots of A. pyrethrum are used as a traditional medicine, for which its medicinal history can be traced back to the time of Dioscorides,5 to treat epilepsy, rheumatism, cephalalgia, paralysis, and hemiplegia.6 Currently, pharmacological research has shown that extracts of the roots of A. pyrethrum possess antidepressant, anticonvulsive, anti-inflammatory, antimicrobial, local anesthetic, oxidative DNA damage preventive, immunostimulatory, saliva-stimulating, male libido enhancing, antimutagenesis, and insecticidal activities.7 However, the chemical constituents of the roots of A. pyrethrum have not been investigated in detail. Only a few N-alkylamides and volatile components have been reported,5,8 suggesting the possibility of the occurrence of other alkaloids with structural diversity or novelty, which inspired the present interest. Altogether, a total of 17 piperidine alkaloids (1−12), including 15 new substances © 2018 American Chemical Society and American Society of Pharmacognosy

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RESULTS AND DISCUSSION Pyracyclumine A (1) gave a molecular formula of C21H30N2O2 with eight indices of hydrogen deficiency, based on its NMR and (+)-HRESIMS (m/z 343.2394 [M + H]+, calcd for C21H31N2O2, 343.2386) data. The combined analysis of its 1H, 13 C (Table 1), DEPT-135, HSQC, and HMBC spectra allowed the designation of 21 carbon resonances as seven methyls (C12, C-13, C-14, C-15, C-16, C-17, C-18), three methylenes (C3, C-4, C-6), one sp2 hybrid methine (C-9), five sp3 hybrid quaternary carbons (C-2, C-3a, C-3b, C-5, C-8), and five sp2 hybrid quaternary carbons, including four amide carbonyls or aromatic quaternary carbons (C-9a, C-6a, C-10a, C-11) and one ketone carbonyl (C-10). The HMBC cross-peaks of H3-13/C-14, C-2, and C-3; H314/C-13, C-2, and C-3; H2-3/C-13, C-14, C-2, C-3a, and C10a; and H3-12/C-11 and C-10a (Figure 1), together with the downfield chemical shifts of C-11 (δ 158.4) and C-2 (δ 53.4), Received: March 21, 2018 Published: May 18, 2018 1474

DOI: 10.1021/acs.jnatprod.8b00239 J. Nat. Prod. 2018, 81, 1474−1482

Journal of Natural Products

Article

Chart 1

Table 1. 1H and 13C NMR Data (δ in ppm and J in Hz) of Compounds 1−4 1a no.

δC type

2 3

53.4 C 36.6 CH2

3a 3b 4

47.2 C 71.6 C 46.0 CH2

4a 4b 5 6 6a 7 8

49.3 C 44.4 CH2

2a δH mult. (J)

α 2.11 d (14.0) β 2.22 d (14.0)

α 1.95 d (14.4) β 0.64 d (14.4)

δC type

3b δH mult. (J)

66.5 C 206.1 C

120.2 C

9a 10 10a 11 12

143.1 C 187.1 C 110.3 C 158.4 C 19.5 CH3

2.38 s

13 14 15 16 17 18 1′ 2′

31.4 33.8 32.6 32.6 30.8 29.2

1.48 1.37 1.30 0.80 1.47 1.43

CH3 CH3 CH3 CH3 CH3 CH3

s s s s s s

55.1 C

56.0 C 7.05 brs

80.0 CH

4.12 s

107.8 C 154.4 C 17.7 CH3

2.36 s

103.5 C 158.9 C 18.4 CH3

2.37 s

α 2.54 d (16.8) β 2.25 d (16.0)

29.1 CH3

1.21 s

28.0 CH3

1.23 s

173.4 C 27.8 CH3

1.38 s

26.8 CH3

1.45 s

26.7 CH3

1.45 s

29.5 CH3 15.1 CH3

1.27 s 1.85 s

23.1 CH3 36.8 CH2

1.34 s 2.55 d (13.8) 2.63 d (14.4)

24.0 CH3 42.4 CH2

1.42 s 1.88 d (16.2) 2.07 d (15.6)

21.1 29.0 32.1 29.9

1.87 1.35 1.31 1.17

54.8 C 27.0 CH3 27.1 CH3

1.28 s 1.29 s

54.6 C 28.7 CH3 28.8 CH3

1.53 s 1.49 s

172.8 C 24.0 CH3

1.89 s

172.8 C 24.2 CH3

1.91 s

51.7 C 47.5 CH2

6.85 s

61.8 C 215.6 C

δH mult. (J)

84.6 C 199.0 C

173.7 C

142.3 CH

δC type

145.6 C 193.7 C

α 2.81 d (12.0) β 2.10 d (12.0)

8a 9

δH mult. (J)

63.5 C 201.3 C

150.5 CH

146.7 C 111.2 C 146.6 C

61.0 C

δC type

4b

40.5 C 52.9 CH2

CH3 CH3 CH3 CH3

172.8 C 24.0 CH3

α 2.06 d (13.6) β 1.47 d (13.2)

s s s s

1.89 s

a

Data were recorded in methanol-d4 at 400 MHz (1H) and 101 MHz (13C). bData were recorded in methanol-d4 at 600 MHz (1H) and 150 MHz ( C). 13

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density functional theory (TDDFT) method at the b3-lyp/defTZVP level. As a result, the mirror symmetrical calculated ECD spectra of 1a and 1b matched well with the experimental data of (−)-1 and (+)-1, respectively, while the calculated ECD spectrum of 1c did not match with the experimental values of either (−)-1 or (+)-1 (Figure 4). This indicated that the absolute configurations of (−)-1 and (+)-1 are (3aS,3bS)-1 and (3aR,3bR)-1, respectively. The molecular formula of pyracyclumine B (2) was deduced as C18H27N2O with seven indices of hydrogen deficiency, on the basis of its NMR and (+)-HRESIMS (m/z 287.2119 [M + H]+, calcd for C18H28N2O, 287.2123) data. A total of 18 carbon resonances observed from the 13C NMR data (Table 1) of 2 were classified as seven methyls (C-10, C-11, C-12, C-13, C-14, C-15, C-16), two methylenes (C-8, C-9), three sp3 hybrid quaternary carbons (C-2, C-7, C-8a), five sp2 hybrid amide carbonyls or aromatic quaternary carbons (C-4, C-4a, C-4b, C5, C-9a), and one ketone carbonyl (C-3) based on the comprehensive analysis of its 1D NMR and HSQC spectra. The HMBC cross-peaks (Figure 2) of H3-14/C-15, C-7, and CFigure 1. Key HMBC and NOESY correlations of 1.

and the molecular formula of 1 were used to establish an aza six-membered ring A. The HMBC cross-peaks from H3-15 to C-16, C-4, C-5, and C-6; H3-16 to C-15, C-4, C-5, and C-6; H24 to C-15, C-16, C-5, C-6, C-3, C-3a, C-3b, and C-10a; H2-6 to C-15, C-16, C-5, C-4, C-3b, and C-6a; and H2-3 to C-4 and C3b, indicated the six-membered ring D as being located at the quaternary carbon C-3a via C-4−C-3a and C-3a−C-3b bonds. Furthermore, the HMBC cross-peaks of H3-17/C-18, C-8, and C-9 (δ 142.3); H3-18/C-17, C-8, and C-9; and H-9 (δ 6.85)/C17, C-18, C-8, C-9a (δ 143.1), C-10, and C-3b enabled the establishment of the structural fragment a (Figure 1) attached to C-3b via a C-9a−C-3b bond. The downfield chemical shift of the sp3 hybrid quaternary C-3b (δ 71.6) suggested the presence of a hydroxy group at this position. The aza six-membered ring C was formed by connecting C-6a and C-8 with a nitrogen atom, which was confirmed by the downfield chemical shifts of C-6a (δ 173.7) and C-8 (δ 61.0), the molecular formula, and the hydrogen deficiency. The remaining one index of hydrogen deficiency, together with the upfield chemical shift of C-10a (δ 110.3), implied that C-10a is linked to the ketone carbonyl C10 (δ 187.1) to form a five-membered ring B, and thus this furnished the planar structure of 1 with a novel 6/5/6/6 dimeric piperidine skeleton, as shown. The unique framework of 1 would permit two possible relative configurations (Figure 1) consistent with the observed NOESY correlations (performed in methanol-d4, Figure 1) of H3-13/H-4α (δ 1.95)/H3-15/H3-16, H-4β (δ 0.64)/H3-16, H315/H-6β (δ 2.10)/H3-16, H-6α (δ 2.81)/H-3β (δ 2.22)/H3-13, H-3β/H3-14/H-3α (δ 2.11), and H3-13/H3-15. In addition, compound 1 was obtained as a racemate, which was further separated by chiral HPLC to yield a pair of optically pure enantiomers, (+)-1 and (−)-1 (Figure S1, Supporting Information). The absolute configurations of (−)-1 and (+)-1 were determined by comparing their calculated ECD spectra with the experimental values. Based on the above-mentioned NOESY results, the possible configurations of 1a [(3aS,3bS)1], 1b [(3aR,3bR)-1], and 1c [(3aS,3bR)-1] (Figure S6, Supporting Information) were constructed for geometrical optimization and electronic circular dichroism (ECD) calculation by TmoleX 4.3 software9 using the time-dependent

Figure 2. Key HMBC and NOESY correlations of 2−4.

8; H3-15/C-14, C-7, and C-8; H2-8/C-14, C-15, C-7, C-8a, C16, and C-4b; H3-13/C-5 and C-4b; and H3-16/C-8, C-8a, and 4b enabled the establishment of an aza six-membered ring C and the attachment of Me-16 to the sp3 hybrid quaternary C-8a. The structure fragment a (Figure 2) was confirmed by the chemical shifts of the ketone carbonyl C-3 (δ 206.1) and sp2 hybrid quaternary carbons of C-4 (δ 120.2) and C-4a (δ 146.7) and the HMBC cross-peaks of H3-10/C-11, C-2, and C-3; H311/C-10, C-2, and C-3; and H3-12/C-3, C-4, and C-4a. The HMBC cross-peaks from H3-16 to C-9 and from H2-9 to C-16, C-8, C-8a, C-4b, C-9a, and C-4a, together with the NOESY correlation (Figure 2) of H3-12/H3-13, the chemical shifts of C9a (δ 173.4) and C-4b (δ 111.2), and the indices of hydrogen deficiency, suggested that the structural fragment a is linked to ring C via the C-4a−C-4b bond to form the five-membered ring B, and C-9a is connected to C-2 by a nitrogen atom to assemble the aza six-membered ring A. Thus, the planar structure of 2 with a unique 6/5/6 dimeric piperidine framework was established as shown. Pyracyclumine C (3) exhibited a molecular formula of C18H26N2O3, which was deduced from the 1D NMR and (+)-HRESIMS (m/z 319.2033 [M + H] + , calcd for C18H27N2O3, 319.2022) data, indicating seven indices of hydrogen deficiency. The 1D NMR (Table 1) and HSQC spectroscopic data of 3 revealed the carbon resonances of seven methyls (C-8, C-9, C-10, C-11, C-14, C-15, C-2′), one 1476



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Table 2. 1H and 13C NMR Data (δ in ppm and J in Hz) of Compounds 5−7

methylene (C-12), one olefinic methine (C-4), three sp3 hybrid quaternary carbons (C-2, C-3a, C-13), and six sp2 hybrid quaternary carbons (C-7, C-6a, C-5, C-1′, C-3, C-6) including two ketone carbonyls (C-3, C-6). The HMBC cross-peaks (Figure 2) of H3-9/C-10, C-2, and C-3; H3-10/C-9, C-2, and C-3; H3-11/C-3, C-3a, and C-6a; and H3-8/C-7 and C-6a, together with the downfield chemical shifts of C-2 (δ 63.5) and C-7 (δ 154.4), and the elemental composition of the molecular formula allowed the establishment of an aza six-membered ring A. The HMBC cross-peaks from H3-14 to C-15, C-13, and C12; H3-15 to C-14, C-13, and C-12; H2-12 to C-15, C-14, C-13, C-4, C-5, and C-6; H-4 to C-3a, C-5, C-6 C-6a, and C-12; and H3-11 to C-4 confirmed the structural fragment a (Figure 2), which was fused with ring A to give the five-membered ring B via C-4−C-3a and C-6−C-6a bonds. The assignment of the acetyl imino group that is attached to C-13 was suggested by the HMBC cross-peak of H3-2′/C-1′ and the downfield chemical shifts of C-13 (δ 54.8) and C-1′ (δ 172.8), which finally completed the structure of 3 with a rare cyclopentane− piperidine framework. Pyracyclumine D (4) had a molecular formula of C18H28N2O5 based on its (+)-HRESIMS (m/z 353.2094 [M + H]+, calcd for C18H29N2O5, 353.2076) and NMR data. Analysis of the 1D (Table 1) and 2D NMR data of 4 revealed the compound to be an analogue of 3. The only difference between these two compounds was that the C-4C-5 double bond in 3 is oxidized and substituted by two hydroxy groups in 4, which was confirmed by the upfield shifts of H-4 (δ 4.12), C4 (δ 80.0), and C-5 (δ 84.6) in 4, and its molecular formula, and the HMBC cross-peaks (Figure 2) of H-4/C-11, C-3a, C-5, C-6, C-6a, and C-12; H2-12/C-4, C-5, and C-6; and H3-11/C-4. The NOESY correlations (Figure 2) of H3-11/H-4; H-4/H212/H3-14/H3-15; and H-4/H3-14/H3-15 suggested the same orientations of Me-11, H-4, and HO-5. Pyracyclumine E (5) was deduced as C18H28N2O2 with six indices of hydrogen deficiency on the basis of its (+)-HRESIMS (m/z 305.2215 [M + H]+, calcd for C18H29N2O2, 305.2229) and NMR data. The 13C NMR (Table 2) of 5 showed 18 carbon resonances, including seven methyls (C-9, C-10, C-11, C-13, C-14, C-15, C-2′), an sp3 hybrid methylene (C-4), two sp3 hybrid methines (C-6, C-7), an sp2 hybrid methine (C-5), two aliphatic quaternary carbons (C-3, C-12), four aromatic quaternary carbons or amide carbonyls (C-1, C-4a, C-8a, C-1′), and a ketone carbonyl (C-8). The HMBC cross-peaks (Figure 3) of H-5/C-4a, C-6, C-7, and C-8a; H-6/C-5, C-4a, C-7, and C-8; H-7/C-5, C-6, C-8, and C-8a; and H3-15/C-6, C-7, and C8 enabled the establishment of a six-membered ring A. The 1methyl-1-acetamido-ethyl group attached to C-6 via a C-6−C12 bond was confirmed by the HMBC cross-peaks from H3-13 to C-14, C-12, and C-6; H3-14 to C-13, C-12, and C-6; H-5 to C-12; H-6 to C-12; H-7 to C-12; and H3-2′ to C-1′, as well as the downfield chemical shifts of C-1′ (δ 172.8) and C-12 (δ 59.3). The aza six-membered ring B fused with ring A via a C4a−C-8a bond was confirmed by the HMBC cross-peaks from H3-11 to C-10, C-3, and C-4; H3-10 to C-11, C-3, and C-4; H24 to C-10, C-11, C-3, C-4a, C-5, and C-8a; H-5 to C-4; and H39 to C-1 and C-8a, the downfield chemical shifts of C-1 (δ 157.8) and C-3 (δ 52.1), and the indices of hydrogen deficiency. Assuming an α-orientation of H-6, the NOESY correlations (Figure 3) of H3-14/H-7/H3-13 and H3-15/H-6/ H-7, together with the coupling constants of H-5 (J = 6.0 Hz) and H-6 (J = 6.0 Hz), indicated the α-orientation of Me-15 and the β-orientation of H-7.

5a no.

δC type

1 3 4

157.8 C 52.1 C 43.8 CH2

4a 5

133.8 C 111.6 CH

6

48.9 CH

7

44.9 CH

8 8a 9 10 11 12 13 14 15

202.2 C 101.2 C 21.8 CH3 27.6 CH3 28.7 CH3 59.3 C 24.1 CH3 25.5 CH3 20.9 CH3

16 17 18 1′ 2′

172.8 C 23.8 CH3

6b δH mult. (J)

α 2.28 d (12.0) β 2.21 d (12.0) 4.99 d (6.0) 2.99 brd (6.0) 2.33 m

2.32 s 1.08 s 1.29 s 1.06 s 1.31 s 1.05 d (5.2)

1.90 s

δC type

7b δH mult. (J)

δC type

161.5 C 55.0 C 123.1 CH 5.80 s

157.5 C 52.1 C 43.9 CH2

132.0 C 199.8 C

134.5 C 112.3 CH

61.8 CH 45.5 CH 196.6 C 100.2 C 21.7 CH3 30.2 CH3 30.8 CH3 56.8 C 25.8 CH3 26.5 CH3 21.4 CH3

173.1 C 23.7 CH3

3.32 d (3.6) 2.59 q (7.2)

2.38 s 1.29 s 1.37 s 1.26 s 1.30 s 1.12 brd (7.8)

1.88 s

48.5 CH 50.5 CH 199.2 C 102.0 C 21.6 CH3 27.6 CH3 28.7 CH3 59.3 C 24.6 CH3 25.6 CH3 126.0 CH 133.6 C 18.6 CH3 26.3 CH3 172.8 C 24.0 CH3

δH mult. (J)

α 2.29 d (13.2) β 2.21 d (13.8) 5.01 d (6.6) 3.03 brd (6.6) 3.20 brd (9.6)

2.29 s 1.08 s 1.30 s 1.08 s 1.33 s 5.06 d (9.6) 1.72 s 1.64 s 1.91 s

a

Data were recorded in methanol-d4 at 400 MHz (1H) and 101 MHz (13C). bData were recorded in methanol-d4 at 600 MHz (1H) and 150 MHz (13C).

Figure 3. Key HMBC and NOESY correlations of 5−7.

The racemized compounds 2−5 were also separated by chiral HPLC to obtain optically pure enantiomers (+)-2/(−)-2 to (+)-5/(−)-5 (Figures S2−S5, Supporting Information). The absolute configurations of the enatiomers obtained were determined by comparing their calculated ECD spectra with experimental values. The geometrical optimization and ECD calculation of the possible configurations of 2a [(8aR)-2]/2b [(8aS)-2], 3a [(3aS)-3]/3b [(3aR)-3], 4a [(3aR,4R,5S)-4]/4b [(3aS,4S,5R)-4], and 5a [(6S,7R)-5]/5b [(6R,7S)-5] (Figures 1477



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Figure 4. Experimental and calculated ECD spectra of 1−5.

of H3-13/H-7 and H3-15/H-6/H-7 and the coupling constant of H-6 (J = 3.6 Hz). Compound 7 showed the same relative configuration as 6, which was demonstrated by the NOESY correlations of H3-13/H-7/H3-14 and H-15/H-6/H-7 and the coupling constants of H-6 (J = 6.6 Hz), H-5 (J = 6.6 Hz), H-7 (J = 9.6 Hz), and H-15 (J = 9.6 Hz). Pyracyclumine H (8) gave a molecular formula of C15H23N3O based on its (+)-HRESIMS (m/z 262.1924 [M + H]+, calcd for C15H24N3O, 262.1919) and NMR data. Analysis of the 1H and 13C NMR (Table 3) and HSQC data of 8 revealed the presence of six methyls (C-9, C-10, C-11, C-12, C13, C-14), two sp3 hybrid methylenes (C-3, C-8), four sp3 hybrid quaternary carbons (C-2, C-5, C-7, C-8a), and three sp2 hybrid quaternary carbons (C-3a, C-5a, C-8b). The HMBC cross-peaks (Figure 5) from H3-9 to C-10, C-2, and C-3; H3-10 to C-9, C-2, and C-3; and H2-3 to C-10, C-2, C-9, C-3a, and C8b were used to establish the structural fragment a (Figure 5). The HMBC cross-peaks of H3-13/C-14, C-7, and C-8; H3-14/ C-13, C-7, and C-8; and H2-8/C-13, C-14, C-7, and C-8a, together with the downfield chemical shift of the sp3 hybrid quaternary C-8a (δ 80.9), enabled the establishment of structural fragment b (Figure 5) with a hydroxy group attached at C-8a. The HMBC cross-peaks of H3-11/C-12, C-5, and C5a; H3-15/C-11, C-5, and C-5a; and H2-8/C-5a revealed the structural fragment c, which was attached to the C-8a of b via a

S7−S10, Supporting Information) were performed by TmoleX 4.3 software using the TDDFT method, with details provided in the Supporting Information. The calculated ECD spectra of 2a, 2b, 3a, 3b, 4a, 4b, 5a, and 5b matched well with the experimental data for (−)-2, (+)-2, (+)-3, (−)-3, (+)-4, (−)-4, (+)-5, and (−)-5 (Figure 4), respectively, and indicated that the absolute configurations of (+)-2/(−)-2, (+)-3/(−)-3, (+)-4/ (−)-4, and (+)-5/(−)-5 are (8aS)-2/(8aR)-2, (3aS)-3/(3aR)-3, (3aR,4R,5S)-4/(3aS,4S,5R)-4, and (6S,7R)-5/(6R,7S)-5, respectively. Pyracyclumine F (6) and pyracyclumine G (7) were obtained as analogues of 5 with molecular formulas of C18H26N2O3 and C21H32N2O2, respectively, based on their 1D (Table 2), 2D NMR, and (+)-HRESIMS data. The carbonylation of C-5 and the presence of a C-4C-4a double bond in 6 were confirmed by the HMBC cross-peaks (Figure 3) of H-4/C-4a, C-5, C-8a, C-3, C-10, and C-11; H-6/C-4a and C-5; and H-7/C-5 and C-6 and the downfield shifts of C-5 (δ 199.8), H-4 (δ 5.80), and C4 (δ 123.1). The presence of a 2-methyl-propenyl group attached to C-7 in 7, instead of the methyl group in 5 or 6, was established by the HMBC cross-peaks (Figure 3) of H3-17/C18, C-16, and C-15; H3-18/C-17, C-16, and C-15; H-15/C-18, C-17, C-16, C-6, C-7, and C-8; H-6/C-15; and H-7/C-15. The relative configuration of 6 with an α-orientation of H-6 and a βorientation of H-7 was determined by the NOESY correlations 1478



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Table 3. 1H and 13C NMR Data (δ in ppm and J in Hz) of Compounds 8−10 8a

9b δH mult. (J)

δC type

δC type

60.9 C 45.3 CH2

2.79 s

168.2 C 118.7 CH

δC type

2 3

70.2 C 44.6 CH2

3a 4 5

167.2 C

166.6 C

60.5 C

67.4 C

5a 6 7 7a 8

8a 8b 9 10 11 12 13 14 15

2.46 d (18.4) 2.53 d (18.0)

10b δH mult. (J)

no.

2-hydroxypropyl group substituted at C-7 in 9 instead of the methyl group in 11 was demonstrated by the HMBC crosspeaks (Figure 5) of H3-11/C-10, C-9, and C-8; H3-10/C-11, C9, and C-8; and H2-8/C-10, C-11, C-9, C-6, C-7, and C-7a and the downfield chemical shift of C-9 (δ 73.9). Pyracyclumine J (10) displayed a molecular formula of C11H17NO2. Analysis of its 1D (Table 3) and 2D NMR data revealed the structure of this compound to be closely related to 4,6,6-trimethyl-5,6-dihydro-2(lH)-pyridone (12).11 The only difference observed is that the methyl group attached to C-4 in 12 is replaced by a 2-methyl-1,2-epoxy-propyl group in 10, which was confirmed by the HMBC cross-peaks (Figure 5) of H3-9/C-10, C-7, and C-8; H3-10/C-9, C-7, and C-8; H-7/C-9, C-10, C-8, C-3, and C-5; H-3/C-7; and H-5/C-7, the downfield chemical shifts of C-7 and C-8, and the indices of hydrogen deficiency. Compounds 6−8 and 10 were found to be optically inactive. The known compounds 4,6,6-trimethyl-5,6-dihydro-2(1H)pyridone (12) and 3,5,5-trimethyl-1,5-dihydro-2H-pyrrol-2one (13)12 were isolated as new natural products, and compound 11 was obtained from A. pyrethrum for the first time. It is interesting to note that all of these isolates contain one or more basic units of a 2,2,4-trimethylpiperidine derivative, which allowed the classification of these compounds as piperidine alkaloids. Intriguingly, the coexisting compounds 12 and 13 might serve as the biosynthesis precursors of 1−11 (Scheme 1). The discovery of compounds 8−12 with evolutionary continuity as shown suggests the occurrence of intermediate A in the biosynthesis of 1−11 (Scheme 1). Compounds 1 and 2 might be assembled from the polymerization of two molecules of derivatives of A to give the 2,2,4substituted piperidine dipolymers 1B and 2C. Also, 1B and 2C might be further catalyzed by an iron-dependent oxidase to produce free-radical transition states of 1C and 2D. In turn, transition state 1C could undergo a [3 + 2] pericyclic reaction to form a five-membered ring and provide the unique 6/5/6/6 skeleton of 1, while the transition state 2C might undergo a C− C coupling to give the 6/5/6 framework of 2. Compounds 3, 4, 6, and 7 might be generated from the same precursor 3B, as was assembled from one molecule of A, one molecule of 13, and one molecule of acetyl-CoA via an intermolecular aza Michael addition. Compound 3B may be catalyzed further by an iron-dependent oxidase to give free-radical transition states of 3C and 3D, which then could further undergo a C−C coupling reaction and oxidation to provide compounds 3 and 5, respectively. Structurally, the common basic units of 2,2,4trimethyl-piperidine derivatives also suggest that these piperidine alkaloids might not be derived from a conserved lysine precursor.13 The isolated compounds 1−13 were tested for their inhibitory activity of the menin−mixed lineage leukemia 1 (MLL1) protein−protein interaction,14 with the chemical entity MI-2-215 as the positive control (IC50 0.19 ± 0.03 μM). All of the isolated compounds showed weak inhibitory effects on the MLL1 protein−protein interaction, with inhibition rates less than 50% at the test concentration of 20 μM (Table S1, Supporting Information).

152.0 C 39.7 CH2

δH mult. (J) 5.69 brd (6.0)

α 2.45 d (18.0) β 2.28 d (18.0)

173.8 C 71.8 C 48.7 CH2

80.9 C 165.8 C 29.3 CH3 29.4 CH3 29.2 CH3 28.6 CH3 30.0 CH3 29.6 CH3

2.04 d (14.0) 2.19 d (14.0)

1.31 1.37 1.55 1.56 1.32 1.38

s s s s s s

203.4 C 102.2 C 150.8 C 37.4 CH2

2.45 s

73.9 29.6 29.6 29.7 29.8 28.6 28.6

1.17 1.17 1.41 1.41 1.35 1.35

C CH3 CH3 CH3 CH3 CH3 CH3

53.0 C 64.9 CH

s s s s s s

3.37 s

63.1 C

24.9 18.1 28.9 29.0

CH3 CH3 CH3 CH3

1.43 1.21 1.32 1.28

s s s s

a

Data were recorded in CDCl3 at 400 MHz (1H) and 101 MHz (13C). Data were recorded in methanol-d4 at 600 MHz (1H) and 150 MHz (13C).

b

Figure 5. Key HMBC correlations of 8−10.

C-8a−C-5a bond. Also, the structural fragment a linked with b via a C-8a−C-8b bond was confirmed by the HMBC cross-peak of H2-8/C-8b. The weak 4J HMBC cross-peak of H3-12 (δ 1.56)/C-3a (δ 167.2), together with the downfield chemical shifts of C-3a, C-5 (δ 60.5), C-2 (δ 70.2), C-8b (δ 165.8), C-7 (δ 71.8), and C-5a (δ 173.8), the molecular formula, and the indices of hydrogen deficiency, allowed the formation of an aza six-membered ring B and the aza five-membered rings A and C. Compound 8 possesses a unique 5/6/5 nitrogen-containing heterocyclic skeleton, which was classified as 1,4,6-triazaindan according to the 1,4-diazaindan framework of agrocybenine (11).10 Pyracyclumine I (9), with a molecular formula of C15H24N2O2 {(+)-HRESIMS, m/z 265.1914 [M + H]+, calcd for C15H25N2O2, 265.1916}, was obtained as an analogue of 11 by analysis of its 1D (Table 3) and 2D NMR data. A 2-methyl-

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EXPERIMENTAL SECTION

General Experimental Procedures. Optical rotations of the racemates and the enantiomers were tested on a Rudolph Research Analytical Autopol VI polarimeter with MeOH as solvent. UV (MeOH as solvent) data were obtained by a Shimadzu UV-2550 spectropho1479



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Scheme 1. Plausible Biogenetic Pathways of 1−11

tometer. ECD spectra of the enantiomers in MeOH were recorded on an Applied Photophysics Chirascan spectropolarimeter. The NMR data of the isolated compounds were obtained by Varian Inova 400 and 600 MHz spectrometers with methanol-d4 or CDCl3 or acetone-d6 as solvents and tetramethylsilane as an internal standard. HRESIMS data of the new alkaloids were measured by a QSTAR Elite LC-MS/ MS spectrometer. Preparative HPLC separations were carried out on a Waters Autopurification System (collector: 2767 sample manager; main pump: 2545 binary gradient module; shunt pump: 515 HPLC pump; column oven: SFO system fluidics organizer; detector: 2489 UV/visible detector). Fluorescence polarizations of the bioactivity screening were measured on a PerkinElmer Envision plate reader. Solvents for UV, ECD, and optical rotation measurement and HPLC separation were of HPLC grade. Plant Material. The roots of Anacyclus pyrethrum (L.) DC. were purchased from the Xinjiang Madison Uygur Pharmaceutical Co., Ltd. (People’s Republic of China) in August 2013. A voucher specimen (WY02329) was authenticated by Professor Ying Feng of Xinjiang Institute of Ecology and Geography, Chinese Academy of Sciences (CAS), and was deposited at the Specimen Museum of Xinjiang Institute of Ecology and Geography, CAS. Extraction and Isolation. The roots of A. pyrethrum (4.5 kg) were powdered and extracted with acetone/MeOH (1:1, 10 L × 8, 24 h for each time) at room temperature. The crude extract (1.2 kg) was dissolved with 5% HCl (1 L) and filtered to give a 5% HCl-soluble aqueous solution, which was further extracted with CH2Cl2 (10 L × 3) to remove the nonalkaloid components. The purified aqueous solution was basified with saturated NaHCO3 solution in an ice water bath to pH 10. The alkaline solution was extracted with CH2Cl2 to give 660 g of total alkaloids. The total alkaloids (460 g) were partitioned with MeOH/n-hexane (1:1, 2 L) to give a MeOH-soluble fraction (140 g). The MeOH fraction (140 g) was dissolved with 1 L of EtOAc and filtered to obtain an EtOAc-soluble fraction (70 g), which was further fractionated by a Waters autopurification system (column: XSelect CSH C18 5 μm, 19 × 150 mm; solvent conditions: 0−30 min, 10% MeOH in H2O to 100% MeOH; flow rate: 20.0 mL/min; wavelength: 230 nm) to afford fractions Fr.1 (2.1 g, 9.0−14.0 min), Fr.2 (6.0 g, 14.0−18.5 min), and Fr.3 (4.1 g, 18.5−21.0 min). Fr.1 (2.1 g) was fractionated by semipreparative HPLC (column: XSelect CSH C18 5 μm, 10 × 250 mm; solvent: MeOH/H2O, 24:76; flow rate: 3.5 mL/min) to give Fr.1.1 (300 mg, 21.0−26.5 min), Fr.1.2 (110 mg, 34.0−42.0 min), and Fr.1.3 (120 mg, 42.0−49.0 min). Fr.1.1 (300 mg) was further separated by semipreparative HPLC (column: XSelect CSH C18 5 μm, 10 × 250 mm; solvent: CH3CN/H2O, 10:90; flow rate: 4.5 mL/min) to afford Fr.1.1.1 (23.0−29.0 min) and Fr1.1.2

(31.0−36.0 min). Fr1.1.1 was purified by semipreparative HPLC (column: XSelect CSH C18 5 μm, 10 × 250 mm; solvent: CH3CN/ H2O, 15:85; flow rate: 5.0 mL/min) to obtain compound 11 (176.7 mg, tR 9.5 min). Fr.1.1.2 was separated by semipreparative HPLC (column: XSelect CSH C18 5 μm, 10 × 250 mm; solvent: CH3CN/ H2O, 10:90; flow rate: 4.5 mL/min) to give compound 12 (11.1 mg, tR 30.1 min). Fr.1.2 (110 mg) was purified by semipreparative HPLC (column: XSelect CSH C18 5 μm, 10 × 250 mm; solvent: CH3CN/ H2O, 12:88; flow rate: 4.5 mL/min) to afford compound 8 (2.1 mg, tR 19.3 min) and compound 10 (3.3 mg, tR 48.5 min). Fr.1.3 (120 mg) was separated by semipreparative HPLC (column: XSelect CSH C18 5 μm, 10 × 250 mm; solvent: CH3CN/H2O, 14.1:85.9; flow rate: 4.5 mL/min) to yield compound 9 (1.9 mg, tR 19.6 min). Fr.2 (6.0 g) was fractionated using a Waters autopurification system (column: XSelect CSH C18 5 μm, 19 × 150 mm; solvent: MeOH/ H2O, 35:65; flow rate: 20.0 mL/min; wavelength: 230 nm) to obtain four fractions, Fr.2.1 (750 mg, 0.0−8.0 min), Fr.2.2 (590 mg, 12.5− 18.0 min), Fr.2.3 (540 mg, 18.0−29.0 min), and Fr.2.4 (760 mg, 29.0− 42.8 min). Fr.2.1 (750 mg) was separated by semipreparative HPLC (column: XSelect CSH C18 5 μm, 10 × 250 mm; solvent: CH3CN/ H2O, 10:90; flow rate: 4.5 mL/min) to afford compound 4 (4.8 mg, tR 42.2 min). Fr.2.2 (590 mg) was purified by semipreparative HPLC (column: XBridge C18 5 μm, 10 × 150 mm; solvent: CH3CN/H2O, 17:83; flow rate: 5.0 mL/min) to give compound 3 (1.8 mg, tR 26.5 min). Fr.2.3 (540 mg) was fractionated by semipreparative HPLC (column: XBridge C18 5 μm, 10 × 150 mm; solvent: CH3CN/H2O, 21:79; flow rate: 4.6 mL/min) to afford Fr.2.3.1 (9.5−11.5 min), which was further purified by semipreparative HPLC (column: XBridge C18 5 μm, 10 × 150 mm; solvent: CH3CN/H2O, 19:81; flow rate: 4.6 mL/min) to afford compound 1 (12.7 mg, tR 16.0 min). Fr.2.4 (760 mg) was fractionated with semipreparative HPLC (column: XSelect CSH C18 5 μm, 10 × 250 mm; solvent: CH3CN/ H2O, 22:78; flow rate: 5.0 mL/min) to give Fr.2.4.1 (35.5−37.5 min), which was further separated by semipreparative HPLC (column: XSelect CSH C18 5 μm, 10 × 250 mm; solvent: CH3CN/H2O, 32:68; flow rate: 5.0 mL/min) to obtain compounds 5 (85.2 mg, tR 8.9 min) and 6 (2.0 mg, tR 4.0 min). Fr.3 (4.1 g) was also fractionated with a Waters autopurification system (column: XSelect CSH C18 5 μm, 19 × 150 mm; solvent: MeOH/H2O, 46:54; flow rate: 20.0 mL/min; wavelength: 230 nm) to give fractions Fr.3.1 (580 mg, 0.0−7.0 min), Fr.3.2 (2.2 g, 13.0−23.0 min), and Fr.3.3 (410 mg, 23.0−36.0 min). Fr.3.1 (580 mg) was separated by semipreparative HPLC (column: XBridge C18 5 μm, 10 × 150 mm; solvent: CH3CN/H2O, 9:91; flow rate: 5.0 mL/min) to afford Fr.3.1.1 (11.0−12.5 min), which was further purified by 1480



Article

semipreparative HPLC (column: XBridge C18 5 μm, 10 × 150 mm; solvent: CH3CN/H2O, 14:86; flow rate: 5.0 mL/min) to obtain compound 13 (5.4 mg, tR 6.1 min). Fr.3.2 (2.2 g) was separated by semipreparative HPLC (column: XBridge C18 5 μm, 10 × 150 mm; solvent: CH3CN/H2O, 25.5:74.5; flow rate: 5.0 mL/min) to give Fr.3.2.1 (19.0−26.0 min), which was further purified by semipreparative HPLC (column: XBridge C18 5 μm, 10 × 150 mm; solvent: CH3CN/H2O, 33:67; flow rate: 5.0 mL/min) to obtain compound 2 (32.8 mg, tR 12.0 min). Fr.3.3 (410 mg) was separated by semipreparative HPLC (column: XBridge C18 5 μm, 10 × 150 mm; solvent: CH3CN/H2O, 27:73; flow rate: 5.0 mL/min) to give compound 7 (7.1 mg, tR 21.5 min). Chiral HPLC Separations and Theoretical ECD Calculations. Details are shown in the Supporting Information. (+)-Pyracyclumine A [(+)-1]: yellow, amorphous powder; [α]25D +82.2 (c 0.07, MeOH); UV (MeOH) λmax (log ε) 366 (4.18) nm, 243 (3.80) nm; ECD (MeOH) 325 (Δε −2.66), 272 (Δε +10.22), 247 (Δε −13.65), 209 (Δε +5.30) nm; 1H and 13C NMR data, see Table 1; (+)-HRESIMS m/z 343.2394 [M + H]+ (calcd for C21H31N2O2, 343.2386). (−)-Pyracyclumine A [(−)-1]: yellow, amorphous powder; [α]25D −68.7 (c 0.07, MeOH); UV (MeOH) λmax (log ε) 366 (4.18) nm, 243 (3.80) nm; ECD (MeOH) 324 (Δε +3.01), 272 (Δε −11.19), 247 (Δε +15.07), 209 (Δε −6.04) nm; 1H and 13C NMR data, see Table 1; (+)-HRESIMS m/z 343.2394 [M + H]+ (calcd for C21H31N2O2, 343.2386). (+)-Pyracyclumine B [(+)-2]: yellow, amorphous powder; [α]25D +352.0 (c 0.10, MeOH); UV (MeOH) λmax (log ε) 450 (4.47) nm, 271 (4.01) nm, 247 (3.93) nm; ECD (MeOH) 382 (Δε +7.37), 275 (Δε +7.36) nm; 1H and 13C NMR data, see Table 1; (+)-HRESIMS m/z 287.2119 [M + H]+ (calcd for C18H28N2O, 287.2123). (−)-Pyracyclumine B [(−)-2]: yellow, amorphous powder; [α]25D −354.0 (c 0.10, MeOH); UV (MeOH) λmax (log ε) 450 (4.47) nm, 271 (4.01) nm, 247 (3.93) nm; ECD (MeOH) 380 (Δε −8.10), 274 (Δε −7.51) nm; 1H and 13C NMR data, see Table 1; (+)-HRESIMS m/z 287.2119 [M + H]+ (calcd for C18H28N2O, 287.2123). (+)-Pyracyclumine C [(+)-3]: white, amorphous powder; [α]25D +300.0 (c 0.02, MeOH); UV (MeOH) λmax (log ε) 344 (4.02), 228 (3.82) nm; ECD (MeOH) 346 (Δε + 11.44), 260 (Δε −14.37), 210 (Δε −5.46) nm; 1H and 13C NMR data, see Table 1; (+)-HRESIMS m/z 319.2033 [M + H]+ (calcd for C18H27N2O3, 319.2022). (−)-Pyracyclumine C [(−)-3]: white, amorphous powder; [α]25D −285.0 (c 0.02, MeOH); UV (MeOH) λmax (log ε) 344 (4.02), 228 (3.82) nm; ECD (MeOH) 346 (Δε −10.29), 260 (Δε +13.04), 209 (Δε + 3.80) nm; 1H and 13C NMR data, see Table 1; (+)-HRESIMS m/z 319.2033 [M + H]+ (calcd for C18H27N2O3, 319.2022). (+)-Pyracyclumine D [(+)-4]: white, amorphous powder; [α]25D +134.8 (c 0.02, MeOH); UV (MeOH) λmax (log ε) 319 (3.69) nm; ECD (MeOH) 338 (Δε +7.16), 290 (Δε −3.54), 226 (Δε +2.04) nm; 1 H and 13C NMR data, see Table 1; (+)-HRESIMS m/z 353.2094 [M + H]+ (calcd for C18H29N2O5, 353.2076). (−)-Pyracyclumine D [(−)-4]: white, amorphous powder; [α]25D −85.0 (c 0.02, MeOH); UV (MeOH) λmax (log ε) 319 (3.69) nm; ECD (MeOH) 338 (Δε −7.78), 291 (Δε +4.05), 224 (Δε −3.03) nm; 1H and 13C NMR data, see Table 1; (+)-HRESIMS m/z 353.2094 [M + H]+ (calcd for C18H29N2O5, 353.2076). (+)-Pyracyclumine E [(+)-5]: yellow, amorphous powder; [α]25D +25.9 (c 0.19, MeOH); UV (MeOH) λmax (log ε) 339 (4.01), 272 (3.88), 231 (3.75), 199 (3.90) nm; ECD (MeOH) 306 (Δε −1.30), 270 (Δε +7.46) nm; 1H and 13C NMR data, see Table 2; (+)-HRESIMS m/z 305.2215 [M + H]+ (calcd for C18H29N2O2, 305.2229). (−)-Pyracyclumine E [(−)-5]: yellow, amorphous powder; [α]25D −23.2 (c 0.19, MeOH); UV (MeOH) λmax (log ε) 339 (4.01), 272 (3.88), 231 (3.75), 199 (3.90) nm; ECD (MeOH) 306 (Δε +1.01), 268 (Δε −7.01) nm; 1H and 13C NMR data, see Table 2; (+)-HRESIMS m/z 305.2215 [M + H]+ (calcd for C18H29N2O2, 305.2229). Pyracyclumine F (6): yellow, amorphous powder; [α]20D +1.0 (c 0.07, MeOH); UV (MeOH) λmax (log ε) 317 (3.76), 226 (3.71), 199

(3.76) nm; 1H and 13C NMR data, see Table 2; (+)-HRESIMS m/z 319.2024 [M + H]+ (calcd for C18H27N2O3, 319.2022). Pyracyclumine G (7): yellow, amorphous powder; [α]20D +0.5 (c 0.20, MeOH); UV (MeOH) λmax (log ε) 339 (3.82), 274 (3.79) nm; 1 H and 13C NMR data, see Table 2; (+)-HRESIMS m/z 345.2554 [M + H]+ (calcd for C21H33N2O2, 345.2542). Pyracyclumine H (8): yellow, amorphous powder; [α]20D +2.5 (c 0.08, MeOH); UV (MeOH) λmax (log ε) 324 (2.43), 222 (3.92) nm; 1 H and 13C NMR data, see Table 3; (+)-HRESIMS m/z 262.1924 [M + H]+ (calcd for C15H24N3O, 262.1919). Pyracyclumine I (9): yellow, amorphous powder; [α]20D +2.0 (c 0.20, MeOH); UV (MeOH) λmax (log ε) 336 (4.07), 224 (4.17) nm; 1 H and 13C NMR data, see Table 3; (+)-HRESIMS m/z 265.1914 [M + H]+ (calcd for C15H25N2O2, 265.1916). Pyracyclumine J (10): white, amorphous powder; [α]20D +4.0 (c 0.10, MeOH); UV (MeOH) λmax (log ε) 219 (3.98) nm; 1H and 13C NMR data, see Table 3; (+)-HRESIMS m/z 196.1334 [M + H]+ (calcd for C11H18NO2, 196.1338). Interfering Menin−Mixed Lineage Leukemia 1 Protein− Protein Interaction Assays. See ref 16.

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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.8b00239. Chiral HPLC separations of compounds 1−5; theoretical ECD calculations of the enantiomers; 1D and 2D NMR spectra of 1−13; UV spectra, (+)-HRESIMS, and ECD data (PDF)

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AUTHOR INFORMATION

Corresponding Author

*Tel: 86-0991-3835679. Fax: 86-0991-3835679. E-mail: haji@ ms.xjb.ac.cn. ORCID

Qi-Bin Chen: 0000-0002-6892-9401 Haji Akber Aisa: 0000-0003-4652-6879 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge the National Natural Science Foundation of China (No. U1703235) and the Central Asian Drug Discovery & Development Centre of Chinese Academy of Sciences for financial support.

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REFERENCES

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