Limonoids from the leaves of Soymida febrifuga and their insect antifeedant activities

Bioorganic & Medicinal Chemistry Letters 24 (2014) 888–892

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Limonoids from the leaves of Soymida febrifuga and their insect antifeedant activities P. Ashok Yadav a, G. Suresh a, M. Suri Appa Rao a, G. Shankaraiah a, P. Usha Rani b, K. Suresh Babu a,⇑ a b

Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 607, India Biology and Biotechnology Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 607, India

a r t i c l e

i n f o

Article history: Received 23 September 2013 Revised 12 December 2013 Accepted 19 December 2013 Available online 26 December 2013 Keywords: Soymida febrifuga Meliaceae Limonoids seco-Limonoids Antifeedant activity

a b s t r a c t Three new phragmalin-type limonoids (1–3) were isolated from the leaves of Soymida febrifuga together with thirteen known limonoids. The structures of these compounds were established on the basis of spectroscopic data. All these isolates were evaluated for their anti-feedant activities in tobacco caterpillar (Spodoptera litura) and castor semilooper (Achaea janata) using a no-choice laboratory bioassay. Among the tested, compounds 9 and 15 demonstrated the potent anti-feedant index (76.46 lg/cm2, 66.61 lg/ cm2 against A. janata, and 61.69 lg/cm2, 51.93 lg/cm2against S. litura). Ó 2013 Elsevier Ltd. All rights reserved.

The severe damage caused to the ecology and environment as well as human health due to the usage of synthetic pesticides necessitated a shift to natural products based agrochemicals, as they are biodegradable, eco-friendly, and safe to the environment.1 Plants produce a diverse range of secondary metabolites such as alkaloids, flavonoids, quinones and limonoids, etc as a part of their defence mechanism against insects. Among these classes, meliaceous limonoids have attracted chemists globally because of their diversified structures and effects against insects; especially those of agricultural importance.2 The meliaceous plants have proved to produce a variety of antifeedant limonoids, such as azadirachtin, etc.3 Soymida febrifuga Juss. is a large meliaceous tree distributed mainly in the tropical areas of Asia and one of the most popular traditional medicines in India.4 The decoction of the bark is extensively used for the treatment of wounds, dental diseases, uterine bleeding, haemorrhage, stomach pains and as anticancer agent.5 The bark is also employed in intermittent fevers and general debility, in advanced stages of dysentery and diarrhoea.6 It is considered to be as good as the cinchona bark for the treatment of malaria.6 Previous phytochemical investigations of this plant yielded an array of structurally diverse limonoids, coumarins, flavones and homoisoflavans.7 As part of our continuing efforts for the novel bioactive limonoids from meliaceae plants,8 recently, we have reported the ⇑ Corresponding author. Tel.: +91 40 27191881; fax: +91 40 27160512. E-mail address: [email protected] (K.S. Babu). 0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmcl.2013.12.077

isolation and characterization of two unusual limonoids from ethyl acetate extract of bark of S. febrifuga.9 These structurally diverse and biologically interesting metabolites have encouraged us to continue our chemical study of this plant. As an ongoing investigation on the constituents of this plant, three new phragmalin type limonoids (1–3) together with thirteen known compounds (4–16) were isolated from the methanol extract of leaves of S. febrifuga. Herein, we describe the isolation and structure elucidation of these new compounds (1–3), along with the antifeedant activity of all the isolates against the third instar larvae of Spodoptera litura and Achaea janata by a conventional leaf disk method. Compound 1 was isolated as a light yellow liquid with ½a25 D +26 (c 1.0, CHCl3), and its molecular formula was established as C38H44O16 by positive molecular ion peak at m/z 757.2700 [M+H]+ (calcd 757.2702) in HRESIMS, indicating 17 degrees of unsaturation. The IR absorptions at 3448, and 1739 cm1 suggested the presence of hydroxy, ester groups. The 1H NMR spectrum (Table 1) displayed resonances for a b-substituted furan ring at d 7.50 (1H, d, J = 0.7 Hz, H-21), 6.47 (1H, d, J = 1.1 Hz, H22) and 7.43 (1H, J = 0.7 Hz, H-23), four oxymethines at d 5.34 (1H, s, H-3), 5.49 (1H, t, J = 3.0 Hz, H-11), 5.82 (1H, s, H-17), and 5.35 (1H, s, H-30) and eight methyl singlets at d 2.05 (3H, s, Ac), 2.18 (3H, s, Ac), 1.40 (3H, s, H-19), 0.66 (3H, s, H-28), 1.51 (3H, s, H-32), and 1.68 (3H, s, H-18), 1.55 (3H, s, H-40 ), 1.31(3H, q, J = 5.4 Hz, H-50 ). The 13C NMR spectrum of 1 (Table 1), together with the information from a DEPT spectrum, showed the presence of 38 carbon signals assigned to eight methyls (including tigloyl, acetyl methyls), three methylenes, ten methines (olefinic, three

889

P. A. Yadav et al. / Bioorg. Med. Chem. Lett. 24 (2014) 888–892 Table 1 H & 13C NMR data of compounds 1, 2 & 3 in CDCl3 (300 MHz, d in ppm, mult, J in Hz)

1

S. no

Compound 1

Compound 2

Compound 3

1

H NMR (d in ppm,mult, J)

13

C NMR (d in ppm)

1

H NMR (d in ppm,mult, J)

13

C NMR (d in ppm)

1

H NMR (d in ppm,mult)

13

1 2 3 4 5 6 7 8 9 10 11

— — 5.34 (1H, s) — 2.37–2.23 (1H, m) 2.38–2.23 (2H, m) — — — — 5.49 (1H, t, J = 3.0 Hz)

84.7 84.3 85.5 44.5 39.4 33.8 173.3 83.2 84.2 48.2 66.0

— — 5.31 (1H, s) — 2.90 (1H, dd, J = 3.0, 12.0 Hz) 2.51–2.35 (2H, m) — — — — 2.09–2.01 (2H, m)

84.1 84.6 82.1 46.2 36.0 34.0 172.8 82.4 84.6 47.5 25.1

79.6 76.1 88.7 42.4 38.1 33.6 173.6 138.7 42.6 45.0 21.8

12

1.86–1.77 (1H, m) 1.54–1.52 (1H, m) — — 6.53 (1H, s) — 5.82 (1H, s) 1.68 (3H, s) 1.40 (3H, s) — 7.50 (1H, d, J = 0.7 Hz) 6.47 (1H, d, J = 1.1 Hz) 7.43 (1H, d, J = 0.7 Hz) 0.66 (3H, s) 1.98 (1H, d, J = 11 Hz) 1.75 (1H, d, J = 11 Hz) 5.35 (1H, s) — 1.51 (3H, s) — — 3.13 (1H, q, J = 5.2 Hz) 1.55 (3H, s) 1.31 (3H, q, J = 5.2 Hz) — — — — 3.70 (3H, s) — 2.05 (3H, s) — 2.18 (3H, s) 3.44 (1H, br s) —

34.5

1.46–1.39 (2H, m)

26.3

— — 4.25 (1H, s) — 2.77–2.72(1H, m) 2.34–2.23 (1H, m) — — 1.97–1.88 (1H, m) — 1.72–1.60 (1H, m), 2.14–2.01 (1H, m) 1.45–1.35 (2H, m)

36.8 148.4 123.7 164.2 79.6 16.0 15.8 119.7 141.8 110.0 143.0 14.1 39.62

— — 6.05 (1H, s) — 5.20 (1H, s) 1.14 (3H, s) 1.19 (3H, s) — 7.55 (1H, br s) 6.47 (1H, br s) 7.43 (1H, br s) 0.90 (3H, s) 2.04–2.0 (1H, m) 1.71–1.61(1H, m) 5.93 (1H, s) — 1.64 (3H, s) — — 3.24 (1H, q, J = 5.2 Hz) 1.66 (3H, s) 1.36 (3H, d, J = 5.2 Hz) — 2.31–2.21 (2H, m) 1.08 (3H, t, J = 7.5 Hz) — 3.69 (3H, s) — — — 2.15 (3H, s) — —

37.8 161.0 120.4 163.3 80.3 19.0 16.7 119.3 141.4 109.8 143.0 14.7 40.0

— 2.34–2.23 (1H, m) 2.88–2.74 (2H, m) — 5.28 (1H, s) 1.04 (3H, s) 1.11 (3H, s) — 7.58 (1H, J = 0.9 Hz) 6.40 (1H, d, J = 1.1 Hz) 7.40 (1H, d, J = 0.9 Hz) 0.93 (3H, s) 2.03–1.97 (1H, m) 1.72–1.64 (1H, m) 5.05 (1H, br s) — — — — 7.01 (1H, q, J = 5.9 Hz) 1.79 (3H, s) 1.52 (3H, d, J = 5.9 Hz) — — — — 3.70 (3H, s) — — — — 3.30 (1H, br s) 3.65 (1H, br s)

37.0 44.7 29.8 169.1 76.0 21.2 16.1 120.8 141.2 109.6 143.0 14.8 41.0

13 14 15 16 17 18 19 20 21 22 23 28 29 30 31 32 10 20 30 40 50 100 200 300 OH-30 OMe OCO (at11) CH3 OCO (at-2) CH3 OH-1 OH-2

74.3 119.7 20.8 170.9 57.8 57.4 13.8 20.8 — — — — 52.1 169.4 21.0 170.1 21.8 — —

furanoid methines, and two methines) and sixteen non-protonated carbons (five ester carbonyl, two olefinic, one orthoester, four oxygen attached, three quaternary carbons in the junction, one epoxide carbon), and one methoxy carbon. Two of the carbonyl resonances were attributed to acetyl groups, on the basis of HMBC correlations between the acetyl methyl protons and the respective carbonyl resonances (Fig. 2). The NMR data (Table 1) were indicative of a polyoxygenated phragmalin, similar to those of soymidin B, which is also isolated from the S. febrifuga,9 with the exception that 1 contains two acetyl groups instead of one. A close comparison of the 13C NMR spectra revealed that C-2 of 1 shifted to d 84.3, 9.2 ppm further downfield in contrast to d 75.1 of the soymidin B. The complete structure of 1 was determined by detailed analysis of 1D and 2D NMR data, especially the HMBC spectrum (Fig. 2). The presence of another acetoxyl group at C-11 was evident from the HMBC correlations of proton at d 5.49 (1H, t, J = 3.0 Hz) with C-8 (d 83.23), C-9 (d 84.25) (Fig. 2). The relative stereochemistry of 1 was proposed based on biosynthesis of limonoids followed by the interpretation of NOE spectra and coupling con-

68.7 119.6 21.0 170.4 57.7 58.1 12.9 13.4 172.7 27.5 8.6 — 52.0 — — 170.0 21.9 — —

C NMR (d in ppm)

34.6

121.9 — — 169.2 127.6 139.7 11.7 14.5 — — — — 51.8 — — — — — —

stants. The configuration of A1, A2, B, C and D rings of 1 were assumed to be the same as that of the several known phragmalintype limonoids bearing the same skeleton.9 As depicted in the Figure 2, the NOE strong cross peaks H-3/H-29a, H3-18/H-3, and H3-18/H3-19 indicated that H-18, H-3, H-29a and H-19 were a-oriented. Similarly, NOE correlations between H-17/H-12b, H-30/H3-28 and H3-28/H-5, H-17/H-11, determined the b-orientation of H-17, H3-28, H-30, H-11 and H-5 (Fig. 2). Based on these spectral data, the gross structure of 1 was established as 2, 11-O, O-diacetyl epoxy febrinin, which was trivially named as 2-acetyl soymidin B. Compound 2 was isolated as white amorphous powder with 1 ½a25 D 31.60 (c 0.3, CHCl3). The IR absorption peaks at 1740 cm implied the presence of carbonyl functional groups. The molecular formula was determined as C39H46O15 by HRESIMS, which provided the molecular ion peak at m/z 755.2908 [M+H]+ (calcd 755.2909), in conjunction with its 13C NMR displaying 39 carbons. A DEPT NMR spectrum permitted the differentiation of 39 carbons into nine methyls, nine methines, five methylene, and sixteen quaternary carbons. The 1H NMR spectrum (recorded in CDCl3)

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22

21 18

20

H3C AcO 12 O O 19 11 13 9 7 H 10 8 14 6 29 5 OHO O 1 30 O 4 3 2 28 OAc O O

O

O

23

O

CH3 O H

O

17

O

16

15

O

31

32

O

O

O

O

CH3 O H

O

O

O OAc O O

O

O O

OH OH O

O

1' 2'

O

3'

4'

O O

O

O

CH3 O H

O

OH OH

O O

O

CH3 O H

O

H

O

O

O

O

CH 3 O H

O

O O

O

O

O

OAc

OAc

9

10

O

O

H3C AcO O H

O

O

O

O

CH3 O H

O O OH

O

O CH3

O O

OR1 O

O R2

11

O

O

O O

H O

12 R1 = H, R2 = 2-methyl butyl 13 R1 = Acetyl, R2 = Ethyl 14 R1 = H, R2 = Ethyl

O

O CH3 O H

8

O O

O

OAc

O

O

O

O O

O

O CH3 O H

O

CH3 O H

6 R = Tigloyl 7 R = Acetyl

5

O

O

O

OR

O CH3 4

O

O

O

O

O

3

2

1

5'

OAc OAc O O

OHO O O OH O O

O O

O 15

16 Figure 1. Isolated compounds (1–16) from Soymida febrifuga.

O

O

O

H3 C O

O CH 3 O H

H OHO

O H O H OAc O O

O

H O

O O

H3 C AcO H O

H O

H OHO H OAc H O O

O O

HMBC O

NOESY

O

Figure 2. Key HMBC and NOESY correlations of compound 1.

displayed resonances for seven methyl groups [d 1.14 (3H, s, H3-18), 1.19 (3H, s, H3-19), 0.90 (3H, s, H3-28), 1.64 (3H, s,

H3-32), 1.66 (3H, s, H3-40 ), 1.36 (3H, d, J = 5.2 Hz, H3-50 ), 1.08 (3H, t, J = 7.5 Hz, H3-300 )] and one methoxy at [d 3.69 (3H, s)], three oxygenated methine protons [d 5.31 (1H, s, H-3), 5.20 (1H, s, H-17), 5.93 (1H, s, H-30)], one acetoxyl group [d 2.15 (3H, s, (CH3)], and a characteristic orthoacetate system [d 1.64 (3H, s, H-32)], respectively. In addition, propanoyl group [d 2.31–2.21 (2H, m, H2-100 ), 1.08 (3H, t, J = 7.5 Hz, H3-300 )], and a characteristic b-furan ring at d 7.55 (1H, br s, H-21), 6.47 (1H, br s, H-22), and 7.43 (1H, br s, H-23) were also distinguished by extensive analysis of the NMR data. The analyses of the 1H and 13C NMR spectral data of 2 (Table 1) showed a high degree of similarity to the limonoid, swietenitin N10 except for the presence of double bond in the lactone ring. The appearance of signal at d 6.05(1H, s, H-15) integrating for one proton provided evidence that compound 2 was a dehydro analogue of swietenitin N. This was further corroborated by the [M++H] ion, which was 2 amu less than that of swietenitin

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N, as well as the DEPT 1350 experiment in which olefinic methine was observed (d 120.46) instead of methylene carbon. Further, HMBC correlations [d 6.05(1H, s, H-15)/C-16 (d 163.3), C-14 (d 161.0), C-13 (d 37.82)] provided the additional evidence that 2 contained the 14,15-double bond (Fig. 3). The detailed elucidation of the 2D NMR data (COSY, HSQC, and HMBC) had determined the planar structure of 2. The relative configuration of 2 was established by NOE experiments. The NOESY spectrum showed close similarities with the reported data of phragmalin type compound, swietenin N. Strong cross-peaks of H-5 with H3-28 in NOESY spectrum indicated the b-orientation of these protons. Similarly, NOE correlation of H-17 with H-30 suggested their b-orientation. Thus, structure of 2 was established as 14, 15-dehydroswietenitin N and trivially named as soymidin D. Compound 3 was isolated as white amorphous powder, with ½a25 D 51.50 (c 1.0, CHCl3), and the molecular formula was determined as C32H40O9 from HRESIMS (m/z 591.2564 [M+Na]+, calcd 591.2565), implying 13 degrees of unsaturation. The IR absorptions at 3525, 1723, 1674 cm1 showing the presence of several limonoid functionalities. The 1H NMR spectrum exhibited three tertiary methyls at d 1.04 (3H, s, H3-18), 1.11 (3H, s, H3-19), and 0.93 (3H, s, H3-28), olefinic proton at d 5.05 (1H, br s, H-30) and the resonances for a b-substituted furan ring [(d 7.58, 1H, br s, H-21), 6.40 (1H, d, J = 0.9 Hz, H-22), 7.40 (1H, d, J = 0.9 Hz, H-23)]. The proton resonances at d 7.01 (1H, q, J = 5.9 Hz, H30 ),1.79 (3H, s, H3-40 ), 1.52 (3H, d, J = 5.9 Hz, H3-50 ) were characteristic of a tigloyl group. These proton features in association with 13 C NMR data (Table 1) were consistent with a phragmalin-type structure and comparison of this spectral data with those of chisomicine B,11 clearly indicated that the structure was closely related, except for the absence of epoxide and presence of double bond at C8–C30, hydroxyl group at C-2. The complete structure of 3 was confirmed by the analysis of its HMBC spectrum (Fig. 4), in which the key HMBC correlations of two mutually coupled proton signals at dH 2.88–2.74 and 2.34–2.23 (H2-15 & H-14) to a lactone carbonyl carbon at dC 169.1 (C-16), inferred the existence of a six-membered lactone (ring D). The key HMBC correlations of H-30 (dH 5.05, 1H, br s) to C-8 (dC 138.7) and C-2 (dc 76.7) confirmed the position of the olefinic bond at C8–C30. Similarly, b-furyl ring was attached to C-17 in the D-ring which was supported by the HMBC correlations of H-17 (dH 5.28, 1H, s)/C-20 (dc 120.8), C-21(dc 141.2), and C-22 (dc 109.6). The presence of tigloyl group in A2 ring at C-3 was supported by HMBC correlation between H-3[dH 4.25(1H, s)/C-10 , H-30 (dH 7.01, 1H, q, J = 5.9 Hz)/ C-10 , H-40 (dH 1.79, 3H, s)/C-10 (d 169.2)] (Fig. 4). The cross-peaks between H-3 (dH 4.25(1H, s)/C-2(76.1), H-30(5.05, 1H, br s)/C-2 (76.1) and H2-29/C-1(79.6), observed in HMBC spectrum confirmed the positions of hydroxyl groups at C-2 and C-1. The relative configuration of 3 corresponded to that of chisomicine B on the basis of similar NMR and NOE data (Fig. 4). Thus, the

O CH 3 O

O

O H

H O

O

H

O

O

O H OAc O H O

O O O

CH 3 O H

O H

H O

O O

O

O H OAc O O

O O

O

Figure 3. Key HMBC & NOESY correlations of 2.

HMBC NOESY

O

O

O H

H 3C O H

O OH

HO

OH O

H

O O

H3C O H

H O OH

H

O

HMBC NOESY

OH O

HO

Figure 4. Key HMBC & NOESY correlations of 3.

structure of 3 was assigned as shown in Figure 1 and trivially named as soymidin E. The other thirteen known compounds were identified as swiemahogin A (4),12 6-desoxyswietenine (5),13 angolensin A(6),14 methyl 3b-acetoxy-l-oxomeliac-14, 15-enoate(7),15 methyl 3b-acetoxy-l-oxo-meliac-8,30-enate (8),16 fissinolide (9),17 methyl 3b-acetoxy-l-oxomeliacate(10),18 methyl angolensate(11),19 swietephragmin C (12),20 and swietephragmin H (13),21 swietephragmin F (14),20 swietenitin O (15),10 and soymidin B (16)9 from 1H and 13C NMR data comparison with those reported in literature. The antifeedant activities of the isolates were evaluated for their efficacy against tobacco caterpillar (Spodoptera litura) and castor semilooper (Achaea janata) by using the conventional nochoice disk method, and azadirachtin was used as an active control for comparison.22 As shown in Table 2, most of the isolates exhibited antifeedant activity against the test insects. Particularly, compounds 9 and 15 demonstrated the potent antifeedant index (76.46 lg/cm2, 66.61 lg/cm2 against A. janata, and 61.69 lg/cm2, 51.93 lg/cm2 against S. litura). In topical bioassay, several of the isolates showed good toxicity (Table 3).23 Among them, compound 15 was extremely toxic with LC50 of 0.65 and 0.75 lg/cm2 against the both insects while 9 showed toxicity against S. litura. The remaining compounds were moderate toxic to the test insects. It must be pointed out that toxicity and antifeedancy are directly proportional, suggesting similar structural requirements for the toxicity studies too. Overall, these results imply that the mode of perception as well as the struc-

Table 2 Antifeedant activity of compounds against Achaea janata and Spodoptera litura by leaf disk method AFI+SEa (1.5 lg/cm2)

Compound

MeOH extract 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Azadirachtinb

A. janata

S.litura

27.69 ± 0.61 56.74 ± 0.75 NI 40.31 ± 1.20 37.92 ± 0.84 NI NI 52.87 ± 1.94 37.14 ± 1.04 76.46 ± 1.62 NI NI 34.83 ± 0.86 NI 41.19 ± 1.15 66.61 ± 0.80 NI 100 ± 0.00

23.32 ± 1.06 43.02 ± 0.79 NI 47.54 ± 0.81 23.83 ± 1.16 NI NI 23.09 ± 0.54 40.09 ± 0.77 61.69 ± 0.58 NI NI 32.81 ± 0.69 NI 30.78 ± 1.16 51.93 ± 0.92 NI 100 ± 0.00

a Values are mean ± SE, NI-not included in statistical data as the activity was low (AFI is below 20). b Azadirachtin at a dose of 1.5 lg/cm2.

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Table 3 Toxicity effects of compounds against Achaea janata and Spodoptera litura by a topical bioassay LC50 (95% FLa) lg/cm2

Compound

MeOH extract 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Azadirachtinb

A. janata

S. litura

60.2 (54.4–65.6) 07.5 (5.3–09.4) — 13.5 (11.1–16.3) 13.4 (11.1–15.9) — — 10.8 (8.5–13.3) 10.7 (08.5–13.2) 8.6 (6.7–10.7) — — 9.3 (7.5–11.2) — 10.0 (9.4–10.7) 0.65 (0.05–0.95) — 0.024 (0.002–0.093)

53.7 (47.1–59.2) 05.4 (02.9–07.9) — 7.4 (3.2–11.2) 10.4 (06.8–16.0) — — 9.7 (0.90–1.04) 8.2 (0.65–0.99) 0.77 (0.551–1.04) — — 8.6 (6.6–10.5) — 11.9 (10.0–14.2) 0.75 (0.61–0.91) — 0.013 (0.006–0.041)

a Values are mean ± SE, NI-not included in statistical data as the activity was low (AFI is below 20). b Azadirachtin at a dose of 1.5 lg/cm2.

ture–activity relationship of the isolates differs considerably between the insect species examined in this study. However, some of these compounds were highly promising as toxicants as well as antifeedants against the two prominent agricultural pests and the future evaluation of the other pest species susceptibility likely to yield better pest management compounds for the use in various other agricultural crops. Considering the advantages of using botanical insecticides for the pest management, it can be concluded that methanol extract of S. febrifuga, could have great potential for the control of pests. From this active extract, three new compounds derivatives (1–3) along with thirteen known compounds were isolated, and were shown to be insect antifeedants and toxicants too. By keeping these results in the mind, the studies will be extended to stored product and a few other agricultural pests.

Acknowledgments This work was financially supported by NaPAHA project grant CSC-0130 from the Council of Scientific and Industrial Research (CSIR), New Delhi, India under XII FYP Network program. Authors thank director, CSIR-Indian Institute of Chemical Technology for her constant encouragement. P.A.Y., M.S.A., and G.S. thank to CSIR for financial support.

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