Alkaloids with Nitric Oxide Inhibitory Activities from the Roots of Isatis tinctoria

Dongdong Zhang; Yanhong Shi; Jingyi Li; Deqing Ruan; Qi Jia; Weiliang Zhu; Kaixian Chen; Yiming Li; Rui Wang

doi:10.3390/molecules24224033

. 2019 Nov 7;24(22):4033. doi: 10.3390/molecules24224033

Alkaloids with Nitric Oxide Inhibitory Activities from the Roots of Isatis tinctoria

Dongdong Zhang ^1,^†, Yanhong Shi ^2,^†, Jingyi Li ¹, Deqing Ruan ¹, Qi Jia ¹, Weiliang Zhu ³, Kaixian Chen ^1,³, Yiming Li ^1,^*, Rui Wang ^1,^*

PMCID: PMC6891263 PMID: 31703370

Abstract

As our ongoing research project on Ban Lan Gen (Isatis tinctoria roots), a total of 23 alkaloids were obtained. Compounds 1 and 2 contain an unusual C–C bond between the 2(1H)-quinolinone moiety and the phenol moiety and between the 2(1H)-quinolinone moiety and the 1H-indole moiety, respectively. Compound 3 possesses an unusual carbon skeleton and its putative biosynthetic pathway was discussed, and Compound 23 was deduced as a new indole alkaloid glycoside. Compounds 4–7 were identified as four new natural products by extensive spectroscopic experiments. Additionally, the anti-inflammatory activity was assessed based on nitric oxide (NO) production using Lipopolysaccharide-stimulated RAW264.7 macrophages. Compounds 9, 15, and 17 showed inhibitory effects with IC₅₀ values of 1.2, 5.0, and 74.4 μM.

Keywords: Isatis tinctoria roots, alkaloids, structure identification, anti-inflammatory activity

1. Introduction

Isatis tinctoria L. (synonym, Isatis indigotica Fort.), named Ban Lan Gen in the Chinese Pharmacopoeia, belongs to the gene Isatis (Brassicaceae family), which is widely distributed and cultivated in the North of the Yangtze River, China [1,2,3,4]. Alkaloids were considered as one of the characteristic constituents of this plant, which possess diverse bioactivities such as anti-inflammatory, antiviral, antibacterial, antitumor, and antioxidant activities [5,6,7]. Up to now, more than 100 alkaloids have been isolated from I. tinctoria, such as indole alkaloids, quinazolone alkaloids, quinoline alkaloids, and so on [1,2,3,4,5]. As our ongoing phytochemical and pharmacological research project on this plant [8,9,10,11,12], four new alkaloids and four new natural products, along with 15 known analogues, were obtained, and their structures and absolute configurations were determined by extensive spectroscopic data analysis, including one-dimensional and two-dimensional-NMR, HRESIMS, and IR, specific rotation data, and electronic circular dichroism (ECD) experiments. The known compounds (4–22, Figure 1) were identified by comparison of their spectroscopic and optical rotation data with those in the reported literature as 4-p-hydroxyphenyl-2(1H)-quinolinone (4) [13], 2-(1H-indol-2-yl)-6-methoxy-4(3H)-quinazolinone (5) [14], 2-(2-hydroxyphenyl)-4(3H)-quinazolinone (6) [15], 2-(but-3-en-1-yl)-4(3H)-quinazolinone (7) [16], 2-(1H-indol-2-yl)-4(3H)-quinolinone (8) [17], tryptanthrin (9) [18], 3-(2,4-dioxo-1,2- dihydroquinazolin-3(4H)-yl)propanoic acid (10) [19], indiforine C (11) [3], 4-(2,4-dioxo-1,2- dihydroquinazolin-3(4H)-yl)butanoic acid (12) [20], methyl 4-(2,4-dioxo-1,2-dihydroquinazolin- 3(4H)-yl)butanoate (13) [21], 3-(2-hydroxyphenyl)-4(3H)-quinazolinone (14) [22], 3-(2-carboxyphenyl)-4(3H)-quinazolinone (15) [23], 4-methyl-1,2-dihydro-2-oxoquinazoline (16) [24], 2-methyl-4(3H)-quinazolinone (17) [25], 4-hydroxy-3-methyl-2(1H)-quinolinone (18) [26], 2-amino-4-quinolinecarboxylic acid (19) [27], 4(1H)-quinolinone (20) [28], 4(1H)-quinolone-3- carboxylic acid (21) [29], and 1,2,3,4-tetrahydro-4-hydroxy-quinolinecarboxylic acid (22) [30]. The NO inhibitory activities of the isolates (1–23) were also evaluated against the LPS-stimulated RAW264.7 macrophages. In the present paper, we report the isolation and structure determination, putative biosynthetic pathway, and the NO inhibitory activities of these alkaloids.

2. Results and Discussion

Isatisindigoticanine E (1) was obtained as a yellow amorphous powder. The molecular formula was assigned as C₁₅H₁₁NO₃ on the basis of the negative ion HRESIMS peak at m/z 252.0666 [M − H]⁻ (calculated 252.0666 [M − H]⁻), together with its one-dimensional-NMR data (Table 1). The ¹H-NMR spectrum displayed signals of a 1,2,4-trisubstituted benzene ring [31] at [δ_H 7.20 (1H, d, J = 2.2 Hz, H-5), 6.63 (1H, dd, J = 8.3, 2.2 Hz, H-7), and 6.66 (1H, d, J = 8.3 Hz, H-8)], a 1,4 disubstituted benzene ring at [δ_H 7.57 (2H, d, J = 8.5 Hz, H-2’,6’) and 6.90 (2H, d, J = 8.5 Hz, H-3’, 5’) and also showed a trisubstituted double bond [9] at δ_H 7.48 (1H, s, H-3) and three exchangeable protons at δ_H 10.19 (1H, brs, NH-1), 10.12 (1H, brs, OH-6), and 8.96 (1H, brs, OH-4’). The ¹³C-NMR spectrum showed 15 carbon signals, among which 7 × C carbons at δ_C (169.5, 159.6, 152.2, 135.4, 126.1, 125.4, 122.5) and 8 × CH carbons at δ_C (136.7, 132.1, 132.1, 116.5, 116.1, 116.1, 110.7, 110.1) were found based on the DEPT 135 experiment. The two-dimensional-NMR spectroscopic features confirmed the inference above. The proton and protonated carbon resonances in the NMR spectra of 1 were unambiguously assigned by the HSQC experiments [32,33]. The ¹H-¹H COSY correlations (Figure 2) of H-2’,6’/H-3’,5’, along with HMBC correlations (Figure 2) of H-2’/C-4’ and H-3’/C-1’, indicated a phenol moiety in 1 [31]; ¹H-¹H COSY correlations of H-7/H-8, along with the HMBCs of NH-1/C-2, C-8, and C-8a, H-3/C-2, and C-4, and H-5/C-4 and C-7, indicated a 6-hydroxy-2(1H)-quinolinone moiety in 1 [34]; HMBCs of H-3/C-1’ and H-2’,6’/C-4 confirmed the 6-hydroxy-2(1H)-quinolinone moiety connected with the phenol moiety via a C-4-C-1’ bond. The structure of 1 was then determined, as depicted in Figure 1.

Table 1.

¹H-NMR (600 MHz in DMSO-d₆) and ¹³C-NMR data (150 MHz in DMSO-d₆) of 1–3.

No.	1		2		3
No.	δH	δC	δH	δC	δH	δC
1	10.19, s		12.06, brs
2		169.5		168.3		156.8
3	7.48, s	136.7	8.63, s	130.6
4		126.1		118.8		160.5
4a		122.5		116.8		120.3
5	7.20, d (2.2)	110.1		155.0	8.13, d (8.0)	126.3
6		152.2	6.67, d (7.5)	102.6	7.47, dd (8.0, 7.2)	126.0
7	6.63, dd (8.3, 2.2)	110.7	7.15, overlap	123.9	7.82, dd (8.1, 7.2)	134.9
8	6.66, d (8.3)	116.5	6.85, d (7.3)	106.2	7.72, d (8.1)	126.2
8a		135.4		138.0		148.8
1’		125.4	10.51, s		11.98, brs
2’	7.57, d (8.5)	132.1		112.5	7.84, d (2.2)	128.3
3’	6.90, d (8.5)	116.1	9.45, s	133.5		112.5
3’a				126.3		127.4
4’		159.6	7.50, d (7.5)	117.9	7.87, d (7.5)	118.5
5’	6.90, d (8.5)	116.1	7.15, overlap	121.1	7.22, dd (8.1, 7.5)	120.9
6’	7.57, d (8.5)	132.1	7.00, dd (7.5, 7.4)	127.0	7.25, dd (8.1, 7.5)	123.0
7’			7.14, overlap	109.5	7.50, d (7.5)	112.6
7’a				139.4		136.4
1’’					8.13, s	122.6
2’’						125.6
3’’					3.17, 2H, m	26.2
4’’					4.25, 2H, t (7.0)	44.7
OMe			4.04, s	55.9
6-OH	10.12, s
4’-OH	8.96, s

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Key ¹H-¹H COSY and HMBC correlations of Compounds 1–3 and 23.

Isatisindigoticanine F (2) was obtained as a yellow amorphous powder. The molecular formula was assigned as C₁₈H₁₄N₂O₂ by the one-dimensional-NMR data and the HRESIMS positive ion peak at m/z 291.1125 [M + H]⁺ (calculated 291.1128 [M + H]⁺). The ¹H-NMR spectrum (Table 1) of 2 showed signals of a 1,2,3-trisubstituted benzene ring at [δ_H 6.67 (1H, d, J = 7.5 Hz, H-6), 7.15 (1H, overlap, H-7) and 6.85 (1H, d, J = 7.3 Hz, H-8)], an ortho-disubstituted benzene ring at [δ_H 7.50 (1H, d, J = 7.5 Hz, H-4’), 7.15 (1H, overlap, H-5’), 7.00 (1H, dd, J = 7.5, 7.4 Hz, H-6’) and 7.14 (1H,overlap, H-7’)] [35]; two trisubstituted double bonds at δ_H 8.63 (1H, s, H-3) and 9.54 (1H, s, H-3’), as well as two exchangeable protons at δ_H 12.06 (1H, brs, NH-1) and 10.51 (1H, brs, NH-1’) and a methoxy group at δ_H 4.04 (3H, s, 5-OMe). After analysis of the ¹³C-NMR, DEPT 135 and HSQC data (Table 1), a 1H-indol-2-yl moiety (112.5, C; 133.5, CH; 126.3, C; 117.9, CH; 121.1, CH; 127.0, CH; 109.5, CH; 139.4, C) [8,10] and a 5-methoxy-2(1H)-quinolinone moiety (168.3, C; 130.6, CH; 118.8, C; 116.8, C; 155.0, C; 102.6, CH; 123.9, CH; 106.2, CH; 138.0, C; 55.9, CH₃) were observed [34]. HMBCs of H-3/C-2’ and H-3’/C-4 indicated the 1H-indol-2-yl moiety connected with the 5-methoxy-2(1H)-quinolinone moiety via a C-4-C-2’ bond. These inferences were confirmed by detailed analysis of the two-dimensional-NMR data including HSQC, HMBC (Figure 2), and ¹H–¹H COSY (Figure 2) experiments. The structure of 2 was thus deduced, as depicted in Figure 1.

Isatisindigoticanine G (3), a yellow amorphous powder, possessed the molecular formula of C₂₀H₁₅N₃O based on the positive HRESIMS ion at m/z 314.1297 [M + H]⁺ (calculated 314.1288 [M + H]⁺) and one-dimensional-NMR data. The ¹H-NMR spectrum (Table 1) of 3 showed signals of two ortho-disubstituted benzene rings at [δ_H 8.13 (1H, d, J = 8.0 Hz, H-5), 7.47 (1H, dd, J = 8.0, 7.2 Hz, H-6), 7.82 (1H, dd, J = 8.1, 7.2 Hz, H-7) and 7.72 (1H, d, J = 8.1 Hz, H-8)] and [δ_H 7.87 (1H, d, J = 7.5 Hz, H-4’),7.22 (1H, dd, J = 8.1, 7.5 Hz, H-5’), 7.25 (1H, dd, J = 8.1, 7.5 Hz, H-6’) and 7.50 (1H, d, J = 7.5 Hz, H-7’)], two trisubstituted double bonds at δ_H 7.84 (1H, d, J = 2.2 Hz, H-2’) and 8.13 (1H, s, H-1’’), as well as an exchangeable proton at δ_H 11.98 (1H, brs, NH-1’) [35]. The ¹³C-NMR and the DEPT 135 spectra (Table 1) displayed 8 × C carbons at δ_C (160.5, 156.8, 148.8, 136.4, 127.4, 125.6, 120.3, 112.5), 10 × CH carbons at δ_C (134.9, 128.3, 126.3, 126.2, 126.0, 123.0, 122.6, 120.9, 118.5, 112.6), and 2 × CH₂ carbons at δ_C (44.7, 26.2). The two-dimensional-NMR spectra (Figure 2) of 3 showed the ¹H-¹H COSY correlations of H-5/H-6/H-7/H-8, H-3’’/H-4’’ and HMBCs from H-5/C-4 from H-1’’/C-2 and C-3’’ and from H-4’’/C-2 and C-4, which indicated a 8H-pyrido[2,1-b]-11(9H)-quinazolinone moiety in 3 [36]; ¹H-¹H COSY correlations of H-4’/H-5’/H-6’/H-7’ and the HMBCs from NH-1’/C-2’, C-3’, C-3’a, and C-7’a indicated a 1H-indol-3-yl moiety in 3 [10]. HMBCs from NH-1’/C-9 and C-6, and from H-2’/C-2’’ and H-1’’/C-3’ determined the 8H-pyrido[2,1-b]-11(9H)-quinazolinone moiety connected with the 1H-indol-3-yl moiety via a C-2’’-C-3’ bond. The structure of 3 was thus determined, as depicted in Figure 1.

Isatindigoside D (23) was isolated as a red amorphous powder with [α] $_{D}^{20}$ + 12.1° (c 0.19, MeOH). Its molecular formula of C₂₃H₂₂N₂O₇ (14 IHD) was deduced from the NMR data and the HRESIMS positive ion peak at m/z 490.1592 [M + Na]⁺, (calculated 490.1585 [M + Na]⁺). When comparing the one-dimensional (Table 2) and two-dimensional-NMR data (Figure 2) with the reported bisindoloside of isatindigobisindoloside C [35], they showed almost identical NMR spectroscopic features except for the differences around C-2 (downfield of C-2’, C-3’, and C-3’’, upfield of C-2’’). These differences, along with the optical rotation data ([α] $_{D}^{20}$ + 12.1, c 0.19 in MeOH) supported Compound 23, would be the C2-epimer of isatindigobisindoloside C ([α] $_{D}^{20}$ − 33.9, c 0.11 in MeOH) [35]. The experimental and calculated ECD curves of (2S)-23 matched well (Figure 3), which confirmed the S absolute configuration of 23 [35,37], and the calculation details are listed in the Supporting Information (Figures S33 and S34). Acid hydrolysis of 23 resulted in the product of d-glucose, which was confirmed by GC analysis of the acetylation derivative of the hydrolysate of 23 and the authentic sugars (t_R d-glucose 45.23 min, t_R l-glucose 45.38 min) [8,9]. The large coupling constant of Glc-H1 (J = 7.8 Hz) revealed the β-glucopyranosyl linkage in 23 [38,39]. Accordingly, the structure of isatindigoside D (23) was elucidated as depicted (Figure 1).

Table 2.

¹H-NMR (600 MHz in DMSO-d₆) and ¹³C-NMR data (150 MHz in DMSO-d₆) of 23.

No.	23		No.	23
No.	δ_H (J in Hz)	δ _C	No.	δ_H (J in Hz)	δ _C
1a	7.45, brs	172.9	3’’		112.1
1b	7.14, brs	172.9	3’’a		126.7
2	5.68, s	38.7	4’’	7.56, d (8.0)	118.4
1’	10.35, brs		5’’	6.93, dd (8.0, 7.1)	118.9
2’		126.8	6’’	7.04, dd (8.1, 7.1)	120.5
3’		133.0	7’’	7.32, d (8.1)	111.4
3’a		121.2	7’’a		136.0
4’	7.77, d (8.0)	118.1	Glc-1	4.63, d (7.8)	106.6
5’	6.92, dd (8.0, 7.2)	118.4	2	3.38, overlap	74.1
6’	6.97, dd (8.1, 7.2)	120.8	3	3.26, m	76.8
7’	7.26, d (8.1)	111.6	4	3.28, m	69.8
7’a		133.3	5	3.14, m	77.2
1’’	10.94, brs		6a	3.56, dd (10.8, 5.6)	61.0
2’’	7.38, s	123.9	6b	3.67, dd (10.8, 1.8)	61.0

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Experimental and calculated ECD spectra of 23.

NO is a messenger molecule that is widespread in cells and can affect a variety of physiological and pathological processes. The production of NO causes tissue damage and can trigger a variety of inflammatory diseases. LPS induces the release of NO from RAW264.7 cells by detecting the release of NO widely used to investigate the anti-inflammatory effects of the compounds [2,10,40]. As our ongoing phytochemical and pharmacological research project on I. tinctoria [8,9,10,11,12], Compounds 1–23 were obtained and were evaluated for their anti-inflammatory activity based on NO inhibitory effects in the LPS-activated RAW 264.7 cells [40]. The cytotoxicity of Compounds 1–23 were tested at three different concentrations (25, 50, and 100 μM), and the results showed that only Compound 9 showed cytotoxicity above 25 μM, while the other compounds were above 100 μM. The results of NO production showed that Compounds 9, 15, and 17 exhibited inhibitory activities with IC₅₀ values of 1.2, 5.0, and 74.4 μM (Table 3).

Table 3.

NO inhibitory activities of Compounds 1–23 in RAW 264.7 cell line.

Compounds	IC₅₀ ^a	Cytotoxicity	Compounds	IC₅₀ ^a	Cytotoxicity
1	>100	>100	1 3	>100	>100
2	>100	>100	1 4	>100	>100
3	>100	>100	1 5	5.0 ± 1.3	>100
4	>100	>100	16	>100	>100
5	>100	>100	17	74.4 ± 3.8	>100
6	>100	>100	18	>100	>100
7	>100	>100	19	>100	>100
8	>100	>100	2 0	>100	>100
9	1.2 ± 0.9	>25	2 1	>100	>100
10	>100	>100	2 2	>100	>100
11	>100	>100	23	>100	>100
12	>100	>100	AG ^b	22.7 ± 0.4	>100

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^a IC₅₀ values were expressed as mean ± SD (n = 3). ^b AG = aminoguanidine hydrochloride was used as the positive control.

Isatisindigoticanine G (3) is the first example of a 8H-pyrido[2,1-b]-11(9H)-quinazolinone moiety connected with a 1H-indol-3-yl moiety via a C–C bond of C-2’’–C-3’. For its unusual structural features, a plausible biosynthetic pathway is discussed in Figure 4. First, myrosinase catalyzed hydrolysis of progoitrin and epiprogoitrin to give 3a [1]. 3a was connected with 2-aminobenzoic acid moiety by steps of dehydration to give 3b [10], and then 3c was obtained via a cyclization reaction of 3b [2,11]. 3c was connected with 1H-indole moiety by enzyme-catalyzed reaction to give 3d [5] and was then changed via a dehydration reaction to give 3 [9,10,11].

3. Experimental Section

The General Experimental Procedures, Extraction and Isolation, Plant Materials, Inhibitory Assay of NO Production and ECD Calculation sections are listed in the Supporting Information.

3.1. Physical and Spectroscopic Data of Isatisindigoticanines E–G and Isatindigoside D

Isatisindigoticanine E (1), a yellow amorphous powder; IR (KBr) ν_max: 3406, 2923, 1647, 1609, 1556, 1517, 1466, 1383, 1273, 1093, 745 cm⁻¹; m/z 356.1398 [M + H]⁺ (calculated 356.1394 [M + H]⁺); ¹H-NMR (DMSO-d₆, 600 MHz) and ¹³C-NMR (DMSO-d₆, 150 MHz); see Table 1.

Isatisindigoticanine F (2), a yellow amorphous powder; IR (KBr) ν_max: 3456, 1679, 1621, 1516, 1461, 1319, 1206, 1135, 1021, 952, 749 cm⁻¹; m/z 291.1125 [M − H]⁻ (calculated 291.1128 [M + H]⁺); ¹H-NMR (DMSO-d₆, 600 MHz) and ¹³C-NMR (DMSO-d₆, 150 MHz); see Table 1.

Isatisindigoticanine G (3), a yellow amorphous powder; IR (KBr) ν_max: 3404, 2919, 1708, 1601, 1468, 1400, 1384, 1092, 745 cm⁻¹; m/z 314.1297 [M + H]⁺ (calculated 314.1288 [M + H]⁺); ¹H-NMR (DMSO-d₆, 600 MHz) and ¹³C-NMR (DMSO-d₆, 150 MHz); see Table 1.

Isatindigoside D (23), a red amorphous powder; [α] $_{D}^{20}$ + 12.1 (c 0.19, MeOH); IR (KBr) ν_max: 3420, 2939, 1722, 1598, 1514, 1461, 1261, 1069, 1025, 859, 813 cm⁻¹; HRESIMS: m/z 490.1592 [M + Na]⁺, (calculated 490.1585 [M + Na]⁺); ¹H and ¹³C-NMR (600 and 150 MHz in DMSO-d₆); see Table 2.

3.2. Absolute Configuration Determination of Sugar

Compound 23 (2 mg) was hydrolyzed in 2 M hydrochloric acid (4 mL) at 80 °C for 2 h. After cooling, the solution was concentrated under vacuum, dissolved with water, and extracted twice with dichloromethane (CH₂Cl₂). The residue was dissolved in distilled water and reduced with NaBH₄ for 3 h at room temperature. After neutralization with AcOH and evaporation to dryness, the residue was acetylated with Ac₂O for 1 h at 100 °C. The resulting alditol acetate was subjected to GC analysis under the following conditions: capillary column, HP-5ms (60 m × 0.25 mm × 0.25 μm); detector, FID; detector temperature, 280 °C; injection temperature, 280 °C; initial temperature 140 °C, subsequently increased to 240 °C at a rate of 5 °C/min, and then 1 min to increase to 260 °C, finally, subsequent increase to 280 °C at a rate of 2 °C/min; carrier, N₂ gas [8,9]. The D glucose moiety in 23 was confirmed by the comparison of their retention times (t_R) with those of authentic sugars (t_R d-glucose 45.23 min, t_R l-glucose 45.38 min).

4. Conclusions

In this paper, a total of 23 alkaloids were reported, including four new ones: isatisindigoticanines E–G (1–3) and isatindigoside D (23). Four new natural products and 15 known analogues were isolated from Ban Lan Gen. Isatisindigoticanine G possesses an unusual carbon skeleton of an 8H-pyrido[2,1-b]-11(9H)-quinazolinone moiety connected with a 1H-indole moiety via a C–C bond of C-2’’–C-3’. Compounds 9, 15, and 17 showed NO inhibitory effects with IC₅₀ values of 1.2, 5.0, and 74.4 μM in the LPS-stimulated RAW264.7 macrophages. This study is important as it explains the chemical and biological diversity of Ban Lan Gen. Furthermore, the new structures need more biocativity experiments to discover their more meaningful uses, which may stimulate us to better develop and utilize these compounds.

Supplementary Materials

The following are available online https://www.mdpi.com/1420-3049/24/22/4033/s1, Copies of IR, HREIMS, ¹H-NMR, ¹³C-NMR, DEPT 135, HSQC, HMBC, and ¹H-¹H COSY of 1–3 and 23. Experimental and calculated ECD spectra of 23.

Click here for additional data file.^{(2.8MB, pdf)}

Author Contributions

R.W., Y.L., and K.C. conducted the experiments; D.R. and J.L. carried out the anti-inflammatory activity experiments; Y.S., Q.J., and W.Z. analyzed the MS, ECD, and NMR data; D.Z. did the isolation, confirmed the structures, and wrote the paper; R.W. oversaw the research project and drafted the paper.

Funding

This work was supported by the National Natural Science Foundation of China (81573571, 81673570), the Excellent Academic Leaders Program of Shanghai (16XD1403500), the programs of the High Level University Innovation Team, the Shanghai E-Research Institute of Bioactive Constituents in Traditional Chinese Medicine, and the Shanghai Scientific and Technological Innovation Program (18401931100).

Conflicts of Interest

No competing financial interests were declared by the authors.

Footnotes

Sample Availability: Samples of the Compounds 1–23 are available from the authors.

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13.Shimokawa Y., Nakakoshi M., Saito S., Suzuki H., Yokoyama Y., Ishigami A., Nishioka H., Tsubuki M. Synthesis and evaluation of 4-aryl-2(1H)-quinolinones as potent amyloid β fibrillogenesis inhibitors. Heterocycles. 2012;85:1933–1940. doi: 10.1002/chin.201249156. [DOI] [Google Scholar]
14.Huang Z.S., Rao Y., Xu Z., Hu Y.T., Yu H., Gao L. Preparation of Heterocycles as Antiobesity Agents. CN 107,721,982. 2018 Feb 23;
15.Javaid K., Saad S.M., Rasheed S., Moin S.T., Syed N., Fatima I., Salar U., Khan K.M., Perveen S., Choudhary M.I. 2-Arylquinazolin-4(3H)-ones: A new class of α-glucosidase inhibitors. Bioorg. Med. Chem. 2015;23:7417–7421. doi: 10.1016/j.bmc.2015.10.038. [DOI] [PubMed] [Google Scholar]
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19.Yamaya N., Chau N., Iwakura Y. Synthesis of quinazolinedione derivatives from 2-carbomethoxyphenyl isocyanate and amino acids. Seikei Daigaku Kogakubu Kogaku Hokoku. 1982;33:2239–2240. [Google Scholar]
20.Goldfarb D.S. Method Using Lifespan-Altering Compounds for Altering the Lifespan of Eukaryotic Organisms and Screening for Such Compounds. U.S. 20,090,163,545. 2008 Jun 25;
21.Suesse M., Cleve D., Johne S. Process for the Preparation of 1,2,3,4-Tetrahydro-1-methyl-2,4-dioxo-3- quinazolinealkanoates. DD 291,085. 1991 Jun 20;
22.Feng Q.T., Zhu G.Y., Gao W.N., Yang Z.F., Zhong N.S., Wang J.R., Jiang Z.H. Two new alkaloids from the roots of Baphicacanthus cusia. Chem. Pharm. Bull. 2016;64:1505–1508. doi: 10.1248/cpb.c16-00315. [DOI] [PubMed] [Google Scholar]
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26.Ikuro A., Tsuyoshi A., Kiyofumi W., Hiroshi N. Enzymatic formation of quinolone alkaloids by a plant type III polyketide synthase. Org. Lett. 2006;8:6063–6065. doi: 10.1021/ol0625233. [DOI] [PubMed] [Google Scholar]
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28.Li Y.C., Kuo P.C., Yang M.L., Chen T.Y., Hwang T.L., Chiang C.C., Thang T.D., Tuan N.N., Tzen J.T.C. Chemical Constituents of the Leaves of Peltophorum pterocarpum and Their Bioactivity. Molecules. 2019;24:240. doi: 10.3390/molecules24020240. [DOI] [PMC free article] [PubMed] [Google Scholar]
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32.Cui Y.W., Yang X.J., Zhang D.D., Li Y.Z., Zhang L., Song B., Yue Z.G., Song X.M., Tang H.F. Steroidal constituents from roots and rhizomes of Smilacina japonica. Molecules. 2018;23:798. doi: 10.3390/molecules23040798. [DOI] [PMC free article] [PubMed] [Google Scholar]
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35.Liu Y.F., Chen M.H., Guo Q.L., Lin S., Xu C.B., Jiang Y.P., Li Y.H., Jiang J.D., Shi J.G. Antiviral glycosidic bisindole alkaloids from the roots of Isatis indigotica. J. Asian. Nat. Prod. Res. 2015;17:689–704. doi: 10.1080/10286020.2015.1055729. [DOI] [PubMed] [Google Scholar]
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38.Song X.M., Zhang D.D., He H., Li Y.Z., Yang X.J., Deng C., Tang Z.S., Cui J.C., Yue Z.G. Steroidal glycosides from Reineckia carnea. Fitoterapia. 2015;105:240–245. doi: 10.1016/j.fitote.2015.07.008. [DOI] [PubMed] [Google Scholar]
39.Zhang D.D., Wang W., Li Y.Z., Li Z., Jiang Y., Tang Z.S., Song X.M., Yue Z.G. Two new pregnane glycosides from Reineckia carnea. Phytochem. Lett. 2016;15:142–146. doi: 10.1016/j.phytol.2015.12.005. [DOI] [Google Scholar]
40.Han M.F., Zhang X., Zhang L.Q., Li Y.M. Iridoid and phenylethanol glycosides from Scrophularia umbrosa with inhibitory activity on nitric oxide production. Phytochem. Lett. 2018;28:37–41. doi: 10.1016/j.phytol.2018.09.011. [DOI] [Google Scholar]

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[B1-molecules-24-04033] 1.Chen M.H., Lin S., Li L., Zhu C.G., Wang X.L., Wang Y.A., Jiang B.Y., Wang S.J., Li Y.H., Jiang J.D., et al. Enantiomers of an indole alkaloid containing unusual dihydrothiopyran and 1,2,4-thiadiazole rings from the root of Isatis indigotica. Org. Lett. 2015;45:1523–7052. doi: 10.1021/ol302660t. [DOI] [PubMed] [Google Scholar]

[B2-molecules-24-04033] 2.Yang L.G., Wang G., Wang M., Jiang H.M., Chen L.X., Zhao F., Qiu F. Indole alkaloids from the roots of Isatis indigotica and their inhibitory effects on nitric oxide production. Fitoterapia. 2014;95:175–181. doi: 10.1016/j.fitote.2014.03.019. [DOI] [PubMed] [Google Scholar]

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[B6-molecules-24-04033] 6.Meng L.J., Guo Q.L., Liu Y.F., Shi J.G. 8,4′-Oxyneolignane glucosides from an aqueous extract of “ban lan gen” (Isatis indigotica root) and their absolute configurations. Acta Pharm. Sin. B. 2017;7:638–646. doi: 10.1016/j.apsb.2017.09.006. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B7-molecules-24-04033] 7.Huang Q.S., Yoshihiro K., Natori S. Isolation of 2-hydroxy-3-butenyl thiocyanate, epigoitrin and adenosine from “Banlangen” Isatis indigotica root. Planta Medica. 1981;42:308–310. doi: 10.1055/s-2007-971650. [DOI] [PubMed] [Google Scholar]

[B8-molecules-24-04033] 8.Zhang D.D., Shi Y.H., Xu R., Du K., Guo F.J., Chen K.X., Li Y.M., Wang R. Alkaloid Enantiomers from the Roots of Isatis indigotica. Molecules. 2019;24:3140. doi: 10.3390/molecules24173140. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B9-molecules-24-04033] 9.Zhang D.D., Du K., Zhao Y.T., Shi S.S., Wu Y.C., Jia Q., Chen K.X., Li Y.M., Wang R. Indole alkaloid glycosides from Isatis tinctoria roots. Nat. Prod. Res. 2019 doi: 10.1080/14786419.2019.1624960. [DOI] [PubMed] [Google Scholar]

[B10-molecules-24-04033] 10.Zhang D.D., Li J.Y., Ruan D.Q., Chen Z.Q., Zhu W.L., Shi Y.H., Chen K.X., Li Y.M., Wang R. Lignans from Isatis indigotica roots and their inhibitory effects on nitric oxide production. Fitoterapia. 2019;137:104189. doi: 10.1016/j.fitote.2019.104189. [DOI] [PubMed] [Google Scholar]

[B11-molecules-24-04033] 11.Zhang D.D., Shi Y.H., Shi S.S., Wu X.M., Zhang L.Q., Chen K.X., Li Y.M., Wang R. Isatisindigoticanine A, a novel indole alkaloid with an unpresented carbon skeleton from the roots of Isatis tinctoria. Nat. Prod. Res. 2019 doi: 10.1080/14786419.2019.1644632. [DOI] [PubMed] [Google Scholar]

[B12-molecules-24-04033] 12.Zhang D.D., Li J.Y., Shi Y.H., Chen K.X., Li Y.M., Wang R. Glycosides from roots of Isatis indigotica. Chin. Tradit. Herb. Drugs. 2019;50:3575–3580. [Google Scholar]

[B13-molecules-24-04033] 13.Shimokawa Y., Nakakoshi M., Saito S., Suzuki H., Yokoyama Y., Ishigami A., Nishioka H., Tsubuki M. Synthesis and evaluation of 4-aryl-2(1H)-quinolinones as potent amyloid β fibrillogenesis inhibitors. Heterocycles. 2012;85:1933–1940. doi: 10.1002/chin.201249156. [DOI] [Google Scholar]

[B14-molecules-24-04033] 14.Huang Z.S., Rao Y., Xu Z., Hu Y.T., Yu H., Gao L. Preparation of Heterocycles as Antiobesity Agents. CN 107,721,982. 2018 Feb 23;

[B15-molecules-24-04033] 15.Javaid K., Saad S.M., Rasheed S., Moin S.T., Syed N., Fatima I., Salar U., Khan K.M., Perveen S., Choudhary M.I. 2-Arylquinazolin-4(3H)-ones: A new class of α-glucosidase inhibitors. Bioorg. Med. Chem. 2015;23:7417–7421. doi: 10.1016/j.bmc.2015.10.038. [DOI] [PubMed] [Google Scholar]

[B16-molecules-24-04033] 16.Hamasharif M.S., Smith O.E.P., Curran C.J., Hemming K. N-alkylation and aminohydroxylation of 2-azidobenzenesulfonamide gives a pyrrolobenzothiadiazepine precursor whereas attempted N-alkylation of 2-azidobenzamide gives benzotriazinones and quinazolinones. ACS Omega. 2017;3:1222–1231. doi: 10.1021/acsomega.7b00211. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B17-molecules-24-04033] 17.Kornsakulkarn J., Saepua S., Srijomthong K., Rachtawee P., Thongpanchang C. Quinazolinone alkaloids from actinomycete Streptomyces sp. BCC 21795. Phytochem. Lett. 2015;12:6–8. doi: 10.1016/j.phytol.2015.02.007. [DOI] [Google Scholar]

[B18-molecules-24-04033] 18.Ruan J.L., Zou J.H., Cai Y.L. Studies on chemical constituents in leaf of Isatis indigotica. China J. Chin. Mater. Med. 2005;30:1525–1526. [PubMed] [Google Scholar]

[B19-molecules-24-04033] 19.Yamaya N., Chau N., Iwakura Y. Synthesis of quinazolinedione derivatives from 2-carbomethoxyphenyl isocyanate and amino acids. Seikei Daigaku Kogakubu Kogaku Hokoku. 1982;33:2239–2240. [Google Scholar]

[B20-molecules-24-04033] 20.Goldfarb D.S. Method Using Lifespan-Altering Compounds for Altering the Lifespan of Eukaryotic Organisms and Screening for Such Compounds. U.S. 20,090,163,545. 2008 Jun 25;

[B21-molecules-24-04033] 21.Suesse M., Cleve D., Johne S. Process for the Preparation of 1,2,3,4-Tetrahydro-1-methyl-2,4-dioxo-3- quinazolinealkanoates. DD 291,085. 1991 Jun 20;

[B22-molecules-24-04033] 22.Feng Q.T., Zhu G.Y., Gao W.N., Yang Z.F., Zhong N.S., Wang J.R., Jiang Z.H. Two new alkaloids from the roots of Baphicacanthus cusia. Chem. Pharm. Bull. 2016;64:1505–1508. doi: 10.1248/cpb.c16-00315. [DOI] [PubMed] [Google Scholar]

[B23-molecules-24-04033] 23.Mohn T., Plitzko I., Hamburger M. A comprehensive metabolite profiling of Isatis tinctoria leaf extracts. Phytochemistry. 2009;70:924–934. doi: 10.1016/j.phytochem.2009.04.019. [DOI] [PubMed] [Google Scholar]

[B24-molecules-24-04033] 24.Bandurco V.T., Wong E.M., Levine S.D., Hajos Z.G. Antihypertensive pyrrolo[1,2-c]quinazolines and pyrrolo[1,2-c]quinazolinones. J. Med. Chem. 1981;24:1455–1460. doi: 10.1021/jm00144a017. [DOI] [PubMed] [Google Scholar]

[B25-molecules-24-04033] 25.Bingi C., Kola K.Y., Kale A., Nanubolu J.B., Atmakur K. A simple one pot synthesis of novel tricyclic quinazolinones. Tetrahedron Lett. 2017;58:1071–1074. doi: 10.1016/j.tetlet.2017.01.106. [DOI] [Google Scholar]

[B26-molecules-24-04033] 26.Ikuro A., Tsuyoshi A., Kiyofumi W., Hiroshi N. Enzymatic formation of quinolone alkaloids by a plant type III polyketide synthase. Org. Lett. 2006;8:6063–6065. doi: 10.1021/ol0625233. [DOI] [PubMed] [Google Scholar]

[B27-molecules-24-04033] 27.Anilkumar G.N., Rosenblum S.B., Venkatraman S., Njoroge F.G., Kozlowski J.A. 2,3-substituted Azaindole Derivatives for Treating Viral Infections. U.S. 8,404,845. 2010 May 7;

[B28-molecules-24-04033] 28.Li Y.C., Kuo P.C., Yang M.L., Chen T.Y., Hwang T.L., Chiang C.C., Thang T.D., Tuan N.N., Tzen J.T.C. Chemical Constituents of the Leaves of Peltophorum pterocarpum and Their Bioactivity. Molecules. 2019;24:240. doi: 10.3390/molecules24020240. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B29-molecules-24-04033] 29.Fuhr U., Strobl G., Manaut F., Anders E., Soergel F., Lopez-de-Binas E., Chu D.T.W., Pernet A.G., Mahr G. Quinolone antibacterial agents: Relationship between structure and in vitro inhibition of the human cytochrome P450 isoform CYP1A2. Mol. Pharmacol. 1993;43:191–199. [PubMed] [Google Scholar]

[B30-molecules-24-04033] 30.Feng C., Shi L., Chen D.Z., Zhang H.C., Zhao R.Q. Chemical constitutes of effective part in Celosia cristata for treatment of homostatic. Chin. Tradit. Herb. Drugs. 2017;48:653–656. [Google Scholar]

[B31-molecules-24-04033] 31.Wang D., Wu X.M., Zhang D.D., Zhu B.R., Jia Q., Li Y.M. Chemical constituents of carboxylic acid and its derivatives in Cinnamomi Ramulus. Chin. Tradit. Herb. Drugs. 2019;50:8–12. [Google Scholar]

[B32-molecules-24-04033] 32.Cui Y.W., Yang X.J., Zhang D.D., Li Y.Z., Zhang L., Song B., Yue Z.G., Song X.M., Tang H.F. Steroidal constituents from roots and rhizomes of Smilacina japonica. Molecules. 2018;23:798. doi: 10.3390/molecules23040798. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B33-molecules-24-04033] 33.Li Y.Z., Wang X., He H., Zhang D.D., Jiang Y., Yang X.J., Wang F., Tang Z.S., Song X.M., Yue Z.G. Steroidal saponins from the roots and rhizomes of Tupistra chinensis. Molecules. 2015;20:13659–13669. doi: 10.3390/molecules200813659. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B34-molecules-24-04033] 34.Tashima T., Kodama H., Murata H. Preparation of Hydroxamic Acid Derivatives as Histone Deacetylase (HDAC) Inhibitors. WO 2,014,196,328. 2014 Dec 11;

[B35-molecules-24-04033] 35.Liu Y.F., Chen M.H., Guo Q.L., Lin S., Xu C.B., Jiang Y.P., Li Y.H., Jiang J.D., Shi J.G. Antiviral glycosidic bisindole alkaloids from the roots of Isatis indigotica. J. Asian. Nat. Prod. Res. 2015;17:689–704. doi: 10.1080/10286020.2015.1055729. [DOI] [PubMed] [Google Scholar]

[B36-molecules-24-04033] 36.Chen Z., Hu G.Y., Li D., Chen J., Li Y.J., Zhou H.Y., Xie Y. Synthesis and vasodilator effects of rutaecarpine analogues which might be involved transient receptor potential vanilloid subfamily, member 1 (TRPV1) Bioorg. Med. Chem. 2009;17:2351–2359. doi: 10.1016/j.bmc.2009.02.015. [DOI] [PubMed] [Google Scholar]

[B37-molecules-24-04033] 37.Chen X.Y., Zhang T., Wang X., Hamann M.T., Kang J., Yu D.Q., Chen R.Y. A chemical investigation of the leaves of Morus alba L. Molecules. 2018;23:1018. doi: 10.3390/molecules23051018. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B38-molecules-24-04033] 38.Song X.M., Zhang D.D., He H., Li Y.Z., Yang X.J., Deng C., Tang Z.S., Cui J.C., Yue Z.G. Steroidal glycosides from Reineckia carnea. Fitoterapia. 2015;105:240–245. doi: 10.1016/j.fitote.2015.07.008. [DOI] [PubMed] [Google Scholar]

[B39-molecules-24-04033] 39.Zhang D.D., Wang W., Li Y.Z., Li Z., Jiang Y., Tang Z.S., Song X.M., Yue Z.G. Two new pregnane glycosides from Reineckia carnea. Phytochem. Lett. 2016;15:142–146. doi: 10.1016/j.phytol.2015.12.005. [DOI] [Google Scholar]

[B40-molecules-24-04033] 40.Han M.F., Zhang X., Zhang L.Q., Li Y.M. Iridoid and phenylethanol glycosides from Scrophularia umbrosa with inhibitory activity on nitric oxide production. Phytochem. Lett. 2018;28:37–41. doi: 10.1016/j.phytol.2018.09.011. [DOI] [Google Scholar]

PERMALINK

Alkaloids with Nitric Oxide Inhibitory Activities from the Roots of Isatis tinctoria

Dongdong Zhang

Yanhong Shi

Jingyi Li

Deqing Ruan

Qi Jia

Weiliang Zhu

Kaixian Chen

Yiming Li

Rui Wang

Abstract

1. Introduction

Figure 1.