Active constituents of Zanthoxylum nitidium from Yunnan Province against leukaemia cells in vitro

Abstract

Zanthoxylum nitidium (Roxb.) DC (Rutaceae) is well known for inhibiting the proliferation of human gastric, liver, kidney and lung cancer cells, though research on its potential use in treating leukaemia is relatively rare. Twenty-six compounds were isolated from the chloroform and petroleum ether extracts of the roots and leaves of Z. nitidium (Zanthoxylum nitidium). They were ( +)-9′-O-transferuloyl-5, 5′-dimethoxylaricriresinol (1), 8-(3′-oxobut-1′-en-1′-yl)-5, 7-dimethoxy-coumarin (2), 5, 7, 8-trimethoxy-coumarin (3), 5-(3′, 3′-dimethyl-2′-butenyloxy)-7, 8-dimethoxy-coumarin (4), 2-(5-methoxy-2-methyl-1H-indol-3-yl) methyl acetate (5), 2′-(5, 6-dihydrochleletrythrine-6-yl) ethyl acetate (6), 6-acetonyldi-hydrochelerythrine (7), 6β-hydroxymethyldihydronitidine (8), bocconoline (9), zanthoxyline (10), O-methylzanthoxyline (11), rhoifoline B (12), N-nornitidine (13), nitidine (14), chelerythrine (15), 4-hydroxyl-7,8-dimethoxy-furoquinoline (16), dictamnine (17), γ-fagarine (18), skimmianine (19), robustine (20), R-( +)-platydesmine (21), 4-methoxyl-1-methyl-2-quinoline (22), 4-methoxy-2-quinolone (23), liriodenine (24), aurantiamide acetate (25), 10-O-demethyl-12-O-methylarnottianamide (26). Four among them, compounds 4 – 6 and 16, were first confirmed in this study by UV, IR, 1D, 2D NMR and HR-ESI–MS spectra. Compounds 1 – 2 and 11 were isolated from Z. nitidium for the first time. Of the assayed compounds, 1, 2, 9, 10, 14, 15 and 24, exhibited good inhibitory activities in the leukaemia cell line HEL, whereas compound 14 (IC50: 3.59 µM) and compound 24 (IC50: 15.95 µM) exhibited potent inhibitory activities. So, to further investigate the possible mechanisms, cell cycle and apoptosis assays were performed, which indicated that compound 14 causes obvious S-phase arrest in HEL cells and induced apoptosis, whereas compound 24 only induced apoptosis. The present results suggested both compounds 14 and 24 are promising potential anti-leukaemia drug candidates.

Insights on Antitumor Activity and Mechanism of Natural Benzophenanthridine Alkaloids

“…A wide variety of benzophenanthridine alkaloids ( Figure 19 ) have been extracted by Deng, Y’s group [ 95 ] in Zanthoxylum avicennae from Yunnan Province, and their antileukemic cell line HLa activity in vitro is determined, with better activity of bocconoline ( 60 ), zanthoxyline ( 61 ), nitidine chloride ( 54 ), chelerythrine ( 2 ), and their IC 50 values (μM) in the order of 7.65 ± 0.11, 24.94 ± 1.99, 3.59 ± 0.82, and 15.52 ± 0.26. Nitidine chloride ( 54) results in significant S-phase arrest and induces apoptosis in HEL cells, thus becoming a promising potential antileukemic candidate.…”

“…Notably, buegenine (56) exhibits better activity against drug-resistant CEM/ADR5000 cell lines than doxorubicin [94]. A wide variety of benzophenanthridine alkaloids (Figure 19) have been extracted by Deng, Y's group [95] in Zanthoxylum avicennae from Yunnan Province, and their antileukemic cell line HLa activity in vitro is determined, with better activity of bocconoline ( 60 The natural product rhoifoline B ( 63) is structurally modified to obtain compound 65 (Figure 20) with the hydroxy substitutions at the 11-position. Compound 66 (Figure 20), originating from compound 65 through structural modification, enhances the inhibition selectivity of tyrosine DNA phosphodiesterase 1 (TDP1), with an IC50 value of 1.7 ± 0.24 µM.…”

“…For instance, compounds with triazole branched chains exhibit poor activity, which may be correlated with poor cell permeability [96]. A wide variety of benzophenanthridine alkaloids (Figure 19) have been extracted by Deng, Y's group [95] in Zanthoxylum avicennae from Yunnan Province, and their antileukemic cell line HLa activity in vitro is determined, with better activity of bocconoline (60), zanthoxyline ( 61 A wide variety of benzophenanthridine alkaloids (Figure 19) have been extracted by Deng, Y's group [95] in Zanthoxylum avicennae from Yunnan Province, and their antileukemic cell line HLa activity in vitro is determined, with better activity of bocconoline ( 60 The natural product rhoifoline B ( 63) is structurally modified to obtain compound 65 (Figure 20) with the hydroxy substitutions at the 11-position. Compound 66 (Figure 20), originating from compound 65 through structural modification, enhances the inhibition selectivity of tyrosine DNA phosphodiesterase 1 (TDP1), with an IC50 value of 1.7 ± 0.24 µM.…”

“…Benzophenanthridine alkaloids 8-methoxynorchelerythrine (90), 11-demethylrhoifoline B (91), 8-methoxynitidine (92), 8-acetylnorchelerythrine (93), 8,9,10,12-tetramethoxynorchelerythrine (94), isointegriamide (95), pancorine (96), 8-methoxychelerythrine (97), oxynitidine (98), and oxysanguinarine (99) (Figure 28) are extracted from Toddalia asiatica. Studies have shown that the above compounds could inhibit eight types of human tumor cell lines in vitro, including A549 (human lung cancer), BGC-823 (human gastric cancer), HCT-15 (human colon cancer), Hela (human cervical cancer), HepG2 (human liver cancer), MCF-7 (human breast cancer), SK-MEL-2 (human skin cancer), and SGC-7901 (human gastric cancer).…”

Synthesis and Antileukemia Activity Evaluation of Benzophenanthridine Alkaloid Derivatives

“…Our previous studies indicated that certain benzophenanthridine alkaloids showed strong inhibitory effects on leukemia cell lines [26,27]. To continue our research, two active benzophenanthridine alkaloids, chelerythrine (1) and sanguinarine (2) (Figure 1), which were found in high abundance, were selected as the starting compounds for structural modification to obtain antileukemia drug candidates with better activity.…”