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Structure–Activity Relationships and the Cytotoxic Effects of Novel Diterpenoid Alkaloid Derivatives Against A549 Human Lung Carcinoma Cells

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Structure–Activity Relationships and the Cytotoxic Effects of Novel Diterpenoid Alkaloid Derivatives Against A549 Human Lung Carcinoma Cells J Nat Med (2011) 65:43–49 DOI 10.1007/s11418-010-0452-3 ORIGINAL PAPER Structure–activity relationships and the cytotoxic effects of novel diterpenoid alkaloid derivatives against A549 human lung carcinoma cells Koji Wada • Masaharu Hazawa • Kenji Takahashi • Takao Mori • Norio Kawahara • Ikuo Kashiwakura Received: 28 April 2010 / Accepted: 5 July 2010 / Published online: 14 August 2010 Ó The Author(s) 2010. This article is published with open access at Springerlink.com Abstract The cytotoxicity of three alkaloids from the Keywords Diterpenoid alkaloids Á Pseudokobusine Á roots of Aconitum yesoense var. macroyesoense as well as Kobusine Á Cytotoxic agents Á A549 human 36 semi-synthetic C20-diterpenoid atisine-type alkaloid lung carcinoma cells Á Structure–activity relationship derivatives against A549 human lung carcinoma cells was examined. Ten acylated alkaloid derivatives, pseudokobu- sine 11-veratroate (9), 11-anisoate (12), 6,11-dianisoate Introduction (14), 11-p-nitrobenzoate (18), 11,15-di-p-nitrobenzoate (22), 11-cinnamate (25) and 11-m-trifluoromethylbenzoate Diterpenoid alkaloids are classified according to their (27), and kobusine 11-p-trifluoromethylbenzoate (35), 11-m- chemical structure as C19-norditerpenoid alkaloids, which trifluoromethylbenzoate (36) and 11,15-di-p-nitrobenzoate consist of an aconitine or a lycoctonine skeleton, and C20- (39), exhibited cytotoxic activity, and 11,15-diani- diterpenoid alkaloids, consisting of an atisine or a veat- soylpseudokobusine (16) was found to be the most potent chine skeleton. A large number of diterpenoid alkaloids cytotoxic agent. Their IC50 values against A549 cells ran- have been isolated from various species of Aconitum and ged from 1.72 to 5.44 lM. In the occurrence of cytotoxic Delphinium (Ranunculaceae) [1, 2]. The pharmacological effects of atisine-type alkaloids, replacement by an acyl properties of C19-norditerpenoid alkaloids, including group at both C-11 and C-15 resulted in the enhancement aconitine, mesaconitine, hypaconitine and jesaconitine, of activity of the parent alkaloids compared to that from have been studied extensively and reviewed [1, 2]. Acon- having hydroxy groups at this position, and the presence of itine and mesaconitine are representative toxins that exhibit a hydroxy group at the C-6 position was required for the activity both centrally and peripherally, with predominant cytotoxic effects. These acylated alkaloid derivatives effects on the cardiovascular and respiratory systems, by inhibit cell growth through G1 arrest. preventing the normal closing of sodium channels [3, 4]. In contrast, there is little information regarding the pharma- cological properties of C20-diterpenoid alkaloids and their chemically transformed products. Kobusine (1) and pseudokobusine (2), the major alkaloid constituents of K. Wada (&) Aconitum yesoense var. macroyesoense, and certain semi- School of Pharmacy, Hokkaido Pharmaceutical University, synthetic derivatives of diterpenoid alkaloids have been 7-1 Katsuraoka-cho, Otaru, Hokkaido 047-0264, Japan shown by using a Doppler-type laser blood flow meter to e-mail: [email protected] significantly increase cutaneous blood flow in the hind feet M. Hazawa Á K. Takahashi Á I. Kashiwakura of anaesthetized mice [5–7]. Graduate School of Health Sciences, Hirosaki University, The majority of drugs used in cancer chemotherapy can 66-1 Hon-cho, Hirosaki, Aomori 036-8564, Japan be divided into alkylating agents, anti-metabolites, antibi- otics, plant alkaloids, topoisomerase inhibitors, monoclonal T. Mori Á N. Kawahara Research Center, North Japan Chemical, Inc., Eniwa RBP 308, antibodies and other antitumor agents [8–16]. However, 1-1, 3-Meguminokita, Eniwa, Hokkaido 061-1374, Japan little information on the cytotoxic properties of Aconitum 123 44 J Nat Med (2011) 65:43–49 alkaloids has been reported, despite their intense toxicities. impact (EI) mass spectra were measured on Hitachi Two reports on the effects of C19-norditerpenoid alkaloids M-2000 and JEOL JMS-700 spectrometers. IR spectra on cancer cells have appeared in recent years. 8-O-Azeloyl- were recorded with an IR spectrophotometer, Perkin-Elmer 1 14-benzoylaconine, an aconitine-type C19-norditerpenoid Spectrum 100. All products reported showed H-NMR alkaloid, exhibited anti-proliferative activity [17] and the spectra and mass spectra in agreement with the assigned cytotoxic effects of various C19-norditerpenoid alkaloids structures. Reactions were carried out under an inert against tumor cell lines have been reported [18]. Our pre- atmosphere of dry nitrogen or argon, unless otherwise vious study demonstrated the effects of various naturally described. Standard syringe techniques were used for occurring and semi-synthetic diterpenoid alkaloids on the transferring dry solvents. Reaction courses and product growth of the A172 human malignant glioma cell line [19]. mixtures were monitored routinely by TLC on silica The results of previous studies showed that seven acylated gel (precoated Merck F254 plates) and visualized with alkaloid derivatives, 12-acetylluciculine, pseudokobusine Dragendorff reagent. Chromatography was performed 11-veratroate (9), 11-anisoate (12), 11-p-nitrobenzoate using silica gel and the indicated solvent system. All other (18), 11-cinnamate (25) and 11-m-trifluoromethylbenzoate chemicals used were of analytical grade. (27), and 11-(m-trifluoromethylbenzoyl)kobusine (36), had significant cytotoxic effects on the growth of A172 cells. Alkaloids Esterification of the hydroxyl group at C-11 may, thus, contribute to the enhancement of activity of the parent The diterpenoid alkaloids kobusine (1), pseudokobusine (2) alkaloids more than that of the OH group at C-11. and 15-veratroylpseudokobusine (10) were used after Cytotoxic properties and radiation-sensitizing effects of extraction from the roots of A. yesoense var. macroyesoense, various types of novel derivatives prepared from Aconitum followed by purification and identification by methods alkaloids have also been investigated [20]. 11-Anisoyl- described previously [22, 23]. Thirty acyl deriva- pseudokobusine (12) and 11-m-trifluoromethylbenzoyl tives, N-benzyl-N,6-seco-6-dehydropseudokobusine (3)[19], pseudokobusine (36) showed significant suppressive effects N,15-dibenzyl-N,6-seco-6-dehydropseudokobusine (4)[19], against the non-Hodgkin’s lymphoma Raji cell line [21]. 6-benzoylpseudokobusine (5)[23], 6,11-dibenzoylpseudo- 11-m-Trifluoromethylbenzoylpseudokobusine (36) clearly kobusine (6)[23], 15-benzoyl-6,11-di-p-nitrobenzoylpseu- inhibited the phosphorylation of extracellular signal-regu- dokobusine (7)[19], 6-veratroylpseudokobusine (8)[7], lated kinase, induced enhanced phosphoinositide 3-kinase 11-veratroylpseudokobusine (9)[7], 6-anisoylpseudokobu- phosphorylation and led to the subsequent accumulation of sine (11)[7], 11-anisoylpseudokobusine (12)[7], 15-anis- G1 and/or sub-G1 phase in Raji cells. In addition, sup- oylpseudokobusine (13)[7], 6,11-dianisoylpseudokobusine pressive effects of 11-anisoylpseudokobusine (12) and (14)[7], 6,15-dianisoylpseudokobusine (15)[7], 11,15- 11-m-trifluoromethylbenzoylpseudokobusine (36) on the dianisoylpseudokobusine (16)[7], 6-p-nitrobenzoylpseu- growth of human CD34? hematopoietic stem/progenitor dokobusine (17)[23], 11-p-nitrobenzoylpseudokobusine cells were observed. (18)[7], 15-p-nitrobenzoylpseudokobusine (19)[24], In the present study, the effects of various semi-syn- 6,11-di-p-nitrobenzoylpseudokobusine (20)[24], 6,15-di-p- thetic novel C20-diterpenoid alkaloids on the growth of the nitrobenzoylpseudokobusine (21)[24], 11,15-di-p-nitro- A549 human lung cancer cell line were examined. Twenty benzoylpseudokobusine (22)[7], 6,11,15-tri-p-nitrobenzoyl novel derivatives were prepared from natural compounds. pseudokobusine (23)[24], 6-cinnamoylpseudokobusine In order to carry out structure–activity relationship studies (24)[6], 11-cinnamoylpseudokobusine (25)[6], 6-(m-tri- of the anti-proliferative effect against A549 cells, three fluoromethylbenzoyl)pseudokobusine (26)[19], 11-(m-tri- natural and 36 semi-synthetic diterpenoid alkaloids were fluoromethylbenzoyl)pseudokobusine (27)[19], 11-benzoyl tested. kobusine (30)[6], 11-anisoylkobusine (31)[7], 11-vera- troylkobusine (32)[7], dihydrokobusine (33)[7], 11-cinna moylkobusine (34)[6] and 11-(m-trifluoromethylben- Materials and methods zoyl)kobusine (36)[19], were prepared by methods described previously. Six semi-synthetic derivatives, General experimental procedures 6-(p-trifluoromethylbenzoyl)pseudokobusine (28), 11-(p-tri- fluoromethylbenzoyl)pseudokobusine (29), 11-(p-trifluoro- Melting points were determined on a Yanagimoto micro methylbenzoyl)kobusine (35), 11-p-nitrobenzoylkobusine melting point apparatus and are uncorrected. 1H-NMR (37), 15-p-nitrobenzoylkobusine (38) and 11,15-di-p-nitro- spectra in CDCl3 were recorded on JEOL GX-270 and benzoylkobusine (39), were prepared from kobusine (1) and AL-400 spectrometers using tetramethylsilane as an inter- pseudokobusine (2). These semi-synthetic alkaloids were nal standard. Chemical shifts are given in ppm. Electron synthesized at controlled reaction times and temperatures. 123 J Nat Med (2011) 65:43–49 45 Synthesis of 6-(28) and 11-(p-trifluoromethylbenzoyl) EIMS m/z: 485 (M?), 312, 296, 173. HREIMS m/z: pseudokobusine (29) 485.2157 (calcd. for C28H30F3NO3: 485.5376). A solution of 2 (0.111 g, 0.34 mmol) and p-trifluoro- Synthesis of 11-(37), 15- (38) and 11,15-di-p- methylbenzoyl chloride (0.1 ml, 0.67 mmol) in pyridine nitrobenzoylkobusine (39)
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