Africa Trypanosomiasis remains a serious health problem, but the approved drugs for this disease are so few that novel trypanocidal compounds are demanded. In search for trypanocidal principles from medicinal plants, we found MeOH extracts of Meliae Cortex with potent activity through the screening from about 300 kinds of methanolic extract. By bioassay-guided fractionation from this extract through the liquid–liquid partition and subsequent chromatographic technique using silica gel and ODS, finally we disclosed toosendanin (1) and its relatives as active principles. These active congeners showed not only potent trypanocidal activity but also little cytotoxicity to display the excellent selective index. Taking the isolated amount as well as trypanocidal activity into consideration, 1 was disclosed to be the responsible active principle in Meliae Cortex. Additionally, the derivatives of 1 were chemically prepared from 1 and bioactivity of them were also evaluated. Through the comparison with their trypanocidal activity among the isolated relatives and the synthesized derivatives of 1, the epoxide moiety was revealed to be essential for their potent trypanocidal activity. Furthermore, 3-O-acetyl group and 7-hydroxyl group were presumed to be important functional groups and introduction of methylpropionyl group into hemiacetal hydroxy moiety was clarified to enhance their typanocidal activity.
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Barrett MP (1999) The fall and rise of sleeping sickness. Lancet 353:1113–1114. https://doi.org/10.1016/S0140-6736(98)00416-4
World Health Organization. "Trypanosomiasis, human African (sleeping sickness)" updated on 17 February, 2020. https://www.who.int/news-room/fact-sheets/detail/trypanosomiasis-human-african-(sleeping-sickness) Accessed 20 March, 2020.
Chretien J-P, Smoak BL (2005) African trypanosomiasis: Changing epidemiology and consequences. Curr Infect Dis Rep 7:54–60. https://doi.org/10.1007/s11908-005-0024-y
19th WHO Model List of Essential Medicines (April 2015) page18.
Deeks ED (2019) Fexinidazole: first global approval. Drugs 79:215–220. https://doi.org/10.1007/s40265-019-1051-6
Bern C, Montgomery SP, Herwaldt BL, Rassi A, Marin-Neto JA, Dantas RO, Maguire JH, Acquatella H, Morillo C, Kirchhoff LV, Gilman RH, Reyes PA, Salvatella R, Moore AC (2007) Evaluation and treatment of Chagas disease in the United States. JAMA 298:2171–2181. https://doi.org/10.1001/jama.298.18.2171
DNAi "Fexinidazole to treat sleeping sickness" updated in January, 2019. https://www.dndi.org/achievements/fexinidazole/ Accessed 20 March, 2020.
Kubata BK, Nagamune K, Murakami N, Merkel P, Kabututu Z, Martin SK, Kalulu TM, Mustakul H, Yoshida M, Ohnishi-Kameyama M, Kinoshita T, Duszenko M, Urade Y (2005) Kola acuminata proanthocyanidins: a class of anti-trypanosomal compounds effective against Trypanosoma brucei. Int J Parasitol 35:91–103. https://doi.org/10.1016/j.ijpara.2004.10.019
Ochi M, Kotsuki H, Ishida H, Tokoroyama T (1978) Limonoids from Melia azedarach LINN. var japonica MAKINO. II. The natural hydroxyl precursor of sendanin. Chem Lett. https://doi.org/10.1246/cl.1978.99
Zhou J-B, Minami Y, Yagi F, Tadera K, Nakatani M (1997) Antifeeding Limonoids from Melia toosendan. Heterocylces 45:1781–1786. https://doi.org/10.3987/COM-97-7831
Zhang T, Li J, Yin F, Lin B, Wang Z, Xu J, Wang H, Zuo D, Wang G, Hua Y, Cai Z (2017) Toosendanin demonstrates promising antitumor efficacy in osteosarcoma by targeting STAT3. Oncogene 36:6627–6639. https://doi.org/10.1038/onc.2017.270
Zhang S, Cao L, Wang ZR, Li Z, Ma J (2019) Anti-cancer effect of toosendanin and its underlying mechanisms. J Asian Nat Prod Res 21:270–283. https://doi.org/10.1080/10286020.2018.1451416
Tang MZ, Wang ZF, Shi YL (2003) Toosendanin induces outgrowth of neuronal processes and apoptosis in PC12 cells. Neurosci Res 45:225–231. https://doi.org/10.1016/s0168-102(02)00225-0
Zhang B, Wang ZF, Tang MZ, Shi YL (2005) Growth inhibition and apoptosis-induced effect on human cancer cells of toosendanin, a triterpenoid derivative from Chinese traditional medicine. Invest New Drugs 23:547–553. https://doi.org/10.1007/s10637-005-0909-5
He Y, Wang J, Liu X, Zhang L, Yi G, Li C, He X, Wang P, Jiang H (2010) Toosendanin inhibits hepatocellular carcinoma cells by inducing mitochondria-dependent apoptosis. Planta Med 76:1447–1453. https://doi.org/10.1055/s-0029-1240902
Ju J, Qi Z, Cai X, Cao P, Liu N, Wang S, Chen Y (2013) Toosendanin induces apoptosis through suppression of JNK signaling pathway in HL-60. Toxicol in Vitro 27:232–238. https://doi.org/10.1016/j.tiv.2012.09.013
Wang G, Feng CC, Chu SJ, Zhang R, Lu YM, Zhu JS, Zhang J (2015) Toosendanin inhibits growth and induces apoptosis in colorectal cancer cells through suppression of AKT/GSK-3β/β-catenin pathway. Int J Oncol 47:1767–1774. https://doi.org/10.3892/ijo.2015.3157
Zhou Q, Wu X, Wen C, Wang H, Wang H, Liu H, Peng J (2018) Toosendanin induces caspase-dependent apoptosis through the p38 MAPK pathway in human gastric cancer cells. Biochem Biophys Res Commun 505:261–266. https://doi.org/10.1016/j.bbrc.2018.09.093
Gao T, Xie A, Liu X, Zhan H, Zeng J, Dai M, Zhang B (2019) Toosendanin induces the apoptosis of human Ewing's sarcoma cells via the mitochondrial apoptosis pathway. Mol Med Rep 20:135–140. https://doi.org/10.3892/mmr.2019.10224
Wang H, Wen C, Chen S, Wang F, He L, Li W, Zhou Q, Yu WK, Huang L, Chen J, Liu R, Li W, Yang X, Liu H (2020) Toosendanin- iduced apoptosis in colorectal cancer cells is associated with the k-opioid receptor/b-catenin signaling axis. Biochem Pharmacol 177:114014. https://doi.org/10.1016/j.bcp.2020.114014
Jimenez A, Villarreal C, Toscano RA, Cook M, Arnason JT, Bye R, Mata R (1998) Limonoids from Swietenia humilins and Guarea grandiflora (Meliaceae). Phytochemistry 49:1981–1988
Carpinella MC, Defago MT, Valladares G, Palacios SM (2003) Antifeedant and insecticide properties of a limonoid from Melia azedarach (Meliaceae) with potential use for pest management. J Agri Food Chem 51:369–374. https://doi.org/10.1021/jf025811w
Shih YL, Hsu K (1983) Anti-botulismic effect of toosendanin and its facilitatory action on miniature end-plate potentials. Jpn J Physiol 33:677–680. https://doi.org/10.2170/jjphysiol.33.677
Zou J, Miao WY, Ding FH, Meng JY, Ye HJ, Jia GR, He XY, Sun GZ, Li PZ (1985) The effect of toosendanin on monkey botulism. J Tradit Chin Med 5:29–30
Shi YL, Wang ZF (2004) Cure of experimental botulism and antibotulismic effect of toosendanin. Act Pharmacol Sin 25:839–848
Li MF, Shi YL (2006) Toosendanin interferes with pore formation of botulinum toxin type A in PC12 cell membrane. Act Pharmacol Sin 27:66–70. https://doi.org/10.1111/j.1745-7254.2006.00236.x
Nakai Y, Pellett S, Tepp WH, Johnson EA, Janda KD (2010) Toosendanin: synthesis of the AB-ring and investigations of its anti-botulinum properties (Part II). Bioorg Med Chem 18:1280–1287. https://doi.org/10.1016/j.mbc.2009.12.030
Fang XF, Cui ZJ (2011) The anti-botulism triterpenoid toosendanin elicits calcium increase and exocytosis in rat sensory neurons. Cell Mol Neurobiol 31:1151–1162. https://doi.org/10.1007/s10571-011-9716-z
Pei Z, Fu W, Wang G (2017) A natual product toosendanin inhibits epithelial-mesenchymal transition and tumor growth in pancreatic cancer via deactivating Akt/mTOR signaling. Biochem Biophys Res Commun 493:455–460. https://doi.org/10.1016/j.bbrc.2017.08.170
Luo W, Liu X, Sun W, Lu JJ, Wang Y, Chen X (2018) Toosendanin, a natural product, inhibited TGF-β1-induced epithelial-mesenchymal transition through ERK/Snail pathway. Phytother Res 32:2009–2020. https://doi.org/10.1002/ptr.6132
Chen TX, Cheng XY, Wang Y, Yin W (2018) Toosendanin inhibits adipogenesis by activating Wnt/b-catenin signaling. Sci Rep 8:4626. https://doi.org/10.1038/s41598-018-22873-x
Fan H, Chen W, Zhu J, Zhang J, Peng S (2019) Toosendanin alleviates dextran sulfate sodium-induced colitis by inhibiting M1 macrophage polarization and regulating NLRP3 inflammasome and Nrf2/HO-1 signaling. Int Immunopharmacol 76:105909. https://doi.org/10.1016/j.intimp.2019.105909
Jin YH, Kwon S, Choi JG, Cho WK, Lee B, Ma JY (2019) Toosndanin from Melia Fructus suppresses influenza A virus infection by altering nuclear localization of viral polymerase PA protein. Front Pharmacol 10:1025. https://doi.org/10.3389/fphar.2019.01025
Kai W, Yating S, Lin M, Kaiyong Y, Baojin H, Wu Y, Fangzhou Y, Yan C (2018) Natural product toosendanin reverses the resistance of human breast cancer cells to adriamycin as a novel PI3K inhibitor. Biochem Pharmacol 152:153–164. https://doi.org/10.1016/jbcp.2018.03.022
Su Z-S, Yang S-P, Zhang S, Dong L, Yue J-M (2011) Miliarachins A-K: eleven limonoids from twigs and leaves of Melia azedarach. Helv Chim Acta 94:1515–1526. https://doi.org/10.1002/hlca.201000444
Huang RC, Okamura H, Iwagawa T, Nakatani M (1994) The structure of azedarachins. limonoid antifeedants from Chinese Melia azedarach LINN. Bull Chem Soc Jpn 67:2468–2472. https://doi.org/10.1246/bcsj.67.2468
Nakatani M, Huang RC, Okamura H, Naoki H, Iwagawa T (1994) Limonoid antifeedants from Chinese Melia azedarach. Phytochemistry 36:39–41. https://doi.org/10.1016/S0031-9422(00)97008-0
Itokawa H, Qiao Z-S, Hirobe C, Takeya K (1995) Cytotoxic limonoids and tetranortriterpenoids from Melia azedarach. Chem Pharm Bull 43:1171–1175. https://doi.org/10.1248/cpb.43.1171
This work was supported by Research funds from San-Ei Gen F. F. I. Inc.
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Mifundu, M.N., Murakami, N., Kawano, T. et al. Toosendanin relatives, trypanocidal principles from Meliae Cortex. J Nat Med (2020). https://doi.org/10.1007/s11418-020-01422-9
- Trypanocidal activity
- Meliae Cortex
- SAR analysis