| ORIGINAL ARTICLES |
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Euchrestifolines A-O, fifteen novel carbazole alkaloids with potent anti-ferroptotic activity from Murraya euchrestifolia |
| Yue-Mei Chen, Nan-Kai Cao, Si-Si Zhu, Meng Ding, Hai-Zhen Liang, Ming-Bo Zhao, Ke-Wu Zeng, Peng-Fei Tu, Yong Jiang |
| State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, People’s Republic of China |
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Abstract Fifteen novel carbazole alkaloids, euchrestifolines A–O (1–15), were obtained from Murraya euchrestifolia. Their structures were elucidated by spectroscopic analysis, Mosher’s ester, calculated ECD, and transition metal complex ECD methods. Notably, euchrestifolines A–C (1–3) are the first naturally occurring pyrrolidone carbazoles to be identified, while euchrestifolines D–F (4–6) represent rare carbazole alkaloids containing a phenylpropanyl moiety; euchrestifoline G (7) features a unique benzopyranocarbazole skeleton. More importantly, these compounds exhibited significant anti-ferroptotic activity, along with inhibitory effects of nitric oxide (NO) production and notable cytotoxicity. This study marks the first disclosure of carbazole's inhibitory effects against ferroptosis, and the EC50 values of some carbazoles ranging from 0.04 to 1 μM, substantially lower than the positive control, ferrostatin-1. In sum, this research not only enhances our understanding of carbazole alkaloids but also opens new avenues for the discovery of ferroptosis-related leading compounds.
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| Keywords
Murraya euchrestifolia
Carbazole
Benzopyranocarbazole
Anti-ferroptosis
NO inhibition
Cytotoxicity
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| Fund:We express our gratitude to the National Natural Science Foundation of China (NSFC) for their financial support through grant numbers 81973199, 82173949, U23A20514, 81773864, and 81473106. Additionally, we acknowledge the funding provided by the Key Research and Development Project of Shandong Province (2021CXGC010507). Thanks to Mr. Cao Fei from Hebei University for his help in quantum chemical calculations. |
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Corresponding Authors:
Yong JIANG,E-mail:yongjiang@bjmu.edu.cn
E-mail: yongjiang@bjmu.edu.cn
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Issue Date: 15 February 2025
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[1] Editorial Committee of Flora of China. Flora of China, Science Press. Beijing; 1997. p. 139-151.
[2] Ji XD, Pu QL, Yang GZ. The chemical constituents of essential oil from Murraya euchrestifolia Hayata. Acta Pharm Sin. 1983;18:626–9.
[3] Wu TS, Wang ML, Wu PL, Furukawa H. Carbazole alkaloids from the leaves of Murraya euchrestifolia. Phytochemistry. 1996;41:1433–5. https://doi.org/10.1016/0031-9422(95)00794-6.
[4] Wu TS, Wang ML, Wu PL, Jong TT. Two carbazole alkaloids from leaves of Murraya euchrestifolia. Phytochemistry. 1995;40:1817–9. https://doi.org/10.1016/0031-9422(95)00447-F.
[5] Furukawa H, Wu TS, Kuoh CS. Structures of murrafoline-B and -C, new binary carbazole alkaloids from Murraya euchrestifolia. Chem Pharm Bull. 1985;33:2611–3.
[6] Furukawa H, Ito C, Wu TS, Mcphail AT. Structural elucidation of murrafolines, six novel binary carbazole alkaloids isolated from Murraya euchrestifolia. Chem Pharm Bull. 1993;41:1249–54.
[7] Knölker HJ, Reddy KR. Isolation and synthesis of biologically active carbazole alkaloids. Chem Rev. 2002;102:4303–428. https://doi.org/10.1021/cr020059j.
[8] Lv HN, Wen R, Zhou Y, Zeng KW, Li J, Guo XY, et al. Nitrogen oxide inhibitory trimeric and dimeric carbazole alkaloids from Murraya tetramera. J Nat Prod. 2015;78(10):2432–9. https://doi.org/10.1021/acs.jnatprod.5b00527.
[9] Schmidt AW, Reddy KR, Knölker H. Occurrence, biogenesis, and synthesis of biologically active carbazole alkaloids. Chem Rev. 2012;112:3193–328. https://doi.org/10.1021/cr200447s.
[10] Nandy BC, Gupta AK, Mittal A, Vyas V. Carbazole: it's biological activity. J Pharm Biomed. 2014;3:42–8.
[11] Ma XL, Cao NK, Zhang C, Guo XY, Zhao MB, Tu PF, et al. Cytotoxic carbazole alkaloid derivatives from the leaves and stems of Murraya microphylla. Fitoterapia. 2018;127:334–40. https://doi.org/10.1016/j.fitote.2018.03.010.
[12] Lv HN, Wen R, Zhou Y, Shi ML, Zeng KW, Xia F, et al. Murradiate and murradiol, two structurally unique heterodimers of carbazole-monoterpene and carbazole-phenylethanol from Murraya tetramera. Phytochem Lett. 2016;15:113–5. https://doi.org/10.1016/j.phytol.2015.12.002.
[13] Zhou Y, Lv HN, Wang WG, Tu PF, Jiang Y. Flavonoids and anthraquinones from Murraya tetramera, C. C. Huang (Rutaceae). Biochem Syst Ecol. 2014;57:78–80. https://doi.org/10.1016/j.bse.2014.07.016.
[14] Uvarani C, Sankaran M, Jaivel N, Chandraprakash K, Ata A, Mohan PS. Palathurai, bioactive dimeric carbazole alkaloids from Murraya koenigii. J Nat Prod. 2013;76:993–1000. https://doi.org/10.1021/np300464t.
[15] Chakraborty DP. Progress in the chemistry of organic natural products. New York: Springer; 1977. p. 299.
[16] Ramsewak RS, Nair MG, Strasburg GM, DeWitt DL, Nitiss JL. Biologically active carbazole alkaloids from Murraya koenigii. J Agr Food Chem. 1999;47:444–7. https://doi.org/10.1021/jf9805808.
[17] Liu WY, Zhang WD, Chen HS, Gu ZB, Li TZ, Zhou Y. Pyrrole alkaloids from Bolbostemma Paniculatum. J Asian Nat Prod Res. 2003;5:159–63. https://doi.org/10.1080/1028602031000066861.
[18] Gruner KK, Hopfmann T, Matsumoto K, Jäger A, Katsuki T, Knölker H. Efficient iron-mediated approach to pyrano[3,2-a]carbazole alkaloids–first total syntheses of O-methylmurrayamine A and 7-methoxymurrayacine, first asymmetric synthesis and assignment of the absolute configuration of (–)-trans-dihydroxygirinimbine. Org Biomol Chem. 2011;9:2057–61. https://doi.org/10.1039/C0OB01088J.
[19] Knölker HJ, Hofmann C. Transition metal complexes in organic synthesis, part 33. Molybdenum-mediated total synthesis of girinimbine, murrayacine, and dihydroxygirinimbine. Tetrahedron Lett. 1996;37:7947–50. https://doi.org/10.1016/0040-4039(96)01830-8.
[20] Xia GY, Wang M, Chen LX, Ding LQ, Qiu F. Application of dirhodium reagent Rh2(OCOCF3)4 to the determination of the absolute configurations of secondary and tertiary alcohols. J Int Pharm Res. 2015;42:726–33. https://doi.org/10.13220/j.cnki.jipr.2015.06.006.
[21] Tachibana Y, Kikuzaki H, Lajis NH, Nakatani N. Antioxidative activity of carbazoles from Murraya koenigii leaves. J Agric Food Chem. 2001;49:5589–94. https://doi.org/10.1021/jf010621r.
[22] Hoye TR, Jeffrey CS, Shao F. Mosher ester analysis for the determination of absolute configuration of stereogenic (chiral) carbinol carbons. Nat Protoc. 2007;2:2451–8. https://doi.org/10.1038/nprot.2007.354.
[23] Tao QQ, Ma K, Yang YL, Wang K, Chen BS, Huang Y, et al. Bioactive sesquiterpenes from the edible mushroom Flammulina velutipes and their biosynthetic pathway confirmed by genome analysis and chemical evidence. J Org Chem. 2016;81:9867–77. https://doi.org/10.1021/acs.joc.6b01971.
[24] Ito C, Nakagawa M, Wu TS, Furukawa H. New carbazole alkaloids from Murraya euchrestifolia. Chem Pharm Bull. 1991;39:2525–8. https://doi.org/10.1248/cpb.39.2525.
[25] Gassner C, Hesse R, Schmidt AW, Knölker H. Total synthesis of the cyclic monoterpenoid pyrano [3,2-a] carbazole alkaloids derived from 2-hydroxy-6-methylcarbazole. Org Biomol Chem. 2014;12:6490–9. https://doi.org/10.1039/C4OB01151A.
[26] Chen YM, Cao NK, Lv HN, Yuan JQ, Guo XY, et al. Anti-inflammatory and cytotoxic carbazole alkaloids from Murraya kwangsiensis. Phytochemistry. 2020;170: 112186. https://doi.org/10.1016/j.phytochem.2019.112186.
[27] Dhara K, Mandal T, Das J, Dash J. Synthesis of carbazole alkaloids by ring-closing metathesis and ring rearrangement–aromatization. Angew Chem Int Edit. 2015;54:15831–5. https://doi.org/10.1002/anie.201508746.
[28] Bringmann G, Tasler S, Endress H, Peters K, Peters E. Synthesis of mukonine and seven further 1-oxygenated carbazole alkaloids. Synthesis-Stuttgart. 1998;10:1501–5. https://doi.org/10.1055/s-1998-2184.
[29] Ito C, Itoigawa M, Nakao K, Murata T, Tsuboi M, Kaneda N, et al. Induction of apoptosis by carbazole alkaloids isolated from Murraya koenigii. Phytomedicine. 2006;13:359–65. https://doi.org/10.1016/j.phymed.2005.03.010.
[30] Li CH, Zhou Y, Tu PF, Zeng KW, Jiang Y. Natural carbazole alkaloid murrayafoline A displays potent anti-neuroinflammatory effect by directly targeting transcription factor Sp1 in LPS-induced microglial cells. Bioorg Chem. 2022;129: 106178. https://doi.org/10.1016/j.bioorg.2022.106178.
[31] Tan QY, Wu DY, Lin YT, Ai HP, Xu J, Zhou HB, et al. Identifying eleven new ferroptosis inhibitors as neuroprotective agents from FDA-approved drugs. Bioorg Chem. 2024;146: 107261. https://doi.org/10.1016/j.bioorg.2024.107261.
[32] Fan K, Zhang LC, Tan BY, Njateng GSS, Qin ML, Guo RR, et al. Antimicrobial indole alkaloids from Tabernaemontana corymbosa. Chin J Nat Med. 2023;21:146–53. https://doi.org/10.1016/S1875-5364(23)60393-0.
[33] Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, et al. Gaussian 09, Revision A.1, Gaussian, Inc., Wallingford CT, 2009.
[34] Chen D, Xu ZR, Chai XY, Zeng KW, Jia YX, Bi D, et al. Nine 2-(2-phenylethyl) chromone derivatives from the resinous wood of Aquilaria sinensis and their inhibition of LPS-induced NO production in RAW 264.7 cells. Eur J Org Chem. 2012;2012:5389–97. https://doi.org/10.1002/ejoc.201200725.
[35] Ma K, Wang JS, Luo J, Yang MH, Kong LY. Tabercarpamines A-J, apoptosis-inducing indole alkaloids from the leaves of Tabernaemontana corymbosa. J Nat Prod. 2014;77:1156–63. https://doi.org/10.1021/np401098y. |
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