This phytochemical study presents the isolation of eight alkaloids from Zephyranthes citrina Baker. The structures of the new alkaloids, zephycitrine (1) and 6-oxonarcissidine (2), were established by analysis of spectroscopic and spectrometric data. Processing the EtOH extract under acid-base conditions yielded the unreported isolation artifacts 3 and 4. This work also provides analytical data for alkaloids not properly described in the literature (5 and 6). The hippeastidine/zephyranine scaffolds in derivatives 3, 4, and 8-10 are also thoroughly discussed. Furthermore, a cytotoxicity screening of 25 Amaryllidaceae alkaloids isolated from Z. citrina was performed. Only the known alkaloids haemanthamine (12), haemanthidine (13), and lycorine (27) showed significant cell growth inhibition.

Department of Medical Biochemistry Faculty of Medicine in Hradec Králové Charles University Šimkova 870 500 03 Hradec Králové Czech Republic

Department of Natural Drugs Faculty of Pharmacy Masaryk University Palackého třída 1946 1 61200 Brno Czech Republic

Zobrazit více v PubMed

Syeed R.; Mujib A.; Malik M. Q.; Mamgain J.; Ejaz B.; Gulzar B.; Zafar N. Mass Propagation through Direct and Indirect Organogenesis in Three Species of Genus Zephyranthes and Ploidy Assessment of Regenerants through Flow Cytometry. Mol. Biol. Rep. 2021, 48, 513–526. 10.1007/s11033-020-06083-1. PubMed DOI

Herrera M. R.; Machocho A. K.; Brun R.; Viladomat F.; Codina C.; Bastida J. Crinane and Lycorane Type Alkaloids from Zephyranthes citrina. Planta Med. 2001, 67, 191–193. 10.1055/s-2001-11495. PubMed DOI

Šafratová M.; Vrabec R.; Blunden G.; Cahlíková L.; Křoustková J. Specialized Metabolites of the Genus Zephyranthes Herb.: a Critical Review on Taxonomy and Phytochemistry. Phytochem. Rev. 2024, 10.1007/s11101-024-09931-1. DOI

Boit H. G.; Dopke W.; Stender W. Alkaloide aus Crinum-, Zephyranthes-, Leucojum- und Clivia-Arten. Chem. Ber./Recl. 1957, 90, 2203–2206. 10.1002/cber.19570901013. DOI

Pellegrino S.; Meyer M.; Zorbas C.; Bouchta S. A.; Saraf K.; Pelly S. C.; Yusupova G.; Evidente A.; Mathieu V.; Kornienko A.; et al. The Amaryllidaceae Alkaloid Haemanthamine Binds the Eukaryotic Ribosome to Repress Cancer Cell Growth. Structure 2018, 26, 416–425.e4. 10.1016/j.str.2018.01.009. PubMed DOI

Doskočil I.; Hošt’álková A.; Šafratová M.; Benešová N.; Havlík J.; Havelek R.; Kuneš J.; Královec K.; Chlebek J.; Cahlíková L. Cytotoxic activities of Amaryllidaceae alkaloids against gastrointestinal cancer cells. Phytochem. Lett. 2015, 13, 394–398. 10.1016/j.phytol.2015.08.004. DOI

Havelek R.; Seifrtova M.; Kralovec K.; Bruckova L.; Cahlikova L.; Dalecka M.; Vavrova J.; Rezacova M.; Opletal L.; Bilkova Z. The Effect of Alkaloids Haemanthamine and Haemanthidine on Cell Cycle Progression and Apoptosis in p53-negative Human Leukemic Jurkat Cells. Phytomedicine 2014, 21, 479–490. 10.1016/j.phymed.2013.09.005. PubMed DOI

Plazas E.; Avila M M. M.; Munoz D. R.; Cuca S L. E. Natural Isoquinoline Alkaloids: Pharmacological Features and Multi-target Potential for Complex Diseases. Pharmacol. Res. 2022, 177, 10612610.1016/j.phrs.2022.106126. PubMed DOI

Uher M.; Hroch M.; Peřinová R.; Havelek R.; Křoustková J.; Řezáčová M.; Muthná D.; Koutová D.; Kuneš J.; Cahlíková L. Semisynthetic Derivatives of Haemanthamine and their In Vitro Antiproliferative Activity Evaluation against a Panel of Human Cell Lines. Arab. J. Chem. 2022, 15, 10374610.1016/j.arabjc.2022.103746. DOI

Tojo E. (+)-Narcidine, a New Alkaloid from Narcissus pseudonarcissus. J. Nat. Prod. 1991, 54, 1387–1388. 10.1021/np50077a023. DOI

Pigni N. B.; Ríos-Ruiz S.; Martínez-Francés V.; Nair J. J.; Viladomat F.; Codina C.; Bastida J. Alkaloids from Narcissus serotinus. J. Nat. Prod. 2012, 75, 1643–1647. 10.1021/np3003595. PubMed DOI

Cedrón J. C.; Oberti J. C.; Estévez-Braun A.; Ravelo A. G.; Del Arco-Aguilar M.; López M. Pancratium canariense as an Important Source of Amaryllidaceae Alkaloids. J. Nat. Prod. 2009, 72, 112–116. 10.1021/np800459d. PubMed DOI

Zhan G.; Gao B.; Zhou J.; Liu T.; Zheng G.; Jin Z.; Yao G. Structurally Diverse Alkaloids with Nine Frameworks from Zephyranthes candida and their Acetylcholinesterase Inhibitory and Anti-inflammatory Activities. Phytochemistry 2023, 207, 11356410.1016/j.phytochem.2022.113564. PubMed DOI

Shitara N.; Hirasawa Y.; Hasumi S.; Sasaki T.; Matsumoto M.; Wong C. P.; Kaneda T.; Asakawa Y.; Morita H. Four New Amaryllidaceae Alkaloids from Zephyranthes candida. J. Nat. Med. 2014, 68, 610–614. 10.1007/s11418-014-0819-y. PubMed DOI

World Flora Online Home Page. https://www.worldfloraonline.org/ (accessed 9 July 2024).

Via J.; Arriortua M. I.; Ochando L. E.; Reventós M. M.; Amigó J. M.; Bastida J. Structure of Eugenine, an Alkaloid from Narcissus eugeniae. Acta Crystallogr. C 1989, 45, 2020–2022. 10.1107/S0108270189007973. DOI

Meijer T. M.; Schmid H. Uber die Konstitution des Eugenins. Helv. Chim. Acta 1948, 31, 1603–1607. 10.1002/hlca.19480310620. PubMed DOI

Le N. T. H.; De Jonghe S.; Erven K.; Neyts J.; Pannecouque C.; Vermeyen T.; Herrebout W. A.; Pieters L.; Tuenter E. Comprehensive study of alkaloids from Scadoxus ultiflorus by HPLC-PDA-SPE-NMR and evaluation of their anti-SARS-CoV-2 activity. Phytochem. Lett. 2023, 57, 156–162. 10.1016/j.phytol.2023.08.015. DOI

Boit H. G.; Ehmke H. Amaryllidaceen Alkaloide. 10. Die Alkaloide Einiger Gartensorten von Narcissus pseudonarcissus und N-incomparabilis. Chem. Ber./Recl. 1956, 89, 163–167. 10.1002/cber.19560890128. DOI

Fales H. M.; Giuffrida L. D.; Wildman W. C. Alkaloids of the Amaryllidaceae. 8. The Structures of Narcissamine, Pseudolycorine and Methylpseudolycorine. J. Am. Chem. Soc. 1956, 78, 4145–4150. 10.1021/ja01597a078. DOI

Kametani T.; Yamaki K.; Terui T. Studies on Syntheses of Heterocyclic Compounds. 507. Synthesis of (±)-N-norgalanthamine. J. Heterocycl. Chem. 1973, 10, 35–37. 10.1002/jhet.5570100108. DOI

Kihara M.; Koike T.; Imakura Y.; Kida K.; Shingu T.; Kobayashi S. Alkaloidal Constituents of Hymenocallis rotata Herb. (Amaryllidaceae). Chem. Pharm. Bull. 1987, 35, 1070–1075. 10.1248/cpb.35.1070. DOI

Wang H.; Wang Y-H.; Zhao F-W.; Huang Q-Q.; Xu J-J.; Ma L-J.; Long C-L. Benzylphenethylamine Alkaloids from the Bulbs and Flowers of Lycoris radiata. Chin. Herb. Med. 2011, 3, 60–63. 10.3969/j.issn.1674-6384.2011.01.012. DOI

Li L.; Yang Q.; Wang Y.; Jia Y. Catalytic Asymmetric Total Synthesis of (−)-Galanthamine and (−)-Lycoramine. Angew. Chem., Int. Ed. 2015, 54, 6255–6259. 10.1002/anie.201411338. PubMed DOI

Philipova I.; Stavrakov G.; Dimitrov V.; Vassilev N. Galantamine Derivatives: Synthesis, NMR Study, DFT Calculations and Application in Asymmetric Catalysis. J. Mol. Struct. 2020, 1219, 12856810.1016/j.molstruc.2020.128568. DOI

Chaichompoo W.; Rojsitthisak P.; Pabuprapap W.; Siriwattanasathien Y.; Yotmanee P.; Suksamrarn A. Amaryllidaceae Alkaloids from the Bulbs of Crinum latifolium L. and Their Cholinesterase Inhibitory Activities. Phytochemistry 2024, 217, 11392910.1016/j.phytochem.2023.113929. PubMed DOI

Kohelová E.; Maříková J.; Korábečný J.; Hulcová D.; Kučera T.; Jun D.; Chlebek J.; Jenčo J.; Šafratová M.; Hrabinová M.; et al. Alkaloids of (Amaryllidaceae) and their Implication to Alzheimer’s Disease: Isolation, Structural Elucidation and Biological Activity. Bioorg. Chem. 2021, 107, 10456710.1016/j.bioorg.2020.104567. PubMed DOI

Prakash J.; Vedanayaki S. In-vitro Cytotoxicity Studies of Methanolic Bulb Extract of Zephyranthes citrina on Cervical Cancer (Hela), Breast Cancer (MCF-7) and Oral Cancer (SCC-9). J. Pharm. Sci. Res. 2019, 11, 2353–2356.

Havelek R.; Muthná D.; Tomšík P.; Královec K.; Seifrtová M.; Cahlíková L.; Hostalkova A.; Šafratová M.; Perwein M.; Čermaková E.; Řezáčová M. Anticancer Potential of Amaryllidaceae Alkaloids Evaluated by Screening with a Panel of Human Cells, Real-time Cellular Analysis and Ehrlich Tumor-bearing Mice. Chem. Biol. Interact. 2017, 275, 121–132. 10.1016/j.cbi.2017.07.018. PubMed DOI

Indrayanto G.; Putra G. S.; Suhud F. Validation of In-Vitro Bioassay Methods: Application in Herbal Drug Research. Profiles of Drug Subst. Excipients Rel. Methodol. 2021, 46, 273–307. 10.1016/bs.podrm.2020.07.005. PubMed DOI

Luo Z.; Wang F.; Zhang J.; Li X.; Zhang M.; Hao X.; Xue Y.; Li Y.; Horgen F. D.; Yao G.; Zhang Y. Cytotoxic Alkaloids from the Whole Plants of Zephyranthes candida. J. Nat. Prod. 2012, 75, 2113–2120. 10.1021/np3005425. PubMed DOI PMC

Breiterová K.; Koutová D.; Maříková J.; Havelek R.; Kuneš J.; Majorošová M.; Opletal L.; Hošt’álková A.; Jenčo J.; Řezáčová M.; Cahlíková L. Amaryllidaceae alkaloids of different structural types from Narcissus L. cv. Professor Einstein and their cytotoxic activity. Plants (Basel) 2020, 9, 137.10.3390/plants9020137. PubMed DOI PMC

Katoch D.; Kumar D.; Padwad Y. S.; Singh B.; Sharma U. Pseudolycorine N-oxide, a New N-oxide from Narcissus tazetta. Nat. Prod. Res. 2020, 34, 2051–2058. 10.1080/14786419.2019.1574785. PubMed DOI

Nair J. J.; van Staden J. Cytotoxic Agents in the Minor Alkaloid Groups of the Amaryllidaceae. Planta Med. 2021, 87, 916–936. 10.1055/a-1380-1888. PubMed DOI

Luchetti G.; Johnston R.; Mathieu V.; Lefranc F.; Hayden K.; Andolfi A.; Lamoral-Theys D.; Reisenauer M. R.; Champion C.; Pelly S. C.; et al. Bulbispermine: a Crinine-type Amaryllidaceae Alkaloid Exhibiting Cytostatic Activity Toward Apoptosis-resistant Glioma Cells. Chemmedchem 2012, 7, 815–822. 10.1002/cmdc.201100608. PubMed DOI PMC

Van Goietsenoven G.; Andolfi A.; Lallemand B.; Cimmino A.; Lamoral-Theys D.; Gras T.; Abou-Donia A.; Dubois J.; Lefranc F.; Mathieu V.; et al. Amaryllidaceae Alkaloids Belonging to Different Structural Subgroups Display Activity against Apoptosis-resistant Cancer Cells. J. Nat. Prod. 2010, 73, 1223–1227. 10.1021/np9008255. PubMed DOI

Evidente A.; Kireev A. S.; Jenkins A. R.; Romero A. E.; Steelant W. F. A.; Van Slambrouck S.; Kornienko A. Biological Evaluation of Structurally Diverse Amaryllidaceae Alkaloids and their Synthetic Derivatives: Discovery of Novel Leads for Anticancer Drug Design. Planta Med. 2009, 75, 501–507. 10.1055/s-0029-1185340. PubMed DOI PMC

Alarcon M.; Cea G.; Weigert G. Clastogenic effect of hippeastidine (HIPP) (1,2,3,4,4a,6 hexahydro-10,hydroxy-3,8,9,trimethoxy-5,10b, ethanophenanthridine). Bull. Environ. Contam. Toxicol. 1986, 37 (4), 508–512. 10.1007/BF01607796. PubMed DOI

McNulty J.; Nair J. J.; Codina C.; Bastida J.; Pandey S.; Gerasimoff J.; Griffin C. Selective Apoptosis-inducing Activity of Crinum-type Amaryllidaceae alkaloids. Phytochemistry 2007, 68, 1068–1074. 10.1016/j.phytochem.2007.01.006. PubMed DOI

Kim Y. H.; Park E. J.; Park M. H.; Badarch U.; Woldemichael G. M.; Beutler J. A. Crinamine from Crinum asiaticum var. japonicum Inhibits Hypoxia Inducible Factor-1 Activity But Not Activity of Hypoxia Inducible Factor-2. Biol. Pharm. Bull. 2006, 29, 2140–2142. 10.1248/bpb.29.2140. PubMed DOI

Sun Q.; Shen Y.-H.; Tian J.-M.; Tang J.; Su J.; Liu R.-H.; Li H.-L.; Xu X.-K.; Zhang W.-D. Chemical Constituents of Crinum asiaticum L. var. sinicum Baker and their Cytotoxic Activities. Chem. Biodivers. 2009, 6, 1751–1757. 10.1002/cbdv.200800273. PubMed DOI

Jitsuno M.; Yokosuka A.; Sakagami H.; Mimaki Y. Chemical Constituents of the Bulbs of Habranthus brachyandrus and their Cytotoxic Activities. Chem. Pharm. Bull. (Tokyo) 2009, 57, 1153–1157. 10.1248/cpb.57.1153. PubMed DOI

Hrabinova M.; Pejchal J.; Hepnarova V.; Muckova L.; Junova L.; Opravil J.; Zdarova Karasova J.; Rozsypal T.; Dlabkova A.; Rehulkova H.; et al. A-series Agent A-234: Initial in vitro and in vivo Characterization. Arch. Toxicol. 2024, 98, 1135–1149. 10.1007/s00204-024-03689-3. PubMed DOI PMC