Ambelline, an alkaloid from the Amaryllidaceae family with a crinane-type skeleton, has not yet demonstrated any outstanding biological activity. However, its analogues prepared by derivatization of the C-11 hydroxyl group show different interesting effects. Continuing our earlier work, twelve novel aromatic esters were developed (10, 14, 16, 17, 22-25, 30-33) and studied, together with previously synthesized derivatives (2-9, 11-13, 15, 18-21, 26-29) in terms of their cytotoxic activity. The cytotoxic potential was determined on a panel of nine human cancer cell lines and one noncancerous cell line to characterize their biological activity spectrum. To describe and foresee the structure-activity relationship for further research, substances synthesized and described in our previous work were also included in this cytotoxicity study. The most significant activity was associated with analogues having methyl (10), methoxy (14-17), or ethoxy (18) substitution on the phenyl condensed to ambelline. However, the 4-chloro-3-nitrobenzoyl derivative (32) showed the most promising IC50 values, ranging from 0.6 ± 0.1 µM to 9.9 ± 0.2 µM. In vitro cytotoxicity studies indicated the most potent antiproliferative activity of 32 in a dose-dependent and time-dependent manner. Besides, 32 was found to be effective in decreasing viability and triggering apoptosis of MOLT-4 T-lymphoblastic leukemia cells.

Department of Analytical Chemistry Faculty of Pharmacy Charles University Heyrovskeho 1203 Hradec Kralove 500 05 Czech Republic

Department of Biological and Biochemical Sciences Faculty of Chemical Technology University of Pardubice Studentska 573 Pardubice 532 10 Czech Republic

Department of Medical Biochemistry Faculty of Medicine in Hradec Kralove Charles University Simkova 870 Hradec Kralove 500 03 Czech Republic

Department of Organic and Bioorganic Chemistry Faculty of Pharmacy Charles University Heyrovskeho 1203 Hradec Kralove 500 05 Czech Republic

Department of Pharmacognosy and Pharmaceutical Botany Faculty of Pharmacy Charles University Heyrovskeho 1203 Hradec Kralove 500 05 Czech Republic

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Baig S., Seevasant I., Mohamad J., et al. Potential of apoptotic pathway-targeted cancer therapeutic research: where do we stand? Cell Death Dis. 2016;7 doi: 10.1038/cddis.2015.275. PubMed DOI PMC

Berkov S., Romani S., Herrera M., et al. Antiproliferative alkaloids from Crinum zeylanicum. Phytother Res. 2011;25:1686–1692. doi: 10.1002/ptr.3468. PubMed DOI

Cahlikova L., Kawano I., Rezacova M., et al. The Amaryllidaceae alkaloids haemanthamine, haemanthidine and their semisynthetic derivatives as potential drugs. Phytochem Rev. 2021;20:303–323. doi: 10.1007/s11101-020-09675-8. DOI

Campbell W.E., Nair J.J., Gammon D.W., et al. Cytotoxic and antimalarial alkaloids from Brunsvigia littoralis. Planta Med. 1998;64:91–93. doi: 10.1055/s-2006-957381. PubMed DOI

Cao Z.F., Yang P., Zhou Q.S. Multiple biological functions and pharmacological effects of lycorine. Sci. China Chem. 2013;56:1382–1391. doi: 10.1007/s11426-013-4967-9. PubMed DOI PMC

Choudhari A.S., Mandave P.C., Deshpande M., et al. Phytochemicals in cancer treatment: from preclinical studies to clinical practice (vol 10, 1614, 2020) Front. Pharmacol. 2020;11 doi: 10.3389/fphar.2020.00175. PubMed DOI PMC

Cragg G.M., Pezzuto J.M. Natural products as a vital source for the discovery of cancer chemotherapeutic and chemopreventive agents. Med. Prin. Pract. 2016;25:41–59. doi: 10.1159/000443404. PubMed DOI PMC

Ding Y., Qu D., Zhang K.M., et al. Phytochemical and biological investigations of Amaryllidaceae alkaloids: a review. J. Asian Nat. Prod. Res. 2017;19:53–100. doi: 10.1080/10286020.2016.1198332. PubMed DOI

Doskocil I., Hostalkova A., Safratova M., et al. Cytotoxic activities of Amaryllidaceae alkaloids against gastrointestinal cancer cells. Phytochem. Lett. 2015;13:394–398. doi: 10.1016/j.phytol.2015.08.004. DOI

Ferlay J., Colombet M., Soerjomataram I., et al. Cancer statistics for the year 2020: an overview. Int. J. Cancer. 2021 doi: 10.1002/ijc.33588. PubMed DOI

Furst R. Narciclasine - an amaryllidaceae alkaloid with potent antitumor and anti-inflammatory properties. Planta Med. 2016;82:1389–1394. doi: 10.1055/s-0042-115034. PubMed DOI

Guichard N., Guillarme D., Bonnabry P., et al. Antineoplastic drugs and their analysis: a state of the art review. Analyst. 2017;142:2273–2321. doi: 10.1039/c7an00367f. PubMed DOI

Habartova K., Cahlikova L., Rezacova M., et al. The biological activity of alkaloids from the Amaryllidaceae: from Cholinesterases inhibition to anticancer activity. Nat Prod Commun. 2016;11:1587–1594. doi: 10.1177/1934578X1601101038. PubMed DOI

Hanh T.T.H., Anh D.H., Huong P.T.T., et al. Crinane, augustamine, and beta-carboline alkaloids from Crinum latifolium. Phytochem Lett. 2018;24:27–30. doi: 10.1016/j.phytol.2018.01.004. DOI

Havelek R., Seifrtova M., Kralovec K., et al. The effect of Amaryllidaceae alkaloids haemanthamine and haemanthidine on cell cycle progression and apoptosis in p53-negative human leukemic Jurkat cells. Phytomedicine. 2014;21:479–490. doi: 10.1016/j.phymed.2013.09.005. PubMed DOI

Havelek R., Muthna D., Tomsik P., et al. 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. doi: 10.1016/j.cbi.2017.07.018. PubMed DOI

He M.M., Qu C.R., Gao O.D., et al. Biological and pharmacological activities of Amaryllidaceae alkaloids. Rsc Adv. 2015;5:16562–16574. doi: 10.1039/c4ra14666b. DOI

Likhitwitayawuid K., Angerhofer C.K., Chai H.B., et al. Traditional Medicinal-Plants of Thailand. 22. Cytotoxic and Antimalarial Alkaloids from the Bulbs of Crinum amabile. J. Nat. Prod. 1993;56:1331–1338. doi: 10.1021/np50098a017. PubMed DOI

Luchetti G., Johnston R., Mathieu V., et al. Bulbispermine: a crinine-type amaryllidaceae alkaloid exhibiting cytostatic activity toward apoptosis-resistant glioma cells. Chemmedchem. 2012;7:815–822. doi: 10.1002/cmdc.201100608. PubMed DOI PMC

Ma D., Pignanelli C., Tarade D., et al. Cancer cell mitochondria targeting by pancratistatin analogs is dependent on functional complex II and III. Sci Rep-Uk. 2017;7:42957. doi: 10.1038/srep42957. PubMed DOI PMC

Marikova J., Ritomska A., Korabecny J., et al. Aromatic Esters of the crinane amaryllidaceae alkaloid ambelline as selective inhibitors of butyrylcholinesterase. J. Nat. Prod. 2020;83:1359–1367. doi: 10.1021/acs.jnatprod.9b00561. PubMed DOI

Masi M., Di Lecce R., Merindol N., et al. Cytotoxicity and antiviral properties of alkaloids isolated from Pancratium maritimum. Toxins. 2022;14(4):262. doi: 10.3390/toxins14040262. PubMed DOI PMC

McNulty J., Nair J.J., Codina C., et al. Selective apoptosis-inducing activity of crinum-type Amaryllidaceae alkaloids. Phytochemistry. 2007;68:1068–1074. doi: 10.1016/j.phytochem.2007.01.006. PubMed DOI

McNulty J., Nair J.J., Bastida J., et al. Structure-activity studies on the lycorine pharmacophore: a potent inducer of apoptosis in human leukemia cells. Phytochemistry. 2009;70:913–919. doi: 10.1016/j.phytochem.2009.04.012. PubMed DOI PMC

Nair J.J., Bastida J., Codina C., et al. Alkaloids of the South African Amaryllidaceae: a review. Nat Prod Commun. 2013;8:1335–1350. doi: 10.1177/1934578X1300800938. PubMed DOI

Nair J.J., van Staden J. The Amaryllidaceae as a source of antiplasmodial crinane alkaloid constituents. Fitoterapia. 2019;134:305–313. doi: 10.1016/j.fitote.2019.02.009. PubMed DOI

Nair J.J., Bastida J., Viladomat F., et al. Cytotoxic agents of the crinane series of Amaryllidaceae alkaloids. Nat. Prod. Commun. 2012;7:1677–1688. doi: 10.1177/1934578X1200701234. PubMed DOI

Nair J.J., Bastida J., Viladomat F., et al. Cytotoxic agents of the crinane series of Amaryllidaceae alkaloids. Nat. Prod. Commun. 2013;8:553–564. doi: 10.1177/1934578X1200701234. PubMed DOI

Nair J.J., Rarova L., Strnad M., et al. Alkaloids from Boophone haemanthoides (Amaryllidaceae) Nat. Prod. Commun. 2013;8:1705–1710. doi: 10.1177/1934578X1300801211. PubMed DOI

Nair J.J., Rarova L., Strnad M., et al. Crinane alkaloids of the Amaryllidaceae with cytotoxic effects in human cervical adenocarcinoma (HeLa) cells. Nat. Prod. Commun. 2014;9:461–466. doi: 10.1177/1934578X1400900406. PubMed DOI

Nair J.J., Rarova L., Strnad M., et al. Mechanistic insights to the cytotoxicity of Amaryllidaceae alkaloids. Nat. Prod. Commun. 2015;10:171–182. doi: 10.1177/1934578X1501000138. PubMed DOI

Nair J.J., Bastida J., van Staden J. In vivo cytotoxicity studies of Amaryllidaceae alkaloids. Nat. Prod. Commun. 2016;11:121–132. doi: 10.1177/1934578X1601100134. PubMed DOI

Nair J.J., van Staden J. Cytotoxicity studies of lycorine alkaloids of the Amaryllidaceae. Nat. Prod. Commun. 2014;9:1193–1210. doi: 10.1177/1934578X1400900834. PubMed DOI

Nair J.J., Van Staden J., Bastida J. Cytotoxic alkaloid constituents of the Amaryllidaceae. Stud. Natural Products Chem. 2016;49:107–156. doi: 10.1016/B978-0-444-63601-0.00003-X. DOI

Pellegrino S., Meyer M., Zorbas C., et al. The Amaryllidaceae alkaloid haemanthamine binds the eukaryotic ribosome to repress cancer cell growth. Structure. 2018;26:416–425. doi: 10.1016/j.str.2018.01.009. PubMed DOI

Qing Z.X., Huang J.L., Yang X.Y., et al. Anticancer and reversing multidrug resistance activities of natural isoquinoline alkaloids and their structure-activity relationship. Curr. Med. Chem. 2018;25:5088–5114. doi: 10.2174/0929867324666170920125135. PubMed DOI

Seifrtova M., Havelek R., Cahlikova L., et al. Haemanthamine alters sodium butyrate-induced histone acetylation, p21(WAF1/Cip1) expression, Chk1 and Chk2 activation and leads to increased growth inhibition and death in A2780 ovarian cancer cells. Phytomedicine. 2017;35:1–10. doi: 10.1016/j.phymed.2017.08.019. PubMed DOI

Uher M., Hroch M., Perinova R., et al. Semisynthetic derivatives of haemanthamine and their in vitro antiproliferative activity evaluation against a panel of human cell lines. Arabian J. Chem. 2022;15 doi: 10.1016/j.arabjc.2022.103746. DOI

Vaneckova N., Hostalkova A., Safratova M., et al. Isolation of Amaryllidaceae alkaloids from Nerine bowdenii W. Watson and their biological activities. Rsc Adv. 2016;6:80114–80120. doi: 10.1039/c6ra20205e. DOI

Youssef D.T.A., Shaala L.A., Altyar A.E. Cytotoxic phenylpropanoid derivatives and alkaloids from the flowers of Pancratium maritimum L. Plants (Basel). 2022;11 doi: 10.3390/plants11040476. PubMed DOI PMC