Sesquiterpene lactones are secondary plant metabolites with sundry biological effects. In plants, they are synthesized, among others, for pesticidal and antimicrobial effects. Two such compounds, archangelolide and trilobolide of the guaianolide type, are structurally similar to the well-known and clinically tested lactone thapsigargin. While trilobolide has already been studied by us and others, there are only scarce reports on the biological activity of archangelolide. Here we present the preparation of its fluorescent derivative based on a dansyl moiety using azide-alkyne Huisgen cycloaddition having obtained the two sesquiterpene lactones from the seeds of Laserpitium archangelica Wulfen using supercritical CO2 extraction. We show that dansyl-archangelolide localizes in the endoplasmic reticulum of living cells similarly to trilobolide; localization in mitochondria was also detected. This led us to a more detailed study of the anticancer potential of archangelolide. Interestingly, we found that neither archangelolide nor its dansyl conjugate did exhibit cytotoxic effects in contrast to the structurally closely related counterparts trilobolide and thapsigargin. We explain this observation by a molecular dynamics simulation, in which, in contrast to trilobolide, archangelolide did not bind into the sarco/endoplasmic reticular calcium ATPase cavity utilized by thapsigargin. Last, but not least, archangelolide exhibited anti-inflammatory activity, which makes it promising compound for medicinal purposes.

Charles University Prague Faculty of Medicine in Pilsen 301 66 Pilsen Czech Republic

Department of Biochemistry and Microbiology University of Chemistry and Technology Prague Technická 5 166 28 Prague 6 Czech Republic

Department of Chemistry of Natural Compounds University of Chemistry and Technology Prague Technická 5 166 28 Prague 6 Czech Republic

Institute of Experimental Medicine Academy of Sciences of the Czech Republic v v i 14220 Prague 4 Czech Republic

Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic Flemingovo náměstí 2 166 10 Prague 6 Czech Republic

Zobrazit více v PubMed

Chadwick M, Trewin H, Gawthrop F, Wagstaff C. Int J Mol Sci. 2013;14:12780–12805. doi: 10.3390/ijms140612780. PubMed DOI PMC

Peterková L, Rimpelová S, Kmoníčková E, Ruml T. Chem Listy. 2019;113:149–155.

Wootton L L, Michelangeli F. J Biol Chem. 2006;281:6970–6976. doi: 10.1074/jbc.m510978200. PubMed DOI

Sagara Y, Fernandez-Belda F, de Meis L, Inesi G. J Biol Chem. 1992;267:12606–12613. PubMed

Quynh Doan N, Christensen S. Curr Pharm Des. 2015;21(38):5501–5517. doi: 10.2174/1381612821666151002112824. PubMed DOI

Mahalingam D, Peguero J, Cen P, Arora S P, Sarantopoulos J, Rowe J, Allgood V, Tubb B, Campos L. Cancers. 2019;11:833. doi: 10.3390/cancers11060833. PubMed DOI PMC

Wictome M, Khan Y M, East J M, Lee A G. Biochem J. 1995;310:859–868. doi: 10.1042/bj3100859. PubMed DOI PMC

Jurášek M, Rimpelová S, Kmoníčková E, Drašar P, Ruml T. J Med Chem. 2014;57:7947–7954. doi: 10.1021/jm500690j. PubMed DOI

Tomanová P, Rimpelová S, Jurášek M, Buděšínský M, Vejvodová L, Ruml T, Kmoníčková E, Drašar P B. Steroids. 2015;97:8–12. doi: 10.1016/j.steroids.2014.08.024. PubMed DOI

Jurášek M, Džubák P, Rimpelová S, Sedlák D, Konečný P, Frydrych I, Gurská S, Hajdúch M, Bogdanová K, Kolář M, et al. Steroids. 2017;117:97–104. doi: 10.1016/j.steroids.2016.08.011. PubMed DOI

Harmatha J, Buděšínský M, Jurášek M, Zimmermann T, Drašar P, Zídek Z, Kmoníčková E, Vejvodová L. Fitoterapia. 2019;134:88–95. doi: 10.1016/j.fitote.2019.02.002. PubMed DOI

Harmatha J, Buděšínský M, Vokáč K, Kostecká P, Kmoníčková E, Zídek Z. Fitoterapia. 2013;89:157–166. doi: 10.1016/j.fitote.2013.05.025. PubMed DOI

Holub M, Samek Z. Collect Czech Chem Commun. 1973;38:731–738. doi: 10.1135/cccc19730731. DOI

Smítalová Z, Buděšínský M, Šaman D, Holub M. Collect Czech Chem Commun. 1986;51:1323–1339. doi: 10.1135/cccc19861323. DOI

Wulff J E, Siegrist R, Myers A G. J Am Chem Soc. 2007;129:14444–14451. doi: 10.1021/ja075327f. PubMed DOI PMC

Liu Y, Lok C-N, Ko B C-B, Shum T Y-T, Wong M-K, Che C-M. Org Lett. 2010;12:1420–1423. doi: 10.1021/ol902890j. PubMed DOI

Kim M, Kleckley T S, Wiemer A J, Holstein S A, Hohl R J, Wiemer D F. J Org Chem. 2004;69(24):8186–8193. doi: 10.1021/jo049101w. PubMed DOI

Deiters A, Cropp T A, Mukherji M, Chin J W, Anderson J C, Schultz P G. J Am Chem Soc. 2003;125:11782–11783. doi: 10.1021/ja0370037. PubMed DOI

Hein J E, Tripp J C, Krasnova L B, Sharpless K B, Fokin V V. Angew Chem, Int Ed. 2009;48:8018–8021. doi: 10.1002/anie.200903558. PubMed DOI PMC

Rimpelová S, Bříza T, Králová J, Záruba K, Kejík Z, Císařová I, Martásek P, Ruml T, Král V. Bioconjugate Chem. 2013;24:1445–1454. doi: 10.1021/bc400291f. PubMed DOI

Paula S, Ball W J., Jr Proteins: Struct, Funct, Bioinf. 2004;56(3):595–606. doi: 10.1002/prot.20105. PubMed DOI

Winther A-M L, Liu H, Sonntag Y, Olesen C, le Maire M, Soehoel H, Olsen C-E, Christensen S B, Nissen P, Møller J V. J Biol Chem. 2010;285(37):28883–28892. doi: 10.1074/jbc.m110.136242. PubMed DOI PMC

Furuya Y, Lundmo P, Short A D, Gill D L, Isaacs J T. Cancer Res. 1994;54:6167–6175. PubMed

Muangphrom P, Seki H, Fukushima E O, Muranaka T. J Nat Med. 2016;70(3):318–334. doi: 10.1007/s11418-016-1008-y. PubMed DOI PMC

Andersen T, López C, Manczak T, Martinez K, Simonsen H. Molecules. 2015;20(4):6113–6127. doi: 10.3390/molecules20046113. PubMed DOI PMC

Dirsch V M, Stuppner H, Ellmerer-Müller E P, Vollmar A M. Bioorg Med Chem. 2000;8:2747–2753. doi: 10.1016/s0968-0896(00)00202-9. PubMed DOI

Coricello A, Adams J D, Lien E, Nguyen C, Perri F, Williams T J, Aiello F. Curr Med Chem. 2018 doi: 10.2174/0929867325666180719111123. PubMed DOI

Kmoníčková E, Melkusová P, Harmatha J, Vokáč K, Farghali H, Zídek Z. Eur J Pharmacol. 2008;588:85–92. doi: 10.1016/j.ejphar.2008.03.037. PubMed DOI

Kmoníčková E, Harmatha J, Vokáč K, Kostecká P, Farghali H, Zídek Z. Fitoterapia. 2010;81:1213–1219. doi: 10.1016/j.fitote.2010.08.005. PubMed DOI

Inhibitory Effect of Selected Guaianolide and Germacranolide Sesquiterpene Lactones on Nitric Oxide Production

PEGylated Purpurin 18 with Improved Solubility: Potent Compounds for Photodynamic Therapy of Cancer