Planta Med 2022; 88(11): 855-880
DOI: 10.1055/a-1482-6381
Biological and Pharmacological Activity
Reviews

Lichen Depsidones with Biological Interest

Isabel Ureña-Vacas
Department of Pharmacology, Pharmacognosy and Botany, Faculty of Pharmacy, Complutense University of Madrid (Spain)
,
Elena González-Burgos
Department of Pharmacology, Pharmacognosy and Botany, Faculty of Pharmacy, Complutense University of Madrid (Spain)
,
Pradeep Kumar Divakar
Department of Pharmacology, Pharmacognosy and Botany, Faculty of Pharmacy, Complutense University of Madrid (Spain)
,
M. Pilar Gómez-Serranillos
Department of Pharmacology, Pharmacognosy and Botany, Faculty of Pharmacy, Complutense University of Madrid (Spain)
› Author Affiliations
Supported by: University Complutense of Madrid CT42/18-CT43/18
Supported by: Santander-University Complutense of Madrid PR87/19-22637
Supported by: Spanish Ministry of Science, Innovation and Universities PID2019-105312GB-100

Abstract

Depsidones are some of the most abundant secondary metabolites produced by lichens. These compounds have aroused great pharmacological interest due to their activities as antioxidants, antimicrobial, and cytotoxic agents. Hence, this paper aims to provide up-to-date knowledge including an overview of the potential biological interest of lichen depsidones. So far, the most studied depsidones are fumarprotocetraric acid, lobaric acid, norstictic acid, physodic acid, salazinic acid, and stictic acid. Their pharmacological activities have been mainly investigated in in vitro studies and, to a lesser extent, in in vivo studies. No clinical trials have been performed yet. Depsidones are promising cytotoxic agents that act against different cell lines of animal and human origin. Moreover, these compounds have shown antimicrobial activity against both Gram-positive and Gram-negative bacteria and fungi, mainly Candida spp. Furthermore, depsidones have antioxidant properties as revealed in oxidative stress in vitro and in vivo models. Future research should be focused on further investigating the mechanism of action of depsidones and in evaluating new potential actions as well as other depsidones that have not been studied yet from a pharmacological perspective. Likewise, more in vivo studies are prerequisite, and clinical trials for the most promising depsidones are encouraged.



Publication History

Received: 09 March 2021

Accepted after revision: 13 April 2021

Article published online:
25 May 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Aschenbrenner IA, Cernava T, Berg G, Grube M. Understanding microbial multi-species symbioses. Front Microbiol 2016; 7: 180 DOI: 10.3389/fmicb.2016.00180.
  • 2 Calcott MJ, Ackerley DF, Knight A, Keysers RA, Owen JG. Secondary metabolism in the lichen symbiosis. Chem Soc Rev 2018; 47: 1730-1760 DOI: 10.1039/c7cs00431a.
  • 3 Ivanova D, Ivanov D. Ethnobotanical use of lichens: lichens for food review. Scr Sci Med 2009; 41: 11 DOI: 10.14748/ssm.v41i1.456.
  • 4 Singh H, Husain T, Agnihotri P, Pande PC, Khatoon S. An ethnobotanical study of medicinal plants used in sacred groves of Kumaon Himalaya, Uttarakhand, India. J Ethnopharmacol 2014; 154: 98-108 DOI: 10.1016/j.jep.2014.03.026.
  • 5 Devkota S, Chaudhary R, Werth S, Scheidegger C. Indigenous knowledge and use of lichens by the lichenophilic communities of the Nepal Himalaya. J Ethnobiol Ethnomed 2017; 13: 1-10 DOI: 10.1186/s13002-017-0142-2.
  • 6 Molnár K, Farkas E. Current results on biological activities of lichen secondary metabolites: A review. Z Naturforsch C J Biosci 2010; 65: 157-173 DOI: 10.1515/znc-2010-3-401.
  • 7 Furmanek Ł, Czarnota P, Seaward MRD. Antifungal activity of lichen compounds against dermatophytes: a review. J Appl Microbiol 2019; 127: 308-325 DOI: 10.1111/jam.14209.
  • 8 Rankovic B, Kosanic M. Lichens as a Potential Lichen Source of bioactive secondary Metabolites. In: Rankovic B. ed. Lichen secondary Metabolites. Bioactive Properties and pharmaceutical Potential. Cham, Switzerland: Springer International; 2015: 1-26
  • 9 Nash TH, Ryan BD, Gries C, Bungartz F. Lichen Flora of the greater Sonoran Desert Region. Dexter, MI: Arizona State University, Thomas-shore, Inc.; 2002
  • 10 Fernández-Moriano C, Gómez-Serranillos MP, Crespo A. Antioxidant potential of lichen species and their secondary metabolites. A systematic review. Pharm Biol 2016; 54: 1-17 DOI: 10.3109/13880209.2014.1003354.
  • 11 Solárová Z, Liskova A, Samec M, Kubatka P, Büsselberg D, Solár P. Anticancer potential of lichensʼ secondary metabolites. Biomolecules 2020; 10: 87 DOI: 10.3390/biom10010087.
  • 12 Piovano M, Garbarino JA, Giannini FA, Correché ER, Feresin G, Tapia A, Zacchino S, Enriz RD. Evaluation of antifungal and antibacterial activities of aromatic metabolites from lichens. Bol Soc Chil Quím 2002; 47: 235-240 DOI: 10.4067/S0366-16442002000300006.
  • 13 Podterob A. Chemical composition of lichens and their medical applications. Pharm Chem J 2008; 42: 582-588 DOI: 10.1007/s11094-009-0183-5.
  • 14 Shukla V, Joshi GP, Rawat MSM. Lichens as a potential natural source of bioactive compounds: A review. Phytochem Rev 2010; 9: 303-314 DOI: 10.1007/s11101-010-9189-6.
  • 15 Vickery ML, Vickery B. Polyketides. In: Secondary Plant Metabolism. London: MacMillan Press; 1981: 88-111
  • 16 Legaz M, de Armas R, Vicente C. Bioproduction of Depsidones for pharmaceutical Purposes. In: Rundfeldt C. ed. Drug Development–A case Study based Insight into modern Strategies. InTech; 2011. DOI: 10.5772/27051 Accessed November 1, 2020 at: http://www.intechopen.com/books/drug-development-a-case-study-based-insight-into-modern-strategies/bioproduction-of-depsidones-for-pharmaceutical-purposes
  • 17 Ibrahim SRM, Mohamed GA, Al Haidari RA, El Kholy AA, Zayed MF, Khayat MT. Biologically active fungal depsidones: chemistry, biosynthesis, structural characterization, and bioactivities. Fitoterapia 2018; 129: 317-365 DOI: 10.1016/j.fitote.2018.04.012.
  • 18 Correché ER, Enriz RD, Piovano M, Giannini F, Garbarino J, Enriz D. Cytotoxic and apoptotic effects on hepatocytes of secondary metabolites obtained from lichens. Altern Lab Anim 2004; 32: 605-615 DOI: 10.1177/026119290403200611.
  • 19 Manojlović N, Ranković B, Kosanić M, Vasiljević P, Stanojković T. Chemical composition of three Parmelia lichens and antioxidant, antimicrobial and cytotoxic activities of some their major metabolites. Phytomedicine 2012; 19: 1166-1172 DOI: 10.1016/j.phymed.2012.07.012.
  • 20 Paluszczak J, Kleszcz R, Studzińska-Sroka E, Krajka-Kuźniak V. Lichen-derived caperatic acid and physodic acid inhibit Wnt signaling in colorectal cancer cells. Mol Cell Biochem 2018; 441: 109-124 DOI: 10.1007/s11010-017-3178-7.
  • 21 Honegger R. Lichen-forming Fungi and their Photobionts. In: Deising HB. ed. Plant Relationships. The Mycota (A comprehensive Treatise on Fungi as experimental Systems for basic and applied Research). Berlin: Springer; 2009: 307-333
  • 22 Brunauer G, Hager A, Grube M, Türk RM, Stocker-Wörgötter E. Alterations in secondary metabolism of aposymbiotically grown mycobionts of Xanthoria elegans and cultured resynthesis stages. Plant Physiol Biochem 2007; 45: 146-151 DOI: 10.1016/j.plaphy.2007.01.004.
  • 23 Elshobary ME, Osman ME, Abo-Shady AM, Komatsu E, Perreault H, Sorensen J, Piercey-Normore MD. Algal carbohydrates affect polyketide synthesis of the lichen-forming fungus Cladonia rangiferina . Mycologia 2016; 108: 646-656 DOI: 10.3852/15-263.
  • 24 Díaz E, Zamora J, Ruibal C, Divakar PK, González-Benítez N, Le Devehat F, Chollet M, Ferron S, Sauvager A, Boustie J, Crespo A, Molina MC. Axenic culture and biosynthesis of secondary compounds in lichen symbiotic fungi, the Parmeliaceae. Symbiosis 2020; 82: 1-15 DOI: 10.1007/s13199-020-00719-3.
  • 25 Gauslaa Y, Bidussi M, Solhaug KA, Asplund J, Larsson P. Seasonal and spatial variation in carbon based secondary compounds in green algal and cyanobacterial members of the epiphytic lichen genus Lobaria. Phytochemistry 2013; 94: 91-98 DOI: 10.1016/j.phytochem.2013.04.003.
  • 26 Nguyen KH, Chollet-Krugler M, Gouault N, Tomasi S. UV-protectant metabolites from lichens and their symbiotic partners. Nat Prod Rep 2013; 30: 1490-1508 DOI: 10.1039/c3np70064j.
  • 27 Stocker-Wörgötter E. Biochemical Diversity and Ecology of Lichen-forming Fungi: Lichen Substances, chemosyndromic Variation and Origin of Polyketide-Type Metabolites (biosynthetic Pathways). In: Upreti DK, Divakar PK, Shukla V, Bajpai R. eds. Recent Advances in Lichenology: Modern Methods and Approaches in Lichen Systematics and Culture Techniques, Volume 2. New Delhi: Springer; 2015: 161-180
  • 28 Parrot D, Legrave N, Delmail D, Grube M, Suzuki M, Tomasi S. Review – Lichen-associated bacteria as a hot spot of chemodiversity: Focus on uncialamycin, a promising compound for future medicinal applications. Planta Med 2016; 82: 1143-1152 DOI: 10.1055/s-0042-105571.
  • 29 Hawksworth D, Grube M. Lichens redefined as complex ecosystems. New Phytol 2020; 227: 1281-1283 DOI: 10.1111/nph.16630.
  • 30 Smith H, Dal Grande F, Muggia L, Keuler R, Divakar PK, Grewe F, Schmitt I, Thorsten Lumbsch H, Leavitt SD. Metagenomic data reveal diverse fungal and algal communities associated with the lichen. Symbiosis 2020; 82: 133-147 DOI: 10.1101/2020.03.04.966853.
  • 31 Mosbach K. Biosynthesis of lichen substances, products of a symbiotic association. Angew Chem 1969; 8: 240-250 DOI: 10.1002/anie.196902401.
  • 32 Elix JA, Stocker-Wörgötter E. Biochemistry and secondary Metabolites. In: Nash III ThomasH. ed. Lichen Biology. 2nd ed.. Cambridge: Cambridge University Press; 2008: 104-133
  • 33 Huneck S, Yoshimura I. Identification of Lichen Substances. Berlin-Heidelberg: Springer; 1996: 493
  • 34 Culberson CF. Joint occurrence of a lichen depsidone and its probable depside precursor. Science 1964; 143: 255-256 DOI: 10.1126/science.143.3603.255.
  • 35 Erdtman HGH. The chemistry of forest, humic acids, lichens, lignans, lignins and conifers. Tappi 1962; 45: 14A 16A, 18A, 20A, 26A, 28A, 30A, 34A, 36A, 38A
  • 36 Culberson WL, Culberson CF. The Lichen Genera Cetrelia and Platismatia (Parmeliaceae). Systematic Plant Studies. Contributions from the United States National Herbarium. Washington, DC: Smithsonian Institution Press; 1968: 449-558
  • 37 Culberson CF. A note on the chemical strains of Pseudevernia furfuracea . Bryologist 1965; 68: 435-439
  • 38 Elix JA, Jenie UA, Parker JL. A novel synthesis of the lichen depsidones divaronic acid and stenosporonic acid, and the biosynthetic implications. Aust J Chem 1987; 40: 1451-1464
  • 39 Stocker-Wörgötter E. Metabolic diversity of lichen-forming ascomycetous fungi: culturing, polyketide and shikimate metabolite production, and PKS genes. Nat Prod Rep 2008; 25: 188-200 DOI: 10.1039/b606983p.
  • 40 Schmitt I, Martín MP, Kautz S, Lumbsch HT. Diversity of non-reducing polyketide synthase genes in the Pertusariales (lichenized Ascomycota): a phylogenetic perspective. Phytochemistry 2005; 66: 1241-1253 DOI: 10.1016/j.phytochem.2005.04.014.
  • 41 Armaleo D, Sun X, Culberson C. Insights from the first putative biosynthetic gene cluster for a lichen depside and depsidone. Mycologia 2011; 103: 741-754 DOI: 10.3852/10-335.
  • 42 Bertrand RL, Abdel-Hameed M, Sorensen JL. Lichen biosynthetic gene clusters. Part I. Genome sequencing reveals a rich biosynthetic potential. J Nat Prod 2018; 81: 723-731 DOI: 10.1021/acs.jnatprod.7b00769.
  • 43 Armaleo D, Müller O, Lutzoni F, Andrésson ÓS, Blanc G, Bode HB, Collart FR, Dal Grande F, Dietrich F, Grigoriev IV, Joneson S, Kuo A, Larsen PE, Logsdon Jr JM, Lopez D, Martin F, May SP, McDonald TR, Merchant SS, Miao V, Morin E, Oono R, Pellegrini M, Rubinstein N, Sanchez-Puerta MV, Savelkoul E, Schmitt I, Slot JC, Soanes D, Szövényi P, Talbot NJ, Veneault-Fourrey C, Xavier BB. The lichen symbiosis re-viewed through the genomes of Cladonia grayi and its algal partner Asterochloris glomerata . BMC Genom 2019; 20: 605 DOI: 10.1186/s12864-019-5629-x.
  • 44 Pizarro D, Divakar PK, Grewe F, Crespo A, Dal Grande F, Lumbsch HT. Genome-wide analysis of biosynthetic gene cluster reveals correlated gene loss with absence of usnic acid in lichen-forming fungi. Genome Biol Evol 2020; 12: 1858-1868 DOI: 10.1093/gbe/evaa189.
  • 45 Hunyadi A. The mechanism(s) of action of antioxidants: From scavenging reactive oxygen/nitrogen species to redox signaling and the generation of bioactive secondary metabolites. Med Res Rev 2019; 39: 2505-2533 DOI: 10.1002/med.21592.
  • 46 Manojlovic NT, Vasiljevic PJ, Maskovic PZ, Juskovic M, Bogdanovic-Dusanovic G. Chemical composition, antioxidant, and antimicrobial activities of lichen Umbilicaria cylindrica (L.) Delise (Umbilicariaceae). Evid Based Complement Alternat Med 2012; 2012: 452431 DOI: 10.1155/2012/452431.
  • 47 Williams D, Loganzo F, Whitney L, Togias J, Harrison R, Singh M, McDonald L, Chelvendran S, Andersen R. Depsides isolated from the Sri Lankan lichen Parmotrema sp. exhibit selective Plk1 inhibitory activity. Pharm Biol 2011; 49: 296-301 DOI: 10.3109/13880209.2010.517540.
  • 48 Hong JM, Suh SS, Kim TK, Kim JE, Han SJ, Youn UJ, Yim JH, Kim IC. Anti-cancer activity of lobaric acid and lobarstin extracted from the antarctic lichen Stereocaulon alpinum . Molecules 2018; 23: 658 DOI: 10.3390/molecules23030658.
  • 49 Huang Z. Bcl-2 family proteins as targets for anticancer drug design. Oncogene 2000; 19: 6627-6631 DOI: 10.1038/sj.onc.1204087.
  • 50 Emsen B, Ozdemir O, Engin T, Togar B, Cavusoglu S, Turkez H. Inhibition of growth of U87MG human glioblastoma cells by Usnea longissima Ach. An Acad Bras Cienc 2019; 91: e20180994 DOI: 10.1590/0001-3765201920180994.
  • 51 Wisastra R, Dekker FJ. Inflammation, cancer and oxidative lipoxygenase activity are intimately linked. Cancers (Basel) 2014; 6: 1500-1521 DOI: 10.3390/cancers6031500.
  • 52 Ebrahim HY, Elsayed HE, Mohyeldin MM, Akl MR, Bhattacharjee J, Egbert S, El Sayed KA. Norstictic acid inhibits breast cancer cell proliferation, migration, invasion, and in vivo invasive growth through targeting c-Met. Phytother Res 2016; 30: 557-566 DOI: 10.1002/ptr.5551.
  • 53 Zhang Y, Xia M, Jin K, Wang S, Wei H, Fan C, Wu Y, Li X, Li X, Li G, Zeng Z, Xiong W. Function of the c-Met receptor tyrosine kinase in carcinogenesis and associated therapeutic opportunities. Mol Cancer 2018; 17: 45 DOI: 10.1186/s12943-018-0796-y.
  • 54 Alam MK, Alhhazmi A, DeCoteau JF, Luo Y, Geyer CR. RecA inhibitors potentiate antibiotic activity and block evolution of antibiotic resistance. Cell Chem Biol 2016; 23: 381-391 DOI: 10.1016/j.chembiol.2016.02.010.
  • 55 McGillick BE, Kumaran D, Vieni C, Swaminathan S. β-Hydroxyacyl-acyl carrier protein dehydratase (FabZ) from Francisella tularensis and Yersinia pestis: structure determination, enzymatic characterization, and cross-inhibition studies. Biochemistry 2016; 55: 1091-1099 DOI: 10.1021/acs.biochem.5b00832.
  • 56 Feibelman KM, Fuller BP, Li L, LaBarbera DV, Geiss BJ. Identification of small molecule inhibitors of the Chikungunya virus nsP1 RNA capping enzyme. Antiviral Res 2018; 154: 124-131 DOI: 10.1016/j.antiviral.2018.03.013.
  • 57 Panzhinskiy E, Ren J, Nair S. Pharmacological inhibition of protein tyrosine phosphatase 1B: a promising strategy for the treatment of obesity and type 2 diabetes mellitus. Curr Med Chem 2013; 20: 2609-2625 DOI: 10.2174/0929867311320210001.
  • 58 Klaman LD, Boss O, Peroni OD, Kim JK, Martino JL, Zabolotny JM, Moghal N, Lubkin M, Kim YB, Sharpe AH, Stricker-Krongrad A, Shulman GI, Neel BG, Kahn BB. Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice. Mol Cell Biol 2000; 20: 5479-5489 DOI: 10.1128/mcb.20.15.5479-5489.2000.
  • 59 Carpentier C, Barbeau X, Azelmat J, Vaillancourt K, Grenier D, Lagüe P, Voyer N. Lobaric acid and pseudodepsidones inhibit NF-κB signaling pathway by activation of PPAR-γ. Bioorg Med Chem 2018; 26: 5845-5851 DOI: 10.1016/j.bmc.2018.10.035.
  • 60 Lee HW, Kim J, Yim JH, Lee HK, Pyo S. Anti-inflammatory activity of lobaric acid via suppressing NF-κB/MAPK pathways or NLRP3 inflammasome activation. Planta Med 2019; 85: 302-311 DOI: 10.1055/a-0777-2420.
  • 61 Millot M, Tomasi S, Articus K, Rouaud I, Bernard A, Boustie J. Metabolites from the lichen Ochrolechia parella growing under two different heliotropic conditions. J Nat Prod 2007; 70: 316-318 DOI: 10.1021/np060561p.
  • 62 Bellio P, Segatore B, Mancini A, Di Pietro L, Bottoni C, Sabatini A, Brisdelli F, Piovano M, Nicoletti M, Amicosante G, Perilli M, Celenza G. Interaction between lichen secondary metabolites and antibiotics against clinical isolates methicillin-resistant Staphylococcus aureus strains. Phytomedicine 2015; 22: 223-230 DOI: 10.1016/j.phymed.2014.12.005.
  • 63 Bellio P, Di Pietro L, Mancini A, Piovano M, Nicoletti M, Brisdelli F, Tondi D, Cendron L, Franceschini N, Amicosante G, Perilli M, Celenza G. SOS response in bacteria: Inhibitory activity of lichen secondary metabolites against Escherichia coli RecA protein. Phytomedicine 2017; 29: 11-18 DOI: 10.1016/j.phymed.2017.04.001.
  • 64 Yilmaz M, Türk AO, Tay T, Kivanç M. The antimicrobial activity of extracts of the lichen Cladonia foliacea and its (−)-usnic acid, atranorin, and fumarprotocetraric acid constituents. Z Naturforsch C J Biosci 2004; 59: 249-254 DOI: 10.1515/znc-2004-3-423.
  • 65 Ranković B, Misić M, Sukdolak S. Antimicrobial activity of extracts of the lichens Cladonia furcata, Parmelia caperata, Parmelia pertusa, Hypogymnia physodes and Umbilicaria polyphylla . Br J Biomed Sci 2007; 64: 143-148 DOI: 10.1080/09674845.2007.11732776.
  • 66 Pompilio A, Pomponio S, Di Vincenzo V, Crocetta V, Nicoletti M, Piovano M, Garbarino JA, Di Bonaventura G. Antimicrobial and antibiofilm activity of secondary metabolites of lichens against methicillin-resistant Staphylococcus aureus strains from cystic fibrosis patients. Future Microbiol 2013; 8: 281-292 DOI: 10.2217/fmb.12.142.
  • 67 Igoli JO, Gray AI, Clements CJ, Kantheti P, Singla RH. Antitrypanosomal activity & docking studies of isolated constituents from the lichen Cetraria islandica: possibly multifunctional scaffolds. Curr Top Med Chem 2014; 14: 1014-1021 DOI: 10.2174/1568026614666140324122323.
  • 68 Fernández-Moriano C, Divakar PK, Crespo A, Gómez-Serranillos MP. In vitro neuroprotective potential of lichen metabolite fumarprotocetraric acid via intracellular redox modulation. Toxicol Appl Pharmacol 2017; 316: 83-94 DOI: 10.1016/j.taap.2016.12.020.
  • 69 de Barros Alves GM, de Sousa Maia MB, de Souza Franco E, Galvão AM, da Silva TG, Gomes RM, Martins MB, da Silva Falcão EP, de Castro CM, da Silva NH. Expectorant and antioxidant activities of purified fumarprotocetraric acid from Cladonia verticillaris lichen in mice. Pulm Pharmacol Ther 2014; 27: 139-143 DOI: 10.1016/j.pupt.2013.07.002.
  • 70 Lohézic-Le Dévéhat F, Legouin B, Couteau C, Boustie J, Coiffard L. Lichenic extracts and metabolites as UV filters. J Photochem Photobiol B 2013; 120: 17-28 DOI: 10.1016/j.jphotobiol.2013.01.009.
  • 71 Pavlovic V, Stojanovic I, Jadranin M, Vajs V, Djordjević I, Smelcerovic A, Stojanovic G. Effect of four lichen acids isolated from Hypogymnia physodes on viability of rat thymocytes. Food Chem Toxicol 2013; 51: 160-164 DOI: 10.1016/j.fct.2012.04.043.
  • 72 Cetin H, Tufan-Cetin O, Turk AO, Tay T, Candan M, Yanikoglu A, Sumbul H. Larvicidal activity of some secondary lichen metabolites against the mosquito Culiseta longiareolata Macquart (Diptera: Culicidae). Nat Prod Res 2012; 26: 350-355 DOI: 10.1080/14786411003774296.
  • 73 Yilmaz M, Tay T, Kivanç M, Türk H, Türk AO. The antimicrobial activity of extracts of the lichen Hypogymnia tubulosa and its 3-hydroxyphysodic acid constituent. Z Naturforsch C J Biosci 2005; 60: 35-38 DOI: 10.1515/znc-2005-1-207.
  • 74 Ogmundsdóttir HM, Zoëga GM, Gissurarson SR, Ingólfsdóttir K. Anti-proliferative effects of lichen-derived inhibitors of 5-lipoxygenase on malignant cell-lines and mitogen-stimulated lymphocytes. J Pharm Pharmacol 1998; 50: 107-115 DOI: 10.1111/j.2042-7158.1998.tb03312.x.
  • 75 Bucar F, Schneider I, Ogmundsdóttir H, Ingólfsdóttir K. Anti-proliferative lichen compounds with inhibitory activity on 12(S)-HETE production in human platelets. Phytomedicine 2004; 11: 602-606 DOI: 10.1016/j.phymed.2004.03.004.
  • 76 Brisdelli F, Perilli M, Sellitri D, Piovano M, Garbarino JA, Nicoletti M, Bozzi A, Amicosante G, Celenza G. Cytotoxic activity and antioxidant capacity of purified lichen metabolites: an in vitro study. Phytother Res 2013; 27: 431-437 DOI: 10.1002/ptr.4739.
  • 77 Haraldsdóttir S, Guolaugsdóttir E, Ingólfsdóttir K, Ogmundsdóttir HM. Anti-proliferative effects of lichen-derived lipoxygenase inhibitors on twelve human cancer cell lines of different tissue origin in vitro . Planta Med 2004; 70: 1098-1100 DOI: 10.1055/s-2004-832657.
  • 78 Morita H, Tsuchiya T, Kishibe K, Noya S, Shiro M, Hirasawaa Y. Antimitotic activity of lobaric acid and a new benzofuran, sakisacaulon A from Stereocaulon sasakii . Bioorg Med Chem Lett 2009; 19: 3679-3681 DOI: 10.1016/j.bmcl.2009.03.170.
  • 79 Ozgencli I, Budak H, Ciftci M, Anar M. Lichen acids may be used as a potential drug for cancer therapy; by inhibiting mitochondrial thioredoxin reductase purified from rat lung. Anticancer Agents Med Chem 2018; 18: 1599-1605 DOI: 10.2174/1871520618666180525095520.
  • 80 Seo C, Sohn JH, Ahn JS, Yim JH, Lee HK, Oh H. Protein tyrosine phosphatase 1B inhibitory effects of depsidone and pseudodepsidone metabolites from the antarctic lichen Stereocaulon alpinum . Bioorg Med Chem Lett 2009; 19: 2801-2803 DOI: 10.1016/j.bmcl.2009.03.108.
  • 81 Kim TK, Kim JE, Youn UJ, Han SJ, Kim IC, Cho CG, Yim JH. Total syntheses of lobaric acid and its derivatives from the antarctic lichen Stereocaulon alpinum . J Nat Prod 2018; 81: 1460-1467 DOI: 10.1021/acs.jnatprod.8b00227.
  • 82 Joo YA, Chung H, Yoon S, Park JI, Lee JE, Myung CH, Hwang JS. Skin barrier recovery by Protease-Activated Receptor-2 antagonist lobaric acid. Biomol Ther (Seoul) 2016; 24: 529-535 DOI: 10.4062/biomolther.2016.011.
  • 83 Kwon IS, Yim JH, Lee HK, Pyo S. Lobaric acid inhibits VCAM-1 expression in TNF-α-stimulated vascular smooth muscle cells via modulation of NF-κB and MAPK signaling pathways. Biomol Ther (Seoul) 2016; 24: 25-32 DOI: 10.4062/biomolther.2015.084.
  • 84 Ingolfsdottir K, Gissurarson SR, Müller-Jakic B, Breu W, Wagner H. Inhibitory effects of the lichen metabolite lobaric acid on arachidonate metabolism in vitro . Phytomedicine 1996; 2: 243-246 DOI: 10.1016/S0944-7113(96)80049-3.
  • 85 Ingólfsdóttir K, Chung GA, Skúlason VG, Gissurarson SR, Vilhelmsdóttir M. Antimycobacterial activity of lichen metabolites in vitro . Eur J Pharm Sci 1998; 6: 141-144 DOI: 10.1016/s0928-0987(97)00078-x.
  • 86 Vankadari N, Jeyasankar NN, Lopes WJ. Structure of the SARS-CoV-2 Nsp1/5′-untranslated region complex and implications for potential therapeutic targets, a vaccine, and virulence. J Phys Chem Lett 2020; 11: 9659-9668 DOI: 10.1021/acs.jpclett.0c02818.
  • 87 Thadhani VM, Choudhary MI, Ali S, Omar I, Siddique H, Karunaratne V. Antioxidant activity of some lichen metabolites. Nat Prod Res 2011; 25: 1827-1837 DOI: 10.1080/14786419.2010.529546.
  • 88 Gissurarson SR, Sigurdsson SB, Wagner H, Ingolfsdottir K. Effect of lobaric acid on cysteinyl-leukotriene formation and contractile activity of guinea pig taenia coli . J Pharmacol Exp Ther 1997; 280: 770-773
  • 89 Brandão LF, Alcantara GB, Matos Mde F, Bogo D, Freitas Ddos S, Oyama NM, Honda NK. Cytotoxic evaluation of phenolic compounds from lichens against melanoma cells. Chem Pharm Bull (Tokyo) 2013; 61: 176-183 DOI: 10.1248/cpb.c12-00739.
  • 90 Ranković B, Kosanić M, Stanojković T, Vasiljević P, Manojlović N. Biological activities of Toninia candida and Usnea barbata together with their norstictic acid and usnic acid constituents. Int J Mol Sci 2012; 13: 14707-14722 DOI: 10.3390/ijms131114707.
  • 91 Ismed F, Dévéhat FL, Rouaud I, Ferron S, Bakhtiar A, Boustie J. NMR reassignment of stictic acid isolated from a Sumatran lichen Stereocaulon montagneanum (Stereocaulaceae) with superoxide anion scavenging activities. Z Naturforsch C J Biosci 2017; 72: 55-62 DOI: 10.1515/znc-2016-0148.
  • 92 Tay T, Türk AO, Yilmaz M, Türk H, Kivanç M. Evaluation of the antimicrobial activity of the acetone extract of the lichen Ramalina farinacea and its (+)-usnic acid, norstictic acid, and protocetraric acid constituents. Z Naturforsch C J Biosci 2004; 59: 384-388 DOI: 10.1515/znc-2004-5-617.
  • 93 Honda NK, Pavan FR, Coelho RG, de Andrade Leite SR, Micheletti AC, Lopes TI, Misutsu MY, Beatriz A, Brum RL, Leite CQ. Antimycobacterial activity of lichen substances. Phytomedicine 2010; 17: 328-332 DOI: 10.1016/j.phymed.2009.07.018.
  • 94 Russo A, Piovano M, Lombardo L, Vanella L, Cardile V, Garbarino J. Pannarin inhibits cell growth and induces cell death in human prostate carcinoma DU-145 cells. Anticancer Drugs 2006; 17: 1163-1169 DOI: 10.1097/01.cad.0000236310.66080.ed.
  • 95 Russo A, Piovano M, Lombardo L, Garbarino J, Cardile V. Lichen metabolites prevent UV light and nitric oxide-mediated plasmid DNA damage and induce apoptosis in human melanoma cells. Life Sci 2008; 83: 468-474 DOI: 10.1016/j.lfs.2008.07.012.
  • 96 Hidalgo ME, Fernández E, Quilhot W, Lissi EA. Photohemolytic activity of lichen metabolites. J Photochem Photobiol B 1993; 21: 37-40 DOI: 10.1016/1011-1344(93)80161-2.
  • 97 Celenza G, Segatore B, Setacci D, Bellio P, Brisdelli F, Piovano M, Garbarino JA, Nicoletti M, Perilli M, Amicosante G. In vitro antimicrobial activity of pannarin alone and in combination with antibiotics against methicillin-resistant Staphylococcus aureus clinical isolates. Phytomedicine 2012; 19: 596-602 DOI: 10.1016/j.phymed.2012.02.010.
  • 98 Fournet A, Ferreira ME, Rojas de Arias A, Torres de Ortiz S, Inchausti A, Yaluff G, Quilhot W, Fernandez E, Hidalgo ME. Activity of compounds isolated from Chilean lichens against experimental cutaneous leishmaniasis. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 1997; 116: 51-54 DOI: 10.1016/s0742-8413(96)00127-2.
  • 99 Fernández E, Reyes A, Hidalgo ME, Quilhot W. Photoprotector capacity of lichen metabolites assessed through the inhibition of the 8-methoxypsoralen photobinding to protein. J Photochem Photobiol B 1998; 42: 195-201 DOI: 10.1016/s1011-1344(98)00070-0.
  • 100 Cardile V, Graziano ACE, Avola R, Piovano M, Russo A. Potential anticancer activity of lichen secondary metabolite physodic acid. Chem Biol Interact 2017; 263: 36-45 DOI: 10.1016/j.cbi.2016.12.007.
  • 101 Kosanić M, Manojlović N, Janković S, Stanojković T, Ranković B. Evernia prunastri and Pseudoevernia furfuraceae lichens and their major metabolites as antioxidant, antimicrobial and anticancer agents. Food Chem Toxicol 2013; 53: 112-118 DOI: 10.1016/j.fct.2012.11.034.
  • 102 Studzińska-Sroka E, Piotrowska H, Kucińska M, Murias M, Bylka W. Cytotoxic activity of physodic acid and acetone extract from Hypogymnia physodes against breast cancer cell lines. Pharm Biol 2016; 54: 2480-2485 DOI: 10.3109/13880209.2016.1160936.
  • 103 Emsen B, Aslan A, Togar B, Turkez H. In vitro antitumor activities of the lichen compounds olivetoric, physodic and psoromic acid in rat neuron and glioblastoma cells. Pharm Biol 2016; 54: 1748-1762 DOI: 10.3109/13880209.2015.1126620.
  • 104 Stojanović IZ, Stanković M, Jovanović O, Petrović G, Smelcerović A, Stojanović GS. Effect of Hypogymnia physodes extracts and their depsidones on micronucleus distribution in human lymphocytes. Nat Prod Commun 2013; 8: 109-112
  • 105 Stojanović IZ, Najman S, Jovanović O, Petrović G, Najdanović J, Vasiljević P, Smelcerović A. Effects of depsidones from Hypogymnia physodes on HeLa cell viability and growth. Folia Biol (Praha) 2014; 60: 89-94
  • 106 Talapatra SK, Rath O, Clayton E, Tomasi S, Kozielski F. Depsidones from lichens as natural product inhibitors of M-Phase Phosphoprotein 1, a human kinesin required for cytokinesis. J Nat Prod 2016; 79: 1576-1585 DOI: 10.1021/acs.jnatprod.5b00962.
  • 107 Bauer J, Waltenberger B, Noha SM, Schuster D, Rollinger JM, Boustie J, Chollet M, Stuppner H, Werz O. Discovery of depsides and depsidones from lichen as potent inhibitors of microsomal prostaglandin E2 synthase-1 using pharmacophore models. ChemMedChem 2012; 7: 2077-2081 DOI: 10.1002/cmdc.201200345.
  • 108 Emsen B, Turkez H, Togar B, Aslan A. Evaluation of antioxidant and cytotoxic effects of olivetoric and physodic acid in cultured human amnion fibroblasts. Hum Exp Toxicol 2017; 36: 376-385 DOI: 10.1177/0960327116650012.
  • 109 Emsen B, Togar B, Turkez H, Aslan A. Effects of two lichen acids isolated from Pseudevernia furfuracea (L.) Zopf in cultured human lymphocytes. Z Naturforsch C J Biosci 2018; 73: 303-312 DOI: 10.1515/znc-2017-0209.
  • 110 Reddy RG, Veeraval L, Maitra S, Chollet-Krugler M, Tomasi S, Dévéhat FL, Boustie J, Chakravarty S. Lichen-derived compounds show potential for central nervous system therapeutics. Phytomedicine 2016; 23: 1527-1534 DOI: 10.1016/j.phymed.2016.08.010.
  • 111 Osawa T, Kumon H, Reece CA, Shibamoto T. Inhibitory effect of lichen constituents on mutagenicity induced by heterocyclic amines. Environ Mol Mutagen 1991; 18: 35-40 DOI: 10.1002/em.2850180107.
  • 112 Nishanth KS, Sreerag RS, Deepa I, Mohandas C, Nambisan B. Protocetraric acid: an excellent broad spectrum compound from the lichen Usnea albopunctata against medically important microbes. Nat Prod Res 2015; 29: 574-577 DOI: 10.1080/14786419.2014.953500.
  • 113 Dieu A, Mambu L, Champavier Y, Chaleix V, Sol V, Gloaguen V, Millot M. Antibacterial activity of the lichens Usnea Florida and Flavoparmelia caperata (Parmeliaceae). Nat Prod Res 2020; 34: 3358-3362 DOI: 10.1080/14786419.2018.1561678.
  • 114 Deraeve C, Guo Z, Bon RS, Blankenfeldt W, DiLucrezia R, Wolf A, Menninger S, Stigter EA, Wetzel S, Choidas A, Alexandrov K, Waldmann H, Goody RS, Wu YW. Psoromic acid is a selective and covalent Rab-prenylation inhibitor targeting autoinhibited RabGGTase. J Am Chem Soc 2012; 134: 7384-7391 DOI: 10.1021/ja211305j.
  • 115 Samatov TR, Wolf A, Odenwälder P, Bessonov S, Deraeve C, Bon RS, Waldmann H, Lührmann R. Psoromic acid derivatives: a new family of small-molecule pre-mRNA splicing inhibitors discovered by a stage-specific high-throughput in vitro splicing assay. Chembiochem 2012; 13: 640-644 DOI: 10.1002/cbic.201100790.
  • 116 Hassan STS, Šudomová M, Berchová-Bímová K, Šmejkal K, Echeverría J. Psoromic acid, a lichen-derived molecule, inhibits the replication of HSV-1 and HSV-2, and inactivates HSV-1 DNA polymerase: shedding light on antiherpetic properties. Molecules 2019; 24: 2912 DOI: 10.3390/molecules24162912.
  • 117 Sweidan A, Chollet-Krugler M, Sauvager A, van de Weghe P, Chokr A, Bonnaure-Mallet M, Tomasi S, Bousarghin L. Antibacterial activities of natural lichen compounds against Streptococcus gordonii and Porphyromonas gingivalis . Fitoterapia 2017; 121: 164-169 DOI: 10.1016/j.fitote.2017.07.011.
  • 118 Hassan STS, Šudomová M, Berchová-Bímová K, Gowrishankar S, Rengasamy KRR. Antimycobacterial, enzyme inhibition, and molecular interaction studies of psoromic acid in Mycobacterium tuberculosis: efficacy and safety investigations. J Clin Med 2018; 7: 226 DOI: 10.3390/jcm7080226.
  • 119 Lauinger IL, Vivas L, Perozzo R, Stairiker C, Tarun A, Zloh M, Zhang X, Xu H, Tonge PJ, Franzblau SG, Pham DH, Esguerra CV, Crawford AD, Maes L, Tasdemir D. Potential of lichen secondary metabolites against Plasmodium liver stage parasites with FAS-II as the potential target. J Nat Prod 2013; 76: 1064-1070 DOI: 10.1021/np400083k.
  • 120 Behera BC, Mahadik N, Morey M. Antioxidative and cardiovascular-protective activities of metabolite usnic acid and psoromic acid produced by lichen species Usnea complanata under submerged fermentation. Pharm Biol 2012; 50: 968-979 DOI: 10.3109/13880209.2012.654396.
  • 121 Candan M, Yilmaz M, Tay T, Erdem M, Türk AO. Antimicrobial activity of extracts of the lichen Parmelia sulcata and its salazinic acid constituent. Z Naturforsch C J Biosci 2007; 62: 619-621 DOI: 10.1515/znc-2007-7-827.
  • 122 Goel M, Dureja P, Rani A, Uniyal PL, Laatsch H. Isolation, characterization and antifungal activity of major constituents of the Himalayan lichen Parmelia reticulata Tayl. J Agric Food Chem 2011; 59: 2299-2307 DOI: 10.1021/jf1049613.
  • 123 Gaikwad S, Verma N, Sharma BO, Behera BC. Growth promoting effects of some lichen metabolites on probiotic bacteria. J Food Sci Technol 2014; 51: 2624-2631 DOI: 10.1007/s13197-012-0785-x.
  • 124 de Paz GA, Raggio J, Gómez-Serranillos MP, Palomino OM, González-Burgos E, Carretero ME, Crespo A. HPLC isolation of antioxidant constituents from Xanthoparmelia spp. J Pharm Biomed Anal 2010; 53: 165-171 DOI: 10.1016/j.jpba.2010.04.013.
  • 125 Burlando B, Ranzato E, Volante A, Appendino G, Pollastro F, Verotta L. Antiproliferative effects on tumor cells and promotion of keratinocyte wound healing by different lichen compounds. Planta Med 2009; 75: 607-613 DOI: 10.1055/s-0029-1185329.
  • 126 Papadopoulou P, Tzakou O, Vagias C, Kefalas P, Roussis V. Beta-orcinol metabolites from the lichen Hypotrachyna revoluta . Molecules 2007; 12: 997-1005 DOI: 10.3390/12050997.
  • 127 Wassman CD, Baronio R, Demir Ö, Wallentine BD, Chen CK, Hall LV, Salehi F, Lin DW, Chung BP, Hatfield GW, Richard Chamberlin A, Luecke H, Lathrop RH, Kaiser P, Amaro RE. Computational identification of a transiently open L1/S3 pocket for reactivation of mutant p53. Nat Commun 2013; 4: 1407 DOI: 10.1038/ncomms2361.
  • 128 Omar SI, Tuszynski J. Ranking the binding energies of p53 mutant activators and their ADMET properties. Chem Biol Drug Des 2015; 86: 163-172 DOI: 10.1111/cbdd.12480.
  • 129 Russo A, Caggia S, Piovano M, Garbarino J, Cardile V. Effect of vicanicin and protolichesterinic acid on human prostate cancer cells: role of Hsp70 protein. Chem Biol Interact 2012; 195: 1-10 DOI: 10.1016/j.cbi.2011.10.005.
  • 130 Sanjaya A, Avidlyandi A, Adfa M, Ninomiya M, Koketsu M. A new depsidone from Teloschistes flavicans and the antileukemic activity. J Oleo Sci 2020; 69: 1591-1595 DOI: 10.5650/jos.ess20209.
  • 131 Bay MV, Nam PC, Quang DT, Mechler A, Hien NK, Hoa NT, Vo QV. Theoretical study on the antioxidant activity of natural depsidones. ACS Omega 2020; 5: 7895-7902 DOI: 10.1021/acsomega.9b04179.
  • 132 Leal A, Rojas JL, Valencia-Islas NA, Castellanos L. New β-orcinol depsides from Hypotrachyna caraccensis, a lichen from the páramo ecosystem and their free radical scavenging activity. Nat Prod Res 2018; 32: 1375-1382 DOI: 10.1080/14786419.2017.1346639.
  • 133 Bui VM, Duong TH, Chavasiri W, Nguyen KP, Huynh BL. A new depsidone from the lichen Usnea ceratina . Nat Prod Res 2020; DOI: 10.1080/14786419.2020.1828405.