Lichen Depsidones with Biological Interest

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.

Key words

secondary metabolites - natural products - pharmacology - antioxidants - antimicrobial - cytotoxic

Abbreviations

8-OH-dG: 8-Oxo-2′-deoxyguanosine

Axin2: axis inhibition protein 2

Bax: Bcl-2 associated X-protein

Bcl-2: B-cell lymphoma 2

BDNF: brain-derived neurotrophic factor

COX: cyclooxygenase

DPPH: 2,2-diphenyl-1-picrilhidrazil

FabZ: 3-hydroxyacyl-[acyl-carrier-protein] dehydratase

FAS: fatty acid biosynthesis

GSH: reduced glutathione

HGF: hepatocyte growth factor

Hsp70: 70 kD heat shock proteins

HSV: herpes simplex virus

IL-1: interleukin-1

JAK/STAT: janus kinase/signal transducers and activators of transcription

LPS: lipopolysaccharide

MAPK: mitogen-activated protein kinases

MIC: minimum inhibitory concentration

MMP7: matrix metalloproteinase-7

MPP1: M-Phase Phosphoprotein 1

MRSA: methicillin-resistant Staphylococcus aureus

NF-κβ : nuclear Factor kappa-light-chain-enhancer of activated B cells

NGF: nerve growth factor

NLRP3: NOD-, LRR- and pyrin domain-containing protein 3

NOS: nitric oxide synthase

Nrf2: nuclear factor E2-related factor 2

nsP1: nonstructural protein 1

ORAC: oxygen radical absorbance capacity

PAR2: proteinase-activated receptor-2

PARP: poly (ADP-ribose) polymerase

PF-UVA: protection Factor-ultraviolet A

PI3K: phosphatidylinositol 3-kinase

PKS: polyketide synthase

Plk1: polo-like kinase-1

PTP1B: protein tyrosine phosphatase 1B

RNS: reactive nitrogen species

ROS: reactive oxygen species

SLIGKV-NH₂ : Ser-Leu-Ile-Gly-Lys-Val-amide

SOR: scavenging superoxide radicals

TNF-α : tumor necrosis factor- α

TRAIL: TNF-related apoptosis-inducing ligand

Trp-P-2: tryptophan pyrolysis product-2
 

Introduction

Lichens are a unique symbiosis between a fungus belonging to Ascomycota and Basidiomycota phylum (mycobiont) and a chlorophyll-containing partner (photobiont), which is an alga or a cyanobacterium. Moreover, recent studies have identified specific bacterial microbiomes as the third component of lichen [1], [2]. Lichens have been traditionally used for their medicinal value as healing (i.e., Heterodermia diademata [Taylor] D. D. Awasthi) and cold (i.e., Everniastrum cirrhatum [Fr.] Hale ex Sipman.), for their culinary value for preparing tea, curry, soup, pickle, and sausages (i.e., Everniastrum nepalense [Taylor] Hale ex Sipman; Cladonia rangiferina [L.] Weber ex F. H. Wigg.), and for their ritual, spiritual, and aesthetic values (i.e., Thamnolia vermicularis [Sw.] Ach. ex Schaer.) [3], [4], [5].

Lichens produce unique and diverse secondary metabolites. So far, over 1000 compounds have been identified, including depsidones, depsides, dibenzofurans, and xanthones, which are synthesized via the acetate-malonate pathway, pulvinic acid derivatives formed in the shikimic acid pathway, and terpenes and steroids via the mevalonic acid pathway. The amount of these secondary metabolites may vary from 0.1% to 30% of the dry weight of the thallus, and they are deposited in both the cortex and the medullary layers. Hence, depsides and dibenzofurans, such as usnic acid (major) and atranorin (trace) in Flavoparmelia caperata L. (Hale) and atranorin and chloroatranorin in Hypogymnia physodes (L.) Nyl., are found in the cortex, whereas depsidones, such as physodic acid, 3-hydroxyphysodic acid, and physodalic acid as major compounds in H. physodes (L.) Nyl., norstictic acid in Parmotrema perforatum (Jacq.) A. Massal., and salazinic acid (major) and consalazinic acids (minor) in Parmelia saxatilis (L.) Ach., are found in the medullary layer [6], [7], [8], [9]. These secondary metabolites play a key role in chemotaxonomy and systematics [6]. Moreover, they exert diverse biological functions including protection against pathogens, herbivores, and UV irradiation [7]. Furthermore, these secondary metabolites of lichens arouse great pharmacological interest due to their activities, mainly as antioxidants, antimicrobials, and cytotoxic agents [10], [11], [12].

Some of the most abundant groups of secondary metabolites in lichens are depsidones (around 100) [13]. Structurally, depsidones consist of a polycyclic system linked through an ether group and an ester group, giving the rigid 11H-dibenzo[b,e][1, 4]dioxepin-11-one ring ([Fig. 1]) [14], [15], [16]. The biosynthesis of depsidones occurs via the acetate-malonate pathway, with acetyl-Coenzyme A as the precursor and PKS as the responsible enzyme ([Fig. 2]) [17]. Several bioactive depsidones such as stictic acid, salazinic acid, and psomoric acid have been identified [18], [19], [20]. The chemical structures of different depsidones of lichens are depicted in [Fig. 3].

Fig. 1 General structure of depsidones.

Fig. 2 Biosynthesis of depsidones.

Fig. 3 Chemical structure of different depsidones of lichens.

Fig. 3 Chemical structure of different depsidones of lichens.continued

Fig. 3 Chemical structure of different depsidones of lichens.continued

This paper aims to provide up-to-date knowledge and an overview of the biological interest of lichen depsidones. This review includes pharmacological information for those depsidones that have been investigated with potential bioactivity. Original papers published in English in PubMed/Medline and Scholar Google without date restriction were included. Those articles with lichen extracts rich in depsidones were excluded from this review. It is important to emphasize that more depsidones have been identified, such as notatic acid, nortotatic acid, and diploicin, but their pharmacological activities have not been investigated yet.

Chemistry and Biochemical Origin

The depsidones and the majority of other secondary metabolites in lichens are produced by lichen-forming fungi and are deposited on the outer surface of the hyphal cell walls in the medullary layer of the lichen thallus ([Fig. 4]) [21]. The interactions between the mycobiont and photobiont affect the production of secondary metabolites in lichens. For example, several studies have shown that mycobionts within the lichen thallus produce a variety of secondary metabolites in contrast with axenic mycobiont cultures [22], [23], [24]. The production of secondary metabolites in the lichen thallus has also been found to be affected by environmental factors (i.e., UV-radiation, climatic conditions, habitats, and presence of non-photosynthetic bacteria and other fungi in lichen thallus) [25], [26], [27], [28], [29], [30].

Fig. 4 Cross-section of lichen thallus showing cortical and medullary hyphae.

Depsidones consist of 2 or rarely 3 aromatic rings joined by ester linkages and an ether linkage between the rings. The rings are based on the structure of orsellinic acid. Depsidones are grouped in an orcinol or B-orcinol series, depending on the presence of a CH₃ on the C3 carbon of their rings ([Fig. 1]) [31], [32], [33].

Acetate and malonate units are condensed to form orsellinic acid or B-orsellinic acid that is a precursor for the biosynthesis of several secondary metabolites in lichens and fungi in general ([Fig. 2]). Depsides are produced by the condensation of 2 or more hydroxybenzoic acids through which the carboxyl group of 1 molecule is esterified with a phenolic hydroxyl group of a second molecule. Depsides are precursors for the biosynthesis of depsidones [34]. It is widely accepted that the depsidones are formed from depsides by a loss of hydrogen in an oxidative cyclization process ([Fig. 2]) [35], [36]. Several depside-depsidone pairs are found in lichens, for example, Pseudevernia furfuracea contains the depside-depsidone pair (i.e., olivetoric acid and physodic acid) [37]. O-methylation (methylation of oxygen) is a common process and the cause of chemical variation in depsidones in lichens [36]. However, from chemical synthesis producing high yields of several depsidones, it is proposed that depsidones are biosynthesized in 4 steps: by hydroxylation, acyl group migration, Smiles rearrangement, and esterification [38].

Both the depside and depsidones are products of a nonreducing PKS encoded in the genome of the mycobiont [26], [39]. Therefore, the phylogenetic studies of PKS domains, sequencing of complete PKS gene clusters, and the availability of whole-genome sequence data have enabled a more detailed study of the biosynthetic origin of the nonreducing polyketides in lichens [40], [41], [42], [43], [44].

Molecular Mechanism of Action of Lichen Depsidones

Little is known about the molecular mechanisms through which depsidones exhibit their activities. This review presents some examples; however, further studies are needed to elucidate the diverse properties of this group of secondary metabolites in lichens.

One of the most investigated activities in lichens is their antioxidant activity. Depsidones have been demonstrated to act as antioxidants by directly scavenging ROS and RNS and by modulating redox enzyme activity and expression (i.e., superoxide dismutase and catalase) and transcription factors expression (i.e., Nrf2) [45]. Depsidones can incorporate into cellular lipid microdomains that make them more efficient as antioxidants than other lichen secondary metabolites [46].

Depsidones have also shown cytotoxic activity against diverse cancer cell lines (i.e., melanoma, breast, and colon). These bioactive compounds exert cytotoxic effects through diverse signaling pathways. Hence, depsidones can attenuate cell tumor growth by acting as selective inhibitors of Plk1 activity. Plk1 is a serine/threonine kinase that is overexpressed in human tumors, and it is related to invasive potential and lower cancer-related survival [47]. In addition, depsidones also directly target antiapoptotic Bcl-2 family proteins [48]. High expression of antiapoptotic Bcl-2 family proteins (i.e., Bcl-2) contributes to the expansion of malignant cells and reduces the therapeutic efficacy of cytotoxic drugs [49]. Moreover, these secondary metabolites are promising cytotoxic agents via oxidative stress induction; the overproduction of ROS disrupts redox homeostasis and leads to severe structural and functional injury in cancer cells [50]. Furthermore, depsidones inhibit lipoxygenases, which are involved in cell viability and proliferation, and migration, invasion, and metastasis of cancer cells [51]. Besides, depsidones can suppress carcinomas by targeting the HGF-c-Met signaling pathway [52]. c-Met is a receptor tyrosine kinase, and HGF is the ligand for this receptor. Dysregulation of the HGF-c-Met signaling pathway promotes tumor progression and metastasis by stimulating different signaling pathways as JAK/STAT and PI3K/AKT [53]. Finally, other depsidones act as cytotoxic agents by targeting the aberrant Wnt/β-catenin signaling [20].

Depsidones have also antimicrobial properties against Gram-positive bacteria, Gram-negative bacteria, and fungi. Particularly, some depsidones are RecA inhibitors, which potentiate bactericidal activity and reduce antibiotic resistance [54]. Moreover, depsidones have also targeted the β-hydroxyacyl-acyl carrier protein FabZ of the bacterial system for FAS [55]. Furthermore, depsidones have proven to be promising antiviral agents against alphaviruses via nsP1 GTP binding and guanylation inhibition. These RNA viruses need a 5′cap structure in whose formation viral protein nsP1 participates and which is necessary to avoid viral RNA degradation [56].

Other depsidones are reported for pharmacological inhibition of protein tyrosine phosphatase 1B (involved in insulin resistance) [57]. Moreover, these compounds act in other signal transduction pathways such as epidermal growth factor receptor, integrin signaling pathways, and cell cycle regulation [58]. Furthermore, they have anti-inflammatory properties by inhibiting cytokine expression and NO production through NF-κB/MAPK and inflammasome NLRP3 pathways [59], [60].

Pharmacological Activity of Lichen Depsidones

Pharmacological activities of lichen depsidones are summarized in [Table 1].

Table 1 Pharmacological activity of lichen depsidones.

Depsidone	Botanical origin	Type of study	Experimental model	Activities	Results	References
α-Alectoronic acid	Ochrolechia parella (L.) Massal	In vitro	Mouse melanoma B16 cell line	Cytotoxic	Cytotoxic activity (IC50 = 10.3 µM)	[61]
Ceratinalone	Usnea ceratina Ach.	In vitro	Human epithelial carcinoma HeLa, Human lung cancer NCI-H46, Liver hepatocellular carcinoma HepG2, Human breast cancer MCF-7 cell lines	Cytotoxic	Moderate activity	[133]
α-Collatolic acid	Lecanora atra (Huds.) Ach.	In vitro	Escherichia coli RecA protein	Antimicrobial	High RecA inhibition (103.4%) Uncompetitive inhibitors for ATP binding	[63]
	Lecanora atra (Huds.) Ach.	In vitro	Methicillin-resistant S. aureus strains	Antimicrobial	Antimicrobial activity (MIC90 = 128 µg/mL) Synergism with gentamicin	[62]
Conhypoprotocetraric acid	Ramalina genus	In silico	Computational studies	Antioxidant	Hydroxyl and superoxide anion radical scavengers in polar environments	[131]
Connorstitic acid	Ramalina genus	In silico	Computational studies	Antioxidant	Hydroxyl and superoxide anion radical scavengers in polar environments	[131]
Cryptostictic acid	Ramalina genus	In silico	Computational studies	Antioxidant	Hydroxyl and superoxide anion radical scavengers in polar environments	[131]
Deoxystictic acid	Hypotrachyna revoluta (Flörke) Hale.	In vitro	Radical scavenging activity	Antioxidant	↑ scavenger (13.176 Trolox equivalents)	[126]
8′-O-ethylstictic	Usnea ceratina Ach.	In vitro	Human epithelial carcinoma HeLa cell line Human lung cancer NCI-H460 cell line Hepatocellular carcinoma HepG2 cell line Human breast cancer MCF-7 cell line	Cytotoxic	Moderate cytotoxicity against all cancer lines	[133]
Flavicansone	Teloschistes flavicans (Sw.) Norman.	In vitro	Human promyelocytic leukemia HL 60 cell line	Cytotoxic	Moderate activity (IC50 value of 58.18 µM)	[130]
Fumarprotocetraric acid	Cetraria islandica (L.) Ach.	In vitro	T. brucei brucei	Antimicrobial	Antitrypanosomal activity	[67]
	–	In vitro	Methicillin-resistant S. aureus strains	Antimicrobial	No activity	[66]
	Cladonia foliacea (Huds.) Willd.	In vitro	Gram-positve bacteria: B. cereus, B. subtilis, S. aureus, S. faecali Gram-negative bacteria: P. vulgaris, L. monocytogenes, A. hydrophila Fungi: C. albicans, C. glabrata	Antimicrobial	Antimicrobial activity against all microorganisms	[64]
	Cladonia furcata (Hudson) Schrade	In vitro	Gram-positve bacteria: B. mycoides, B. subtilis, S. aureus Gram-negative bacteria: E. cloaceae, E. coli, K. pneumoniae Fungi: A. flavus, A. fumigatu, B. cinerea, C. albicans, F. oxysporum, M. mucedo, P. variotii, P. purpurescens, P. verrucosum, T. harsianum	Antimicrobial	More activity against bacteria than fungi The lowest MIC value (0.031 mg/mL) against K. pneumoniae	[65]
	Cetraria islandica (L.) Ach.	In vitro	Human neuroblastoma SH-SY5Y cell line Human U373 MG astrocytoma cell line Hydrogen peroxide-induced oxidative stress model	Antioxidant	↑ Cell viability ↓ ROS formation, lipid peroxidation, and GSH depletion ↓ Apoptosis, ↓ caspase-3 activity, and expression; ↓ Bax and ↑ Bcl-2 proteins levels ↑ CAT, SOD-1, and HO-1 expression	[68]
	Cladonia verticillaris (Raddi) Fr.	In vivo	Albino Swiss mice	Antioxidant Expectorant	↑ Expectorant activity ↓ Lipid peroxidation	[69]
	Lasallia pustulata (L.) Mérat	In vitro	Sun protection factor (SPF) protection Factor-UVA (PF-UVA)	Photoprotection	SPF value: 1.91 (commercial filters ranged 3.91 to 11.16) PF-UVA value: 1.75. Commercial filter: 2.76	[70]
Gangaleoidin	Ramalina genus	In silico	Computational studies	Antioxidant	Hydroxyl and superoxide anion radical scavengers in polar environments	[131]
3-Hydroxyphysodic acid	Hypogymnia tubulosa (Schaer.) Hav.	In vitro	Second and third instar larvae of the mosquito Culiseta longiareolata	Antimicrobial	Larvicidal activity (LC50 values 0.97 ppm)	[72]
	Hypogymnia tubulosa (Schaerer) Hav.	In vitro	Gram-positive bacteria: Bacillus cereus, Staphylococcus aureus Gram-negative bacteria: Escherichia coli, Salmonella typhimurium Fungi: Candida albicans	Antimicrobial	MIC values from 0.08 to 2.57 mM	[73]
	Hypogymnia physodes (L.) Nyl.	In vitro	Rat thymocytes	Cytotoxic	↑ cytotoxicity ↓ proliferation No effects on MMP and ROSA	[71]
Hypoprotocetraric	Ramalina genus	In silico	Computational studies	Antioxidant	Hydroxyl and superoxide anion radical scavengers in polar environments	[131]
Hypostictic acid	Pseudoparmelia sphaerospora (Nyl.) Hale.	In vitro	M. tuberculosis	Antimicrobial	Antitubercular activity Moderate inhibitory activity (MIC = 94.0 µg/mL)	[93]
Lobaric acid	Stereocaulon alpinum Laurer	In vitro	Human breast adenocarcinoma MCF-7 Human cervix adenocarcinoma HeLa Human colon carcinoma HCT-116 cell lines	Cytotoxic	↓ HeLa and HCT-116 cell viability	[76]
	Stereocaulon alpinum Laurer	In vitro	Peripheral venous blood	Cytotoxic	Potent 12(S)-LOX inhibitor (93.4%)	[75]
	Usnea longissima Ach.	In vitro	Papillary renal cell carcinoma cell line Human malignant glioma U87MG cell line	Cytotoxic	↑ LDH and 8-oxo-dG levels PRCC cells (IC50 = 9.08 mg/L) U87MG (IC50 = 5.77 mg/L)	[50]
	Stereocaulon alpinum Laurer	In vitro	Pancreas cell cancer (Capan-1, Capan-2) Breast cell cancer (T47-D) Prostate cell cancer (PC-3) Lung cell cancer (NCI-H1417) Ovary cell cancer (NIH: OVCAR-3) Stomach cell cancer (AGS) Colorectal cell cancer (WiDr) Blood cell cancer (HL-60, K-562) cell lines	Cytotoxic	5-LOX and 12-LOX inhibitory activity ↑ Inhibitory effect against all cell lines (EC50 = 15.2 – 65.5 µg/mL)	[77]
	Stereocaulon paschale (L.) Hoffm.	In vitro	LPS-stimulated macrophages	Anti-inflammatory	↓ NF-κB activation ↓ IL-1β and TNF-α secretion	[59]
	Stereocaulon alpinum Laurer	In vitro	Porcine leucocytes	Anti-inflammatory	Inhibitory effects on 5-LOX (IC 50 7.3 µM)	[84]
	–	In vitro	Human HaCaT keratinocytes cell line	Anti-inflammatory	Block trypsin-induced and SLIGKV-NH2-induced PAR2 activation ↓ mobilization of intracellular Ca² ↓ expression of IL-8 PAR2 antagonist	[82]
	Stereocaulon alpinum Laurer	In vitro	TNF-α-Stimulated Vascular Smooth Muscle Cells	Anti-inflammatory	↓ VCAM-1 and TNF-R1 expression	[83]
	Stereocaulon alpinum Laurer	In vitro	LPS-stimulated macrophages	Anti-inflammatory	↓ NO production, COX-2 expression, and PG2 expression ↓ TNF-α, IL-1, β IL-6, and IL-18 production Inhibition of NLRP3 inflammasome activation Downregulating NF-κB/MAPK pathways	[60]
	Stereocaulon alpinum Laurer	In vitro	E. coli RecA protein	Antimicrobial	High RecA inhibition (96.8%)	[63]
	Stereocaulon alpinum Laurer	In vitro	Methicillin-resistant S. aureus strains	Antimicrobial	Antimicrobial activity (MIC50 = 32 µg/mL MIC90 = 64 µg/mL) Synergic only for gentamicin	[62]
	–	In vitro	Baby hamster kidney BHK17 cell line Monkey Vero E6 cell line Human liver Huh7 cell line Sindbis virus and Chikungunya virus	Antimicrobial	Anti-alphaviral ↓ CHIKV nsP1 GTP-binding and guanylation activities ↓ virus growth	[56]
	Stereocaulon alpinum Laurer	In vitro	M. aurum	Antimicrobial	Antimycobacterial activity (MIC values ≥ 125 µg/mL)	[85]
	–	In silico	Drug-binding studies on the structure of Nsp1 from SARS-CoV-2	Antimicrobial	Lobaric acid bind to Nsp1 Potential inhibitor blocking viral RNA binding	[86]
	Cladonia sp.	In vitro	SOR assay, NO assay, DPPH assay	Antioxidant	SOR (IC50 = 97.9 µmol) No DPPH activity	[87]
	Stereocaulon alpinum Laurer	In vitro	Human cervix adenocarcinoma HeLa cell line Colon carcinoma HCT116 cell line	Cytotoxic	↓ Hela and HCT116 cells proliferation ↑ Apoptosis ↓ Bcl-2 ↑ PARP	[48]
	Stereocaulon sasakii Zahlbr.	In vitro	Tubulin protein	Cytotoxic	Inhibition tubulin polymerization (IC50 = 100 µM)	[78]
	Stereocaulon alpinum Laurer	In vitro	Breast cell cancer (T-47D and ZR-75-1) Erythro-leukemia cell cancer (K-562) Normal skin fibroblasts Peripheral blood lymphocytes	Cytotoxic	↓ DNA synthesis in malignant cells ↑ Cell death in malignant cells 5-LOX inhibitory activity	[74]
	–	In vitro	Mitochondrial TrxR purified from rat lung	Cytotoxic	↑ Inhibitory effect	[79]
	Stereocaulon alpinum Laurer	In vitro	PTP1B inhibition assay	Enzyme inhibition	PTP1B inhibitory activity	[81]
	Stereocaulon alpinum Laurer	In vitro	PTP1B inhibition assay	Enzyme inhibition	Potent PTP1B inhibitory activity (IC50 = 0.87 µM)	[80]
	Stereocaulon alpinum Laurer	In vivo	T. coli from guinea pigs	Muscle relaxant	↓ Spontaneous muscle contractile activity	[88]
8′-O-methylstictic	Hypotrachyna revoluta (Flörke) Hale.	In vitro	Radical scavenging activity	Antioxidant	(61.85) Trolox® equivalents	[126]
	Hypotrachyna caraccensis (Taylor) Hale	In vitro	DPPH assay	Antioxidant	Low-moderate scavenging activity	[132]
Norstictic acid	Ramalina sp.	In vitro	M. tuberculosis	Antimicrobial	Antitubercular activity (MIC = 62.5 µg/mL)	[93]
	Toninia candida (Weber) Th.Fr.	In vitro	Gram-positive bacteria: B. mycoides, B. subtilis, S. aureus Gram-negative bacteria: E. coli, K. pneumoniae Fungi: A. flavus, A. fumigatus, C. albicans, P. purpurescens, P. verrucosum	Antimicrobial	Moderate antimicrobial activity (MIC value = 0.25 to 1 mg/mL)	[90]
	Ramalina farinacea (L.) Ach.	In vitro	Gram-positive bacteria: B. subtilis, L. monocytogenes, P. vulgaris, S. aureus, E. faecalis Gram-negative bacteria: A. hydrophila Fungi: C. albicans, C. glabrata	Antimicrobial	Low antimicrobial activity	[92]
	Rhizoplaca aspidophora (Vain.) Redón	In vitro	E. coli RecA protein	Antimicrobial	Low RecA inhibition (18.2%)	[63]
	Stereocaulon montagneanum I. M. Lamb.	In vitro	DPPH assay SOR assay	Antioxidant	Low DPPH radical scavenging activity High SOR scavenging activity	[91]
	Toninia candida (Weber) Th.Fr.	In vitro	DPPH assay SOR assay	Antioxidant	High antioxidant activity (DPPH IC50 = 102.65 µg/mL and SOR IC50 = 133.46 µg/mL)	[90]
	Ramalina sp.	In vitro	Human melanoma UACC-62 cell line Mouse melanoma B16-F10 cell line Mouse 3T3 normal cells	Cytotoxic	↑ Stronger activity against UACC-62 melanoma cells Selective action against malignant cells	[89]
	Usnea strigosa (Ach.)	In vitro	Human breast cancer (MDA-MB-231, MDA-MB-468, MCF-7, T-47D, BT-474, SK-BR-3) cell lines Human mammary epithelial (MCF-10A) cell line Female athymic nude mice	Cytotoxic	↓ MDA-MB-231 cell proliferation, migration, and invasion ↓ Tumor size and tumor weight ↑ Tolerability	[52]
	Stereocaulon montagneanum I. M. Lamb.	In vitro	Murine melanocytes B16 cell line Human keratinocyte HaCaT cell line UV-model	Cytotoxic	No cytotoxic No sunscreen action	[91]
	Toninia candida (Weber) Th.Fr.	In vitro	Human melanoma FemX cell line Human colon carcinoma LS174 cell line	Cytotoxic	High cytotoxic activity ↑ Number of cells in sub-G1 phase	[90]
Pannarin	Psoroma sp.	In vitro	E. coli RecA protein	Antimicrobial	Low RecA inhibition (13.1%)	[63]
	Psoroma spp.	In vitro	Methicillin-resistant S. aureus	Antimicrobial	Bactericidal (MIC50 = 4 µg/mL; MIC90 = 8 µg/mL)	[97]
	Psoroma pallidum Nyl.	In vitro	Promastigotes forms of Leishmania ssp	Antimicrobial	Total lysis of parasites (50 µg/mL)	[98]
	Psoroma spp.	In vitro	pBR322 plasmid DNA model SOR assay	Antioxidant	↓ NO-induced DNA damage Dose-dependent SOR scavenging effect	[95]
	Psoroma spp.	In vitro	Human PBMC cell line	Cytotoxic	Moderate cytotoxic effect	[97]
	Psoroma spp.	In vitro	Red blood cells	Cytotoxic	Significant hemolytic capacity	[96]
	Psoroma spp.	In vitro	Normal human prostatic epithelial DU-145 cell line	Cytotoxic	↓ Cell growth ↑ LDH release at 50 mM ↑ DNA fragmentation ↑ ROS	[94]
	Psoroma spp.	In vitro	Human melanoma M14 cell line	Cytotoxic	↓ Cell growth ↑ LDH release at 50 mM ↑ DNA fragmentation ↑ ROS	[95]
	Psoroma spp.	In vitro	8-MOP-human serum albumin photobinding	Photoprotection	Inhibition of photobinding (35.2%)	[99]
Peristictic acid	Stereocaulon montagneanum I. M. Lamb.	In vitro	DPPH assay SOR assay	Antioxidant	DPPH scavenging activity (10%) High SOR scavenging activity	[91]
	Stereocaulon montagneanum I. M. Lamb.	In vitro	Murine melanocytes B16 cell line Human keratinocyte HaCaT cell line UV-model	Cytotoxic	No cytotoxic No sunscreen action	[91]
Physodic acid	Pseudevernia furfuracea (L.) Zopf	In silico In vitro	Virtual screening using validated pharmacophore models Microsomal fraction IL-1β -stimulated A549 cells	Anti-inflammatory	Potential inhibitors of microsomal prostaglandin E2 synthase 1 Inhibitors of mPGES-1 (IC50 = 0.4 µM)	[107]
	Hypogymnia physodes (L.) Nyl.	In vitro	Gram-positive bacteria: B. mycoides, B. subtilis, S. aureus Gram-negative bacteria: E. coli, K. pneumoniae Fungi: A. flavus, A. fumigatu, C. albicans, P. purpurescens, P. verrucosum	Antimicrobial	Antimicrobial activity (especially against B. subtilis and B. mycoides with MIC values of 0.0008 and 0.0016 mg/mL, respectively)	[101]
	Pseudevernia furfuracea (L.) Zopf	In vitro	Cultured human amnion fibroblasts	Antioxidant	< 50 mg/L no oxidative stress and genotoxicity	[108]
	Pseudevernia furfuracea (L.) Zopf	In vitro	Cultured Human lymphocytes (HLs)	Antioxidant	↑Total antioxidant capacity (0.5 – 10 mg/L)	[109]
	Hypogymnia physodes (L.) Nyl.	In vitro	DPPH assay SOR assay Reducing power	Antioxidant	High DPPH radical scavenging activity (IC50 69.11 µg/mL) High SOR scavenging activity (IC50 = 118.17 µg/mL) High reducing power	[101]
	Hypogymnia lugubris (Pers.) Krog	In vitro	A375 melanoma cancer cell line	Cytotoxic	Apoptosis ↓ Hsp70 expression	[100]
	Pseudevernia furfuracea (L.) Zopf	In vitro	Human U87MG-GBM cell lines Primary rat cerebral cortex (PRCC) cells	Cytotoxic	↓ Cell viability (IC50 values of 698.19 mg/l for PRCC cells and 410.72 mg/L for U87MG cells) ↑ 8-OH-dG levels	[103]
	Hypogymnia physodes (L.) Nyl.	In vitro	Human melanoma FemX cell line Human colon carcinoma LS174 cell line	Cytotoxic	Cytotoxic activity (IC50 = 19.52 µg/mL for FemX, IC50 = 17.89 µg/mL for LS174) ↑ Number cells in sub-G1 phase ↓ Number cells in S phase and G2/M phase	[101]
	Hypogymnia enteromorpha (Ach.) Nyl.	In vitro	S. typhimurium TA 98	Cytotoxic	Inhibition of reactive metabolites formation	[111]
	Hypogymnia physodes (L.) Nyl.	In vitro	Colorectal cancer cell lines (HCT116 and DLD-1) Human keratinocytes HaCaT cell line	Cytotoxic	↓ Axin2 expression (especially in HCT116 cells) ↓ Survivin and MMP7 expression	[20]
	Hypogymnia physodes (L.) Nyl.	In vitro	Isolated rat thymocytes	Cytotoxic	↓ Thymocytes proliferation ↑ Cytotoxicity ↑ ROS production↓ MMP	[71]
	Hypogymnia physodes (L.) Nyl.	In vitro	Human cancer HeLa cell lines	Cytotoxic	↓ Cell viability: IC50 (24 h incubation) of 171 µg/mL and IC50 (72 h incubation) of 63 µg/mL	[105]
	Hypogymnia physodes (L.) Nyl.	In vitro	Peripheral human lymphocytes	Cytotoxic	↓ Frequency of MN (28.2%)	[104]
	Hypogymnia physodes (L.) Nyl.	In vitro	Breast cancer cell lines (MDA-MB-231, MCF-7, and T-47D) Nontumorigenic MCF-10A cell line	Cytotoxic	Cytotoxic activity (IC50 46.0 – 93.9 µM)	[102]
	–	In vitro	Human colon cancer HTC116 cell line Human leukemic K562 cell line Bladder cancer J82 and UM-UC-3 cell lines Human primary pancreatic adenocarcinoma BxPC-3 cell line	Cytotoxic	Inhibition of M-Phase Phosphoprotein 1 (MPP1) ATPase activity Weak cancer cell inhibitor (EC50 values ≈ 30 µM)	[106]
	Pseudevernia furfuracea (L.) Zopf	In vitro Ex vivo	Murine neuroblastoma Neuro2A cells Murine hippocampal primary cultures	Neuroprotection	No cytotoxic effects Neurotrophic and neurogenic activity Modulation gene expression of BDNF and NGF	[110]
Physodalic acid	Hypogymnia enteromorpha (Ach.) Nyl.	In vitro	S. typhimurium TA 98	Cytotoxic	Inhibition mutagenicity of a heterocyclic amine, Trp-P-2	[111]
	Hypogymnia physodes (L.) Nyl.	In vitro	Isolated rat thymocytes	Cytotoxic	↓ Thymocytes proliferation ↑ Cytotoxicity ↑ ROS production ↓ MMP	[71]
	Hypogymnia enteromorph (Ach.) Nyl.	In vitro	S. typhimurium strain TA 100	Cytotoxic	↑ Mutagenicity	[111]
	Hypogymnia physodes (L.) Nyl.	In vitro	Human cancer HeLa cell lines	Cytotoxic	↓ Cell viability: IC50 (24 h incubation) of 964 µg/mL and IC50 (72 h incubation) of 283 µg/mL	[105]
	Hypogymnia physodes (L.) Nyl.	In vitro	Peripheral human lymphocytes	Cytotoxic	↓ Frequency of MN (30.3%)	[104]
Protocetraric acid	Hypogymnia lugubris (Pers.) Krog	In vitro	E. coli RecA protein	Antimicrobial	Low RecA inhibition (11.5%)	[63]
	Flavoparmelia caperata L.	In vitro	S. aureus	Antimicrobial	Antibacterial activity (MIC 12.5 µg/mL)	[113]
	Usnea albopunctata Nyl.	In vitro	Gram-positive bacteria: B. subtilis, S. faecalis, S. aureus, S. epidermis, M. smegmatis Gram-negative bacteria: E. coli, P. mirabilis, P. vulgaris V. cholerae K. pneumoniae P. aeruginosa S. typhi Fungi: A. flavus C. albicans,C. tropicalis C. glabrata,C. gastri, T. rubrum	Antimicrobial	High activity against S. typhi (MIC value = 0.5 mg/mL), K. pneumoniae (MIC value = 1 mg/mL) and T. rubrum (MIC value = 1 mg/mL)	[112]
	Cetraria islandica (L.) Ach.	In vitro	T. brucei brucei	Antimicrobial	Antitrypanosomal activity	[67]
	Parmelia caperata (Ehrh. ex Ach.) Ach	In vitro	Gram-positve bacteria: B. mycoides, B. subtilis, S. aureus Gram-negative bacteria: E. coli, K. pneumoniae Fungi: A. flavus, A. fumigatus, C. albicans, P. purpurescens, P. verrucosum	Antimicrobial	↑ Antibacterial activity than antifungal activity High activity against B. mycoides, B. subtilis, and S. aureus (MIC value = 0.015 mg/mL)	[19]
	Parmotrema dilatatum (Vain.) Hale.	In vitro	M. tuberculosis	Antimicrobial	Antitubercular activity (MIC value = 125 µg/mL)	[93]
	Ramalina farinacea (L.) Ach.	In vitro	Gram-positive bacteria: B. subtilis, L. monocytogenes, S. aureus, S. faecalis Gram-negative bacteria: A. hydrophila, P. vulgaris Fungi: C. albicans, C. glabrata	Antimicrobial	Active against C. albicans and C. glabrata	[92]
	Parmelia caperata (Ehrh. ex Ach.) Ach	In vitro	DPPH assay SOR assay	Antioxidant	Strong antioxidant activity (IC50 = 119.10 µg/mL for DPPH and 177.60 µg/mL for SOR)	[19]
	Parmotrema dilatatum (Vain.) Hale.	In vitro	Human melanoma UACC-62 cell line Mouse melanoma B16-F10 cell line Mouse 3T3 normal cells	Cytotoxic	↑ Stronger activity against UACC-62 melanoma cells Selective action against malignant cells	[89]
	Parmelia caperata (Ehrh. ex Ach.) Ach	In vitro	Human melanoma FemX cell line Human colon carcinoma LS174 cell line	Cytotoxic	Cytotoxic activity (IC50 = 58.68 µg/mL for FemX, IC50 = 60.18 µg/mL for LS174) ↑ Number cells in sub-G1 phase ↓ Number cells in S phase	[19]
Psoromic acid	–	In vitro	Monkey kidney epithelial Vero cell line HSV-1 and HSV-2 models of infection	Antimicrobial	Antiherpetic activity HSV-1 replication inhibition (IC50 = 1.9 µM) HSV-2 replication inhibition (IC50 = 2.7 µM) HSV-1 DNA polymerase inactivation (IC50 = 0.7 µM)	[116]
	Squamarina cartilaginea (With.) P. James	In vitro	S. gordonii, P. gingivalis	Antimicrobial	Antibacterial activity against S. gordonii (MIC value = 11.72 µg/mL) and P. gingivalis (MIC value = 5.86 µg/mL)	[117]
	–	In vitro	M. tuberculosis strains	Antimicrobial	Antituberculosis activity (MIC values = 3.2 – 4.1 µM) Remarkable inhibition UGM (85.8%) and TBNAT (77.4%)	[118]
	–	In vitro	S. aureus E. coli M. tuberculosis P. berghei liver stage (LS) parasites P. falciparum blood-stage (BS) parasites	Antimicrobial	Antibacterial/Antimycobacterial Activity ↓ Growth bacterial Antiplasmodial activity Moderate LS activity (IC50 = 31.6 µM), high BS potential (IC50 = 29.2 µM) Plasmodial FAS-II enzyme (PfFabI, PfFabG, and PfFabZ) inhibition	[119]
	Usnea complanata (Müll. Arg.) Motyka.	In vivo	FRSA assay NORSA assay LPI assay HMGR inhibitory activity ACE inhibitory activity	Antioxidant	Moderate-to-strong antioxidant activity (IC50 values 0.174 – 0.271 mg/mL) Competitive type of HMGR inhibition and mixed type of ACE inhibition	[120]
	–	In vitro	Fluorometric Assay	Cytotoxic	↑ RabGGTase inhibition (IC50 = 1.3 µM)	[114]
	–	In vitro	Splicing assay	Cytotoxic	Pre-mRNA splicing inhibitor	[115]
	–	In vitro	Primary cultures of rat hepatocytes	Cytotoxic	↑ Caspase 3 activity ↑ Subdiploid nuclei %	[18]
	Usnea sp	In vitro	Human melanoma UACC-62 cell line Mouse melanoma B16-F10 cell line Mouse 3T3 normal cells	Cytotoxic	↑ Stronger activity against UACC-62 melanoma cells Selective action against malignant cells	[89]
	–	In vivo	Zebrafish embryos (B. rerio) model	Toxicity	Hepatotoxicity (≥ 40%)	[119]
Salazinic acid	Parmelia saxatilis (L.) Ach	In vitro	E coli RecA protein	Antimicrobial	Low RecA inhibition (8.4%)	[63]
	Parmelia sulcata Taylor	In vitro	Gram-positve bacteria: B. cereus, B. subtilis, L. monocytogenes, S. aureus, S. faecalis Gram-negative bacteria: A. hydrophila, P. vulgaris, Y. enterocolitica, P. aeruginosa, S. typhimurium Fungi: C. albicans, C. glabrata, A. niger, A. fumigatus, P. notatum	Antimicrobial	Antimicrobial activity specially against B. cereus (MIC values = 63 µg/mL)	[121]
	Parmelia reticulata Taylor.	In vitro	Fungi: S.rolfsii, R. solani, R. bataticola, F. udum, P. aphanidermatum, P. debaryanum	Antimicrobial	Moderate active against F. udum (IC50 = 88.20 µg/mL)	[122]
	Parmelia saxatilis (L.) Ach. Parmelia sulcata Taylor	In vitro	Gram-positve bacteria: B. mycoides, B. subtilis, S. aureus Gram-negative bacteria: E. coli, K. pneumoniae Fungi: A. flavus, A. fumigatus, C. albicans, P. purpurescens, P. verrucosum	Antimicrobial	↑ Antibacterial activity than antifungal activity	[19]
	Xanthoparmelia camtschadalis (Ach.) Hale.	In vitro	ORAC assay Human U373 MG astrocytoma cell line Hydrogen peroxide-induced oxidative stress model	Antioxidant	ORAC value (2.74 µmol Trolox equivalents per milligram) ↑ Cell viability ↓ ROS production	[124]
	Everniastrum cirrhatum (Fr.) Hale ex Sipman Rimelia cetrata (Ach.) Hale & Fletcher	In vitro	DPPH assay Anti-linoleic acid peroxidation assay Trolox-equivalent antioxidant capacity assay	Antioxidant	Antioxidant activity (46.4 to 57.2%)	[123]
	–	In vitro	DPPH assay NBT assay Human keratinocytes HaCaT cell line	Antioxidant	Superoxide anion scavenger Good PF-UVA candidate (PF-UVA > 2)	[70]
	Parmelia saxatilis (L.) Ach. Parmelia sulcata Taylor	In vitro	DPPH assay SOR assay	Antioxidant	Strong antioxidant activity (IC50 = 91.57 for DPPH and 138.23 µg/mL for SOR)	[19]
	–	In vitro	Primary cultures of rat hepatocytes	Cytotoxic	↑ Caspase 3 activity ↑ Subdiploid nuclei %	[18]
	Parmelia saxatilis (L.) Ach. Parmelia sulcata Taylor	In vitro	Human melanoma FemX cell line Human colon carcinoma LS174 cell line	Cytotoxic	Cytotoxic activity (IC50 = 39.02 µg/mL for FemX and IC50 = 5.67 µg/mL for LS174) ↑ Number cells in sub-G1 phase ↓ Number cells in S phase	[19]
	Parmelia sulcata Taylor	In vitro	Colorectal cancer HCT116 and DLD-1 cell lines.	Cytotoxic	Moderate cytotoxic effects (100 µM)	[20]
	Everniastrum cirrhatum (Fr.) Hale ex Sipman Rimelia cetrata (Ach.) Hale & Fletcher	In vitro	L. casei	Probiotic	Moderate growth stimulating activity	[123]
	Xanthoparmelia somloensis (Gyeln.) Hale	In vitro	Malignant mesothelioma MM98 cell line Vulvar carcinoma A431 cell line Human keratinocyte HaCaT cell line	Wound healing	Intermediate wound closure	[125]
Stictic acid	Rhizoplaca aspidophora (Vain) Redon	In vitro	E. coli RecA protein	Antimicrobial	Low RecA inhibition (16.7%)	[63]
	–	In vitro	F. tularensis, Y. pestis	Antimicrobial	Inhibition of FabZ (F. tularensis, IC50 = 13.0 µM and Y. pestis, IC50 = 27.8 µM)	[55]
	Xanthoparmelia camtschadalis (Ach.) Hale.	In vitro	ORAC assay Human U373 MG astrocytoma cell line Hydrogen peroxide-induced oxidative stress model	Antioxidant	ORAC value (2.32 µmol Trolox equivalents per milligram) ↑ Cell viability ↓ ROS production	[124]
	Stereocaulon montagneanum I. M. Lamb.	In vitro	DPPH assay SOR assay Murine melanocytes B16 cell line Human HaCaT keratinocyte cell lines	Antioxidant	Low DPPH radical scavenging activity ↑ SOR scavenging activity	[91]
	Hypotrachyna revoluta (Flörke) Hale.	In vitro	Hydroxyl radical scavenging assay	Antioxidant	Noteworthy antioxidant activity	[126]
	–	In vitro	Primary cultures of rat hepatocytes	Cytotoxic	↑ Caspase 3 activity ↑ Subdiploid nuclei %	[18]
	–	In silico	Docking studies	Cytotoxic	p53 activator ↓ Toxic adverse effects	[128]
	–	In vitro In silico	Human Saos-2 cells expressing cancer mutant R175H Docking studies	Cytotoxic	p53 activity restoration Cell cycle inhibitor p21 inductor	[127]
Variolaric acid	Ochrolechia deceptionis (Hue) Darb	In vitro	E. coli RecA protein	Antimicrobial	Low RecA inhibition (3.2%)	[63]
	Ochrolechia deceptionis (Hue) Darb.	In vitro	Human breast adenocarcinoma MCF-7 cell line Human cervix adenocarcinoma HeLa cell line Human colon carcinoma HCT-116 cell line	Cytotoxic	No effect	[76]
Vicanicin	Psoroma pallidum Nyl., P. pulchrum Malme	In vitro	E. coli RecA protein	Antimicrobial	Moderate RecA inhibition (73.7% inhibition)	[63]
	Psoroma pallidum Nyl. P. pulchrum Malme	In vitro	Human breast adenocarcinoma MCF-7 cell line Human cervix adenocarcinoma HeLa cell line Human colon carcinoma HCT-116 cell line	Cytotoxic	↓ Cell viability (HeLa, IC50 = 67 µM and HCT-116, IC50 = 40.5 µM)	[76]
	Psoroma dimorphum Malme	In vitro	Androgen-sensitive LNCaP and androgen-insensitive DU-145 human prostate cancer cells	Cytotoxic	↓ Cell viability ↑ Apoptosis	[129]
	Teloschistes flavicans (Sw.) Norman.	In vitro	HL-60 cells	Cytotoxic	Higher cytotoxicity against HL-60 cells	[130]

Alectoronic acid

Alectoronic acid has been shown to have cytotoxic activity against the B16 murine melanoma cell line. It reduced cancer cell viability with a higher potency than the reference compound cisplatin (IC₅₀ of 10.3 µM for alectoronic acid and IC₅₀ of 30.3 µM for cisplatin) [61].

Collatolic acid

Collatolic acid showed antimicrobial properties against methicillin-resistant clinical isolates strains of Staphylococcus aureus with an MIC₉₀ value of 128 µg/mL. Moreover, combinations of collatolic acid and gentamicin led to a synergistic antimicrobial effect, whereas antagonism occurred when collatolic acid and levofloxacin were associated [62]. Additional antimicrobial action against Escherichia coli RecA protein has been reported for collatolic acid. This compound exhibited a percentage of RecA inhibition of 103.4%, and it acted as a noncompetitive inhibitor for ATP binding site [63].

Fumarprotocetraric acid

Fumarprotocetraric acid has been mainly investigated for its antimicrobial properties. Hence, this compound showed antimicrobial action against Gram-positive bacteria (especially Bacillus cereus and Bacillus subtilis with MIC values of 4.6 µg/mL), Gram-negative bacteria (especially, Listeria monocytogenes with MIC value of 4.6 µg/mL), and fungi (Candida albicans and Candida glabrata with MIC values of 18.7 µg/mL) in the disk diffusion method [64]. In another study, this depsidone was more active against bacteria than fungi, and its action against Klebsiella pneumoniae (MIC value of 0.031 mg/mL) was particularly remarkable [65]. However, fumarprotocetraric acid has resulted to be ineffective towards MRSA strains [66]. Apart from its antibacterial activity, fumarprotocetraric acid showed antitrypanosomal activity against Trypanosoma brucei brucei [67].

In addition to antimicrobial properties, fumarprotocetraric acid is a promising antioxidant compound. The neuroprotection exerted in neuroblastoma and astrocytoma cell lines by fumarprotocetraric acid has been related to its ability to reduce ROS formation, lipid peroxidation, and GSH depletion [68]. Moreover, fumarprotocetraric acid demonstrated in vivo expectorant and antioxidant properties in an albino Swiss mice model at 25 and 50 mg/kg as evidenced in an increase of excretions and a reduction of lipid peroxidation in lung tissue [69].

Finally, fumarprotocetraric acid did not show photoprotective properties (SPF value [1.91] and PF-UVA value [1.75]) [70].

3-Hydroxyphysodic acid

This compound induced cytotoxicity against rat thymocytes and diminished their proliferation via antioxidant/oxidant imbalance [71]. In addition, 3-hydroxyphysodic showed antimicrobial activities. It acted as a larvicidal agent against second and third instar larvae of the mosquito Culiseta longiareolata (LC₅₀ values 0.97 ppm) as well as antibacterial and antifungal agent with MIC values from 0.08 to 2.57 mM against B. cereus, E. coli, L. monocytogenes, Salmonella typhimurium, S. aureus, and C. albicans [72], [73].

Lobaric acid

The in vitro cytotoxic activity of lobaric acid has been tested in many different cancer cell lines such as human breast adenocarcinoma MCF-7 cells, human colon carcinoma HCT-116 cells, and human malignant glioma U87MG cells [48], [50], [74], [75], [76], [77]. Lobaric acid effectively reduced cancer cell viability and proliferation, targeting the anti-apoptotic Bcl-2 protein and the cleaved form of the PARP [48]. This depsidone also exerted cytotoxic action via oxidative stress induction as evidenced in high levels of 8-OH-dG (DNA damage) [50]. Further, lobaric acid reduced cancer cell growth through the inhibition of 5-lipoxygenase and 12-lipoxygenase [74], [75], [77]. Furthermore, this compound inhibited the polymerization of tubulin in a concentration-dependent manner, and this activity is structurally related to hydroxyl groups at C-1′ and C-2′ and carboxylic acid [78]. Finally, lobaric acid also inhibited mitochondrial thioredoxin reductase in rat lungs [79].

Lobaric acid showed high inhibition of PTP1B with an IC₅₀ value of 0.87 µM [80], [81]. Tyrosine phosphatase protein is overexpressed in insulin-resistant states [80]. Indeed, Klaman et al. showed that PTP-1B regulates energy balance, insulin sensitivity, and body fat stores in in vivo studies [58].

Lobaric acid could inhibit inflammation in LPS-activated macrophages through regulation of NF-κB/MAPK pathways, NLRP3 inflammasome activation, proinflammatory cytokines suppression (TNF-α, IL-1, IL-6, and IL-18), and NO production inhibition [59], [60]. Moreover, lobaric acid reduced IL-8 expression and targeted PAR2 in an in vitro SLIGKV-NH₂-induced atopic dermatitis model in HaCaT keratinocytes [82]. Additionally, lobaric acid exerted anti-inflammatory activity by inhibiting NF-κB and MAPK signaling pathways in TNF-α-stimulated mouse vascular smooth muscle cells [83]. Furthermore, lobaric acid turned out to be a potent arachidonate-5-lipoxygenase inhibitor (IC₅₀ value of 7.3 µM) [84].

Lobaric acid also showed antimicrobial activity against bacteria and viruses. Thus, this depsidone inhibited RecA from E. coli by noncompetitively binding the ATP site [63]. While it showed moderate activity against Mycobacterium aurum [85], the activity against methicillin-resistant clinical isolates strains of S. aureus with an MIC₉₀ value of 64 µg/mL was good [62]. Moreover, lobaric acid showed anti-alphaviral activity against Chikungunya virus via NsP1 GTP binding and guanylation inhibition in hamster BHK21 and human Huh 7 cell lines [56]. Furthermore, binding studies of Nsp1 from SARS-CoV-2, a nonstructural protein 1 related to viral processes as viral replication and translation regulation, showed greater binding affinities with lobaric acid [86].

Other assayed activities were its antioxidant activity (superoxide radical scavenging action with IC₅₀ value of 97.9 µmol) [87] and muscle relaxant as evidenced in the reduction of spontaneous muscle contractile activity in guinea-pig taenia coli [88].

Norstictic acid

The cytotoxic and antitumor role of norstictic acid has been evaluated in diverse in vitro (using different cancer cell lines) and in vivo models. Therefore, this compound has been shown to be effective for breast cancer treatment and prevention by targeting the c-Met signaling pathway and by suppressing the MDA-MB-231/GFP tumor growth in mammary cancer cells and breast cancer xenograft models in athymic nude mice [52]. Moreover, norstictic acid exerted a noticeable cytotoxic effect against different human melanoma cell lines (FemX, UACC-62, and B16-F10) [89], [90] by increasing apoptotic cells in the sub-G1 phase [89]. Contrary, other studies reported that norstictic acid was not cytotoxic for melanocyte cells [91].

Concerning its antimicrobial activity, norstictic acid showed low to moderate antibacterial and antifungal action against a wide range of Gram-positive bacteria, Gram-negative bacteria, and fungi [63], [90], [92], [93]. For instance, norstictic acid inhibited Mycobacterium tuberculosis growth with a MIC value of 62.5 µg/mL [93] and E. coli with a value of 18.2% [63].

Norstictic acid has also been shown to be a promising antioxidant agent against superoxide anion. On the other hand, its DPPH radical scavenging activity is not entirely clear, since its activity is contradictory in published works [90], [91].

Pannarin

Pannarin was able to inhibit the growth of the human melanoma M14 cell line and the human prostatic epithelial DU-145 cell line. Its cytotoxic activity has been related to oxidative stress induction as evidenced in ROS overproduction and DNA fragmentation [94], [95]. Moreover, pannarin showed cytotoxic activity against blood cells through a mechanism of hemolysis [96], [97].

Regarding antimicrobial activity, pannarin acted as bactericidal against methicillin-resistant S. aureus, and it also had a low capacity to inhibit E. coli RecA protein [63], [97]. Moreover, pannarin was effective as an antiparasitic agent against promastigote forms of Leishmania spp [98].

Pannarin also showed antioxidant properties as evidenced in its superoxide radical scavenging capacity and NO-induced DNA damage [95], and it has photoprotector capacity (35.2%) [99].

Physodic acid

There are several studies on the cytotoxic activity of physodic acid against different cancer and nontumorigenic cell lines from diverse origins (human or animal). Against A375 melanoma cancer cell line, physodic acid exhibited good cytotoxicity via apoptosis with a concentration-response relationship (range 6.25 – 50 µM), showing inhibition of Hsp70 expression [100]. Other studies on FemX and LS174 cell lines revealed significant cytotoxic activity (IC₅₀ value of 19.52 µg/mL for FemX, IC₅₀ value of 17.89 µg/mL for LS174) with moderate proapoptotic activity. The number of cells in the sub-G1 phase increased, and the number of cells in the S phase and G2/M phase was lower, indicating a G0/G1 cell cycle arrest [101]. Moreover, physodic acid was cytotoxic on different breast cancer cell lines (MDA-MB-231, MCF-7, and T-47D) with IC₅₀ values that ranged from 46.0 to 93.9 µM [102]. Physodic acid displayed weak cytotoxic activity on human U87MG-GBM cell lines and primary rat cerebral cortex (PRCC) cells (IC₅₀ value of 698.19 mg/mL for PRCC cells and IC₅₀ value of 410.72 mg/mL for U87MG cells) [103]. Moreover, physodic acid reduced thymocyte proliferation-induced cytotoxicity via oxidative stress mainly through ROS production [71]. On lymphocytes, this depsidone significantly decreased micronucleus frequency (28.2%) compared to the positive control [104]. Furthermore, this compound proved to significantly reduce human cancer HeLa cell viability (IC₅₀ [24 h] value of 171 µg/mL and IC₅₀ [72 h] value of 63 µg/mL) [105]. In another study, Talapatra et al. concluded that physodic acid was a weak cancer cell inhibitor (EC₅₀ values ≈ 30 µM) on multiple cancer cell lines (human colon cancer HTC116 cell line, human leukemic K562 cell line, bladder cancer J82 and UM-UC-3 cell lines, and human primary pancreatic adenocarcinoma BxPC-3 cell line) [106]. Physodic acid was studied as a modulator of β-catenin-dependent transcription on colorectal cancer (HCT116 and DLD-1). β-catenin transcription is related to cell survival and proliferation. Physodic acid reduced Axin2 (β-catenin target gene) expression (especially in HCT116 cells) and decreased survivin and MMP7 expression [20]. Also, this depsidone was probed as an inhibitor of MPP1, essential for the cytokinesis process, indicating noncompetitive ATP binding in in silico studies [106].

Antimicrobial activity was also examined in bacteria and fungi. Physodic acid had strong inhibitory capacity especially against B. subtilis and B. mycoides with MIC values of 0.0008 and 0.0016 mg/mL, respectively [101].

In addition to cytotoxic and antimicrobial properties, in vitro and in silico models showed the anti-inflammatory activity of physodic acid. Virtual screening evaluation revealed that this depsidone inhibits microsomal prostaglandin E2 synthase-1 [107]. Determination of mPGES-1 inhibition was performed using a microsomal fraction of IL-1β-stimulated A549 cells (IC₅₀ = 0.43 µM) [107].

Physodic acid was also investigated as an antioxidant agent, showing high DPPH radical scavenging activity (IC₅₀ value of 69.11 µg/mL), high SOR scavenging activity (IC₅₀ value of 118.17 µg/mL), and high reducing power [101]. Lower concentrations of physodic acid tested in cultured human amnion fibroblasts (< 50 mg/L) and cultured human lymphocytes (0.5 – 10 mg/L) showed antioxidant capacities [108], [109].

Moreover, physodic acid showed neuroprotective properties, exhibiting neurotrophic and neurogenic activity via modulation of gene expression of BDNF and NGF in ex vivo (murine hippocampal primary cultures) and in vivo (murine neuroblastoma Neuro2A cells) assays [110].

Physodalic acid

Cytotoxic activity of physodalic acid is also described. However, compared to physodic acid, physodalic presented weaker activity. Physodalic acid demonstrated a weak reduction of viability (IC₅₀ [24 h] value of 964 µg/mL and IC₅₀ [72 h] value of 283 µg/mL) on human cancer HeLa cell lines [105].

This compound also diminished the proliferation of thymocytes inducing cytotoxicity via ROS production. Physodalic acid reduced the frequency of micronucleus (30.3%) on lymphocytes [71], [104].

Despite being reported as mutagenic in S. typhimurium TA 100 [83], physodalic acid inhibited the mutagenicity of a heterocyclic amine, Trp-P-2, in S. typhimurium TA 98 [111].

Protocetraric acid

Most of the studies on protocetraric acid referred to its antimicrobial activity. Particularly, this depsidone inhibited pathogenic bacteria growth such as S. aureus (MIC value of 12.5 µg/mL), M. tuberculosis (MIC value of 125 µg/mL), S. typhi (MIC value of 0.5 mg/mL), K. pneumoniae (MIC value of 1 mg/mL), and B. mycoides, B. subtilis, and S. aureus (MIC value of 0.015 mg/mL) [19], [93], [112], [113]. Moreover, protocetraric acid revealed a marked antifungal activity against T. rubrum (MIC value of 1 mg/mL), C. albicans, and C. glabrata (MIC value of 3.9 µg/µl) [92], [112]. Furthermore, protocetraric acid showed trypanocidal activity against T. brucei brucei with a MIC value of 6.30 µM [67].

Protocetraric acid also demonstrated cytotoxic activity against melanomas cell lines (IC₅₀ values of 0.52 µg/mL for UACC-62 cells and 58.68 µg/mL for FemX cells) and colon carcinoma cell line (IC₅₀ value of 60.18 µg/mL for LS174 cells) [19], [89].

This depsidone had also an effective antioxidant action as evidenced in DPPH and superoxide anions radical scavenging activity [19].

Psoromic acid

Psoromic acid presented an inhibitory effect against melanoma cell lines (UACC-62 and B16-F10) and primary cultures of rat hepatocytes [18], [89]. The cytotoxic activity of psomoric acid was related to its capacity to induce an apoptotic response and to inhibit splicing and Rab GTPase [18], [114], [115].

Psoromic acid was also of interest as an antiviral agent, as it blocked HSV-1 and HSV-2 replication and DNA synthesis [116]. Moreover, this depsidone reduced bacterial growth of Streptococcus gordonii (MIC value of 11.72 µg/mL), Porphyromonas gingivalis (MIC value of 5.86 µg/mL), and M. tuberculosis strains (3.2 – 4.1 µM) [116], [117], [118]. Furthermore, psoromic acid acts as an inhibitor of Plasmodium liver stages targeting the plasmodial FAS-II pathway [119]. In vivo studies determined that psoromic acid was hepatotoxic in fabp10a: DsRed2 zebrafish larvae (≥ 40%) [119].

Using different in vitro antioxidant assays, Behera et al. revealed that psomoric acid had moderate to strong antioxidant activity [120].

Salazinic acid

Salazinic acid displayed cytotoxic activity against colorectal cancer cell lines (HCT116, DLD-1, and LS174), melanoma cancer cell lines (FemX), and primary cultures of rat hepatocytes by inducing apoptosis and cell cycle arrest [18], [19], [20].

Considering its antimicrobial activity, salazinic acid inhibited B. mycoides and B. subtilis growth with a MIC value of 0.0008 µg/m and B. cereus with a MIC value of 63 µg/mL [19], [121]. However, this depsidone was ineffective as an E. coli Rec A protein inhibitor [63]. Moreover, salazinic acid showed moderate antifungal activity against Fusarium udum (IC₅₀ value of 88.20 µg/mL) [122]. Furthermore, this compound promoted growth effects on probiotic bacteria Lactobacillus casei [123].

Salazinic acid has also turned out to be interesting as an antioxidant compound as revealed in different in vitro assays (DPPH assay, SOR assay, ORAC assay) [19], [70], [123], [124] Because of its antioxidant properties, this depsidone increased cell viability and reduced ROS production in a hydrogen peroxide-induced oxidative stress model in the human U373 MG astrocytoma cell line [124]. Moreover, salazinic acid proved to protect against UVA sunrays (PF-UVA > 2) [70].

Another property attributed to salazinic action is its ability to heal wounds on HaCaT keratinocytes [125].

Stictic acid

Stictic acid has been investigated for its antioxidant, antimicrobial, and cytotoxic properties. This promising compound showed antioxidant activity in diverse in vitro test models. Despite its low DPPH radical scavenging activity (less than 10%), stictic acid exhibited moderate ORAC values (2.32 µmolTE/mg), high SOR scavenging activity (IC₅₀ value of 35 µM), and good hydroxyl radical scavenging activity (7.63 Trolox equivalents) [91], [124], [126]. Furthermore, in hydrogen peroxide-induced oxidative stress conditions, this depsidone protected human U373 MG astrocytoma cell line at 5, 10, and 25 g/mL concentrations via inhibition of ROS production [124]. These findings showed that stictic acid may be a potential neuroprotective compound.

On the other hand, cytotoxicity evaluation on murine melanocytes B16 cells and human HaCaT keratinocyte cell lines showed no safety; therefore, its possible cosmetic use was dismissed [91].

Enzymes involved in fatty acid biosynthesis processes such as FabZ are excellent targets for developing broad-spectrum antibiotics. Differences between FAS systems (bacterial and human) imply that the inhibition process does not interfere with the host. Stictic acid exhibited a significant inhibitory effect against Francisella tularensis (IC₅₀ value of 13 µM) and Yersinia pestis (IC₅₀ value of 27 µM) β-hydroxyacyl-acyl carrier protein dehydratase (FabZ) [55]. Stictic acidʼs antimicrobial properties have been investigated, along with other depsidones through E. coli RecA protein inhibition. RecA is related to bacterial SOS response regulation, which is involved in resistance to antimicrobials. Stictic acid exhibited low RecA inhibition (16.7%) [63].

In vitro and in silico assays reported cytotoxic activity of this compound. In human cancer, p53 genes mutate frequently. Using docking studies, stictic acid showed potential p53 reactivation by binding to a transiently open L1/S3 pocket of the p53 core domain [127]. In another study, stictic acid showed great potential as a p53 activator and less adverse effect but poor pharmacokinetic properties [128]. To support in silico assays, stictic acid was biologically evaluated in human Saos-2 cells expressing cancer mutant R175H, restoring p53 activity via induction of the cell cycle inhibitor p21 [127]. Moreover, stictic acid displayed cytotoxic activity in different cell lines. In primary cultures of rat hepatocytes, this depsidone showed significant concentration-dependent activation of caspase 3 and an increased percentage of subdiploid nuclei (DNA fragmentation) [18].

Variolaric acid

While variolaric acid was tested to evaluate its cytotoxic and antimicrobial activity, the viability assays reported no significant effect on human breast adenocarcinoma cell line MCF-7, human cervical adenocarcinoma cell line HeLa, and human colon carcinoma HCT-116 [76]. Moreover, this depsidone had a low capacity to inhibit E. coli RecA protein (3.2%) [63].

Vicanicin

Cytotoxic activity of vicanicin was evaluated in different cell cancer lines, showing significant loss of viability in a concentration-dependent manner on human cervix adenocarcinoma HeLa cell lines and human colon carcinoma HCT-116 (IC₅₀ values of 67 µM and 40.5 µM, respectively). However, vicanicin did not have effects on human breast adenocarcinoma MCF-7 cells. This depsidone neither exhibited antiradical activity nor reduced intracellular ROS level, dismissing both as the potential mechanism of cytotoxicity [76].

In the model of androgen-sensitive (LNCaP) and androgen-insensitive (DU-145) human prostate cancer cells, vicanicin decreased cell growth by the induction of apoptosis. The expression of Bcl-2, Bax, TRAIL, COX-2, NOS2, and Hsp70 proteins was analyzed, and the inhibition of Hsp70 proteins expression as a mediator of the process should be highlighted [129]. Moreover, this depsidone exhibited moderate activity against HL-60 cells as revealed on antileukemic assay [130]. Regarding its antimicrobial activity, this depsidone showed moderate inhibition of E. coli RecA protein (73%) [63].

Other Depsidones

Many depsidones have been identified but barely studied. Computational studies have revealed that connorstictic acid, cryptostictic acid, conhypoprotocetraric acid, hypoprotocetraric acid, and gangaleoidin, among other depsidones, are potent hydroxyl and superoxide anion radical scavengers in polar environments [131]. Other stictic acid derivatives also displayed antioxidant activities such as peristictic acid and cryptostictic acid that showed weak DPPH radical scavenging activity (about 10%) and potent superoxide anion radical scavenging activity equivalent to that of ascorbic acid. These compounds showed no cytotoxicity on B16 murine melanoma and HaCaT human keratinocyte cell lines (IC₅₀ higher than 100 µM) [91]. The compounds 8′-O-methylstictic and deoxystictic acid showed radical scavenging activity (61.85 and 13.176 Trolox equivalents, respectively) [126]. Moreover, 8′-O-methylstictic acted as a DPPH scavenger and had good properties for skin penetration (lipophilicity and permeability) [132].

These derivatives have also displayed other activities. For example, hypostictic acid showed antimicrobial properties due to its moderate inhibitory activity against M. tuberculosis (MIC value of 94 µg/mL) [93]. The compound 8′-O-ethylstictic presented moderate cytotoxicity against human epithelial carcinoma HeLa, human lung cancer NCI-H460, liver hepatocellular carcinoma HepG2, and human breast cancer MCF-7 cell lines [133].

Other depsidones recently identified, such as ceratinalone and flavicansone, isolated from Usnea ceratina Ach. and Teloschistes flavicans (Sw.) Norman, respectively, have also shown cytotoxic properties [130], [133]. Ceratinalone has been tested against different cancer cell lines such as human epithelial carcinoma HeLa, human lung cancer NCI-H460, liver hepatocellular carcinoma HepG2, and human breast cancer MCF-7. It acted as a moderate cytotoxic agent [133]. On the other hand, flavicansone exhibited cytotoxic activity as evidenced in an antileukemic assay against HL-60 cells (IC₅₀ value of 58 µM) [130].

Conclusions and Future Perspectives

Indeed, lichens produce unique bioactive secondary metabolites such as depsidones. Most pharmacological studies of depsidones focus on fumarprotocetraric acid, lobaric acid, norstictic acid, physodic acid, salazinic acid, and stictic acid compounds. Lichen depsidones have proven their ability to perform diverse biological activities, with cytotoxic, antimicrobial, and antioxidant the most studied. While many published works are on in vitro studies, the in vivo studies are very limited, and no clinical trials are yet available.

The cytotoxic activity has been evaluated against different cell lines of animal and human origin. Most of these works on cytotoxic activity are based on assessing their effect on cell viability, however, there are fewer studies that clarify the molecular targets and signaling pathways. The most interesting depsidones with cytotoxic activity included lobaric and physodic acids. Regarding the antimicrobial activity, most of the studies evaluated antibacterial activity against both Gram-positive bacteria and Gram-negative bacteria and fungi, mainly Candida spp. Among depsidones, fumarprotocetraric and protocetraric acids are emphasized for their antimicrobial properties. The antioxidant activity has been investigated using techniques such as the DPPH method and ORAC assay as well as in cellular and animal models of oxidative stress. The compounds salazinic acid and stictic acid stand out for their antioxidant properties.

Our study revealed that the future perspectives of pharmacological research on depsidones should focus on:

1. Deepening the activities for these depsidones, clarifying the mechanism of action.

2. Evaluating other and novel potential actions and properties of depsidones.

3. Investigating the potential therapeutic activity of unstudied depsidones from a pharmacological perspective as notatic acid, nortotatic acid, constictic acid, and diploicin.

4. Performing more in vivo studies confirming the activity shown in in vitro studies.

5. Conducting clinical trials for those depsidones that have shown potential pharmacological activities.

Contributorsʼ Statement

Data collection: I. M. Ureña-Vacas, E. González-Burgos; drafting the manuscript: I. M. Ureña-Vacas, E. González-Burgos; critical revision of the manuscript: P. K. Divakar, M. P. Gómez-Serranillos.

Conflict of Interest

The authors declare that they have no conflict of interest.

Acknowledgements

This study was supported by the Spanish Ministry of Science, Innovation, and Universities (PID2019-105312GB-100) and the Santander-University Complutense of Madrid (PR87/19-22637). I. Ureña-Vacas is supported by a grant CT42/18-CT43/18 from Complutense University of Madrid for predoctoral research.

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Publication History

Received: 09 March 2021

Accepted after revision: 13 April 2021

Article published online:
25 May 2021