Draft:Norlichexanthone

The term norlichexanthone was first mentioned in 1978 by Sundholm, E. G.{{Cite journal |last=Sundholm |first=E. G. |date=1978-01-01 |title=Total syntheses of lichen xanthones: Revision of structures11Part 34 of the series Chemical Studies on Lichens.22Part 33. Sundholm, G., Acta Chem. Scand. B28, 1102 (1974). |url=https://www.sciencedirect.com/science/article/abs/pii/0040402078800556 |journal=Tetrahedron |volume=34 |issue=5 |pages=577–586 |doi=10.1016/0040-4020(78)80055-6 |issn=0040-4020}} However, it was not until 1990 that it was reported as a naturally occurring compound isolated from lichens by Elix J. A., Jiang H., and Wardlaw J. H. Initially, the compound was isolated from various lichen species, particularly Pertusaria laeviganda, where it exhibited notable antioxidant activity. Later studies documented its presence in other lichens and fungi, including Penicillium species. It has also been found in endophytic fungi from plants, such as ARL-13, where it demonstrated potential anti-osteoporosis effects, and in fungi such as Cucurbitaria sp., where it exhibited antibacterial properties.{{Cite journal |last1=Kawakami |first1=Hiroko |last2=Suzuki |first2=Chihiro |last3=Yamaguchi |first3=Haruka |last4=Hara |first4=Kojiro |last5=Komine |first5=Masashi |last6=Yamamoto |first6=Yoshikazu |date=2019-06-03 |title=Norlichexanthone produced by cultured endolichenic fungus induced from Pertusaria laeviganda and its antioxidant activity |url=https://academic.oup.com/bbb/article-abstract/83/6/996/5937695?redirectedFrom=fulltext |journal=Bioscience, Biotechnology, and Biochemistry |volume=83 |issue=6 |pages=996–999 |doi=10.1080/09168451.2019.1585746 |issn=0916-8451 |pmid=30835638}}

Norlichexanthone shares structural similarities with lichexanthone, another lichen-derived xanthone, but differs in its substitution pattern. Specifically, norlichexanthone has hydroxy groups at positions 3 and 6, whereas lichexanthone contains methoxy groups at those positions.

Research on norlichexanthone's biological activity expanded in the late 20th and early 21st centuries, with growing interest in its potential pharmacological applications. The first report of its antioxidant activity was published by Hiroko Kawakami in 2019.

A study by Ikeda et al. (2011) investigated norlichexanthone derived from the fungus P16, revealing that it could promote adiponectin secretion in adipocyte cultures—suggesting potential applications in metabolic disorder treatments. {{Cite journal |last1=Ikeda |first1=Megumi |last2=Kurotobi |first2=Yoshiko |last3=Namikawa |first3=Aiko |last4=Kuranuki |first4=Sachi |last5=Matsuura |first5=Nobuyasu |last6=Sato |first6=Mayumi |last7=Igarashi |first7=Yasuhiro |last8=Nakamura |first8=Teiji |last9=Oikawa |first9=Tsutomu |date=2011 |title=Norlichexanthone Isolated from Fungus P16 Promotes the Secretion and Expression of Adiponectin in Cultured ST-13 Adipocytes |url=https://www.eurekaselect.com/article/33194 |journal=Medicinal Chemistry |language=en |volume=7 |issue=4 |pages=250–256 |doi=10.2174/157340611796150950 |pmid=21568875}} Additionally, research by Baldry, M. (2016) explored its role in targeting Staphylococcus aureus infections, indicating its relevance in antibacterial drug development. {{Cite web |last=Team |first=EBI Web |title=norlichexanthone (CHEBI:7632) |url=https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:7632 |access-date=2025-03-13 |website=www.ebi.ac.uk |language=en}}{{Cite journal |last1=Calheiros |first1=Juliana |last2=Raimundo |first2=Liliana |last3=Morais |first3=João |last4=Matos |first4=Ana Catarina |last5=Minuzzo |first5=Sonia Anna |last6=Indraccolo |first6=Stefano |last7=Sousa |first7=Emília |last8=Silva |first8=Marta Correia da |last9=Saraiva |first9=Lucília |date=January 2023 |title=Antitumor Activity of the Xanthonoside XGAc in Triple-Negative Breast, Ovarian and Pancreatic Cancer by Inhibiting DNA Repair |journal=Cancers |language=en |volume=15 |issue=24 |pages=5718 |doi=10.3390/cancers15245718 |issn=2072-6694 |pmc=10741784 |pmid=38136266 |doi-access=free}} Overview of findings of Norlichexanthone made between 1978-2024 can be found in Table 1.

Table 1: Key Milestones in Norlichexanthone Research and Discovery (1978–2024)

Despite its promising biological activities, norlichexanthone has not received regulatory approval for medical use in humans. There is no record of it undergoing clinical trials or being approved by agencies such as the U.S. Food and Drug Administration (FDA) for therapeutic applications. However, its effects on bacterial virulence, biofilm formation, and antioxidant properties continue to be subjects of research.

Norlichexanthone is a xanthone with hydroxy groups at positions 1, 3, and 6 and a methyl group at position 8. The xanthone core is the cyclic system of the 2 benzene rings connected via a ketone and an ether, which form a fully aromatized structure, which is more stable than the individual bonds would suggest. {{Cite journal |last1=Masters |first1=Kye-Simeon |last2=Bräse |first2=Stefan |date=2012-07-11 |title=Xanthones from Fungi, Lichens, and Bacteria: The Natural Products and Their Synthesis |url=https://pubs.acs.org/doi/10.1021/cr100446h |journal=Chemical Reviews |volume=112 |issue=7 |pages=3717–3776 |doi=10.1021/cr100446h |issn=0009-2665 |pmid=22617028}}{{Cite web |date=2014-06-19 |title=15.1: Aromatic Compounds Are Unusually Stable |url=https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Map:_Organic_Chemistry_(Bruice)/15:_Aromaticity_(Reactions_of_Benzene)/15.01:_Aromatic_Compounds_Are_Unusually_Stable |access-date=2025-03-13 |website=Chemistry LibreTexts |language=en}}There is not much research on the reactivity of norlichexanthone, but there are other chemicals with the same functional groups.

Norlichexanthone is produced by the polyacetate/polymalonate pathway, which involves the ring-closure of a single folded polyketide chain, potentially via a benzophenone intermediate. In this pathway, a single polyketide undergoes aldol condensation and Claisen-type cyclization, forming a benzophenone intermediate that may dehydrate spontaneously to form the central pyrone core. The oxygen substitution pattern of lichexanthone and norlichexanthone, characterised by a methyl group in the 8-position, is subsequently produced.{{Cite journal |last1=Badiali |first1=Camilla |last2=Petruccelli |first2=Valerio |last3=Brasili |first3=Elisa |last4=Pasqua |first4=Gabriella |date=January 2023 |title=Xanthones: Biosynthesis and Trafficking in Plants, Fungi and Lichens |journal=Plants |language=en |volume=12 |issue=4 |pages=694 |bibcode=2023Plnts..12..694B |doi=10.3390/plants12040694 |issn=2223-7747 |pmc=9967055 |pmid=36840041 |doi-access=free}}

Beyond synthetic modifications, research has also explored the biological effects of norlichexanthone and its chemically transformed derivatives. For example, oxidation reactions have been conducted on norlichexanthone to generate quinone-like species. These oxidized derivatives have been investigated for their potential to modulate bacterial virulence. In one study, norlichexanthone was shown to inhibit the expression of virulence factors in Staphylococcus aureus, an effect partially attributed to subtle changes in its oxidation state.

Alternariol (AOH) is a dibenzopyrone mycotoxin produced by various Alternaria molds. For many years, its biosynthesis was believed to involve the direct cyclization of a heptaketide chain. However, research by Stinson et al. (1986) suggested that AOH is synthesized via an intermediate, norlichexanthone.{{Cite journal |last1=Stinson |first1=E. E. |last2=Wise |first2=W. B. |last3=Moreau |first3=R. A. |last4=Jurewicz |first4=A. J. |last5=Pfeffer |first5=P. E. |date=August 1986 |title=Alternariol: evidence for biosynthesis via norlichexanthone |url=https://cdnsciencepub.com/doi/10.1139/v86-263 |journal=Canadian Journal of Chemistry |volume=64 |issue=8 |pages=1590–1594 |bibcode=1986CaJCh..64.1590S |doi=10.1139/v86-263 |issn=0008-4042}} This hypothesis was later disproven by Dasenbrock and Simpson (1987), who demonstrated that the observed incorporation of 14C-labeled norlichexanthone likely occurs through its prior degradation into labeled acetyl-CoA.{{Cite journal |last1=Dasenbrock |first1=Johannes |last2=Simpson |first2=Thomas J. |date=1987-01-01 |title=Alternariol is not biosynthesised via norlichexanthone |url=https://pubs.rsc.org/en/content/articlelanding/1987/c3/c39870001235 |journal=Journal of the Chemical Society, Chemical Communications |language=en |issue=16 |pages=1235–1236 |doi=10.1039/C39870001235 |issn=0022-4936}}

The initial step in griseofulvin biosynthesis involves the formation of the intermediate 2-(2,4-dihydroxy-6-methylbenzoyl)benzene-1,3,5-triol. This occurs via a holo-[acyl-carrier protein]-bound metabolite undergoing C8-C13 aldol condensation and C1-C6 Claisen-type cyclization. The enzyme responsible, norlichexanthone synthase, catalyses the formation of this compound only when the downstream genes in the pathway are present. Otherwise, the reaction leads to the spontaneous release of water, resulting in the formation of norlichexanthone.{{Cite web |title=MetaCyc griseofulvin biosynthesis |url=http://vm-trypanocyc.toulouse.inra.fr/META/NEW-IMAGE?type=PATHWAY&object=PWY-7653&detail-level=2 |access-date=2025-03-13 |website=vm-trypanocyc.toulouse.inra.fr}}

2-(2,4-dihydroxy-6-methylbenzoyl)benzene-1,3,5-triol → norlichexanthone + H₂O

Besides the chemical reactions that norlichexanthone can undergo, the molecule itself can set in motion different biological processes within different cell types and organisms. A variety of mechanisms of action have been identified in differing levels of detail.

One such mechanism of action involves the effect of norlichexanthone in preventing postmenopausal osteoporosis. It was found that norlichexanthone functions as a natural ligand for the estrogen receptor-alpha (ERα). Through this interaction, norlichexanthone can inhibit osteoclast formation. This process happens by interfering with the receptor activator of the nuclear factor-kappa B ligand signaling pathway (RANKL). Under normal conditions, RANKL binds to RANK, leading to TRAF6 auto-ubiquitination, induced by an interaction between TRAF6 and ERα. This process eventually leads to the transcription of NFATc1, leading to osteoclast differentiation. However, when norlichexanthone is present, it binds to ERα, making it impossible to interact with TRAF6 and thus inhibiting the ubiquitination of TRAF6, leading to RANKL signaling inhibition.

A different mechanism of action influenced by norlichexanthone that does not affect human cells but can be used for their protection against viruses is the expression of RNAIII and thus virulence gene expression in S. aureus. Due to a direct interaction of norlichexanthone with ArgA, the ability of ArgA to bind with the P2-P3 promotor region on the locus of the arg gene is blocked. This means that the transcription of arg, and thus translation of its important product RNAIII is reduced. Simultaneously, this leads to a reduction in virulence factors controlled by RNAIII.{{Cite journal |last1=Gupta |first1=Ravi Kr. |last2=Luong |first2=Thanh T. |last3=Lee |first3=Chia Y. |date=2015-11-10 |title=RNAIII of the Staphylococcus aureus agr system activates global regulator MgrA by stabilizing mRNA |journal=Proceedings of the National Academy of Sciences |volume=112 |issue=45 |pages=14036–14041 |bibcode=2015PNAS..11214036G |doi=10.1073/pnas.1509251112 |pmc=4653210 |pmid=26504242 |doi-access=free}}

However, norlichexanthone can also be dangerous for human cells due to its cytotoxic properties. They have been specifically demonstrated in the HepG2 cells. In these cells, norlichexanthone increased apoptosis by activating the degradation of poly (ADP-ribose) polymerase (PARP) and activation of caspase 3 via cleavage.{{Cite journal |last1=Ming |first1=Qianliang |last2=Li |first2=Yunong |last3=Jiang |first3=Xiuxing |last4=Huang |first4=Xiuning |last5=He |first5=Yimo |last6=Qin |first6=Lingyue |last7=Liu |first7=Yanxia |last8=Tang |first8=Yu |last9=Gao |first9=Ning |date=2022-03-01 |title=Xanthones and benzophenones isolated from the endophytic fungus Penicillium sp. ct-28 of Corydlis tomentella and their cytotoxic activity |url=https://www.sciencedirect.com/science/article/abs/pii/S0367326X22000053 |journal=Fitoterapia |volume=157 |pages=105127 |doi=10.1016/j.fitote.2022.105127 |issn=0367-326X |pmid=35033607}} These two processes contribute to apoptosis via different pathways. PARP degradation leads to the formation of PAR. The formation of this molecule causes a mitochondrial release of apoptosis-inducing factor (AIF), which will then be translocated to the nucleus. This will lead to apoptosis due to DNA fragmentation and condensation of chromatin induced by AIF.{{Cite journal |last1=Yu |first1=Seong-Woon |last2=Andrabi |first2=Shaida A. |last3=Wang |first3=Hongmin |last4=Kim |first4=No Soo |last5=Poirier |first5=Guy G. |last6=Dawson |first6=Ted M. |last7=Dawson |first7=Valina L. |date=2006-11-28 |title=Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell death |journal=Proceedings of the National Academy of Sciences |volume=103 |issue=48 |pages=18314–18319 |bibcode=2006PNAS..10318314Y |doi=10.1073/pnas.0606528103 |pmc=1838748 |pmid=17116881 |doi-access=free}} Caspase 3 activation, on the other hand, causes apoptosis by cleaving crucial proteins involved in cellular repair processes.{{Cite journal |last1=Silva |first1=Fábio França Vieira e |last2=Padín-Iruegas |first2=María Elena |last3=Caponio |first3=Vito Carlo Alberto |last4=Lorenzo-Pouso |first4=Alejandro I. |last5=Saavedra-Nieves |first5=Paula |last6=Chamorro-Petronacci |first6=Cintia Micaela |last7=Suaréz-Peñaranda |first7=José |last8=Pérez-Sayáns |first8=Mario |date=January 2022 |title=Caspase 3 and Cleaved Caspase 3 Expression in Tumorogenesis and Its Correlations with Prognosis in Head and Neck Cancer: A Systematic Review and Meta-Analysis |journal=International Journal of Molecular Sciences |language=en |volume=23 |issue=19 |pages=11937 |doi=10.3390/ijms231911937 |issn=1422-0067 |pmc=9569947 |pmid=36233242 |doi-access=free}}

The final possible danger for humans is the suspected ability of norlichexanthone to inhibit aromatase/CYP19A1, an important enzyme involved in estrogen synthesis. A computational study showed that norlichexanthone can bind effectively to CYP19A1 and inhibit its function along the steroid production pathway. However, these results have not yet been confirmed by either in vitro or in vivo studies. Thus, it cannot be said with complete certainty whether this inhibition will occur.{{Cite journal |last1=Singh |first1=Anamika |last2=Tiwari |first2=Nikita |last3=Mishra |first3=Anil |last4=Gupta |first4=Monika |date=2023-11-01 |title=DFT study and docking of xanthone derivatives indicating their ability to inhibit aromatase, a crucial enzyme for the steroid biosynthesis pathway |url=https://www.sciencedirect.com/science/article/abs/pii/S2468111323000300 |journal=Computational Toxicology |volume=28 |pages=100289 |bibcode=2023CmTox..2800289S |doi=10.1016/j.comtox.2023.100289 |issn=2468-1113}}

There have currently been no metabolic studies of norlichexanthone itself, but there is enough information for a likely metabolic pathway for low concentrations of norlichexanthone. Metabolism is split into phases: phase 1 generally makes polar functional groups available, but because norlichexanthone already has 3 hydroxy groups, it is likely to skip this step. Phase 2 makes molecules more hydrophilic so they can be excreted more easily by adding hydrophilic groups to the molecule.{{Citation |last1=Phang-Lyn |first1=Simone |title=Biochemistry, Biotransformation |date=2025 |work=StatPearls |url=https://www.ncbi.nlm.nih.gov/books/NBK544353/ |access-date=2025-03-13 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=31335073 |last2=Llerena |first2=Valerie A.}} Norlichexanthone is likely to be glucuronidated or sulphonated before it is excreted as this is also what has been found to happen in vivo with phenol, which is a hydroxyl group connected to benzene, and in vitro with α-Mangostin, which is also a hydroxylated xanthone.{{Cite web |title=Phenol: toxicological overview |url=https://www.gov.uk/government/publications/phenol-properties-incident-management-and-toxicology/phenol-toxicological-overview |access-date=2025-03-13 |website=GOV.UK |language=en}}{{Cite journal |last1=Gutierrez-Orozco |first1=Fabiola |last2=Chitchumroonchokchai |first2=Chureeporn |last3=Lesinski |first3=Gregory B. |last4=Suksamrarn |first4=Sunit |last5=Failla |first5=Mark L. |date=2013-04-24 |title=α-Mangostin: Anti-Inflammatory Activity and Metabolism by Human Cells |journal=Journal of Agricultural and Food Chemistry |volume=61 |issue=16 |pages=3891–3900 |bibcode=2013JAFC...61.3891G |doi=10.1021/jf4004434 |issn=0021-8561 |pmc=3793015 |pmid=23578285}}

Studies have highlighted the potential of norlichexanthone in preventing postmenopausal osteoporosis and its broader therapeutic applications. Research indicates that norlichexanthone functions as a ligand for estrogen receptor-alpha (ERα), selectively modulating its activity. This modulation leads to the inhibition of RANKL signaling, a key pathway in osteoclast differentiation and bone resorption. By suppressing excessive bone breakdown, norlichexanthone effectively mitigates bone loss associated with postmenopausal osteoporosis.

Beyond its role in bone health, norlichexanthone has demonstrated notable antimicrobial properties. Studies involving Staphylococcus aureus, including methicillin-resistant strains (MRSA), revealed that norlichexanthone suppresses the expression of key virulence genes and inhibits biofilm formation. Since biofilm production plays a significant role in antibiotic resistance and persistent infections, these findings suggest that norlichexanthone could serve as an effective antivirulence agent.

Additionally, norlichexanthone has exhibited antioxidant activity. Isolated from endolichenic fungi, it has been shown to scavenge free radicals and reduce oxidative stress at levels comparable to ascorbic acid.

As of now, there is limited information regarding the side effects of norlichexanthone. Most studies have been conducted in vitro, and comprehensive toxicity profiles have not yet been established. Further research, including animal and clinical trials, is necessary to determine the safety and potential adverse effects of norlichexanthone in humans.{{cn}}

Norlichexanthone has been found to be cytotoxic to a number of tumour cell lines.{{cn}}

Table 2: IC₅₀ (µM) values for norlichexanthone cytotoxicity of different cell lines.

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