Protocetraric acid

Protocetraric acid
Names
	IUPAC name 10-Formyl-3,9-dihydroxy-4-(hydroxymethyl)-1,7-dimethyl-6-oxobenzo[b][1,4]benzodioxepine-2-carboxylic acid
Identifiers
CAS Number	489-51-0 ;
3D model (JSmol)	Interactive image;
ChEBI	CHEBI:144203;
ChemSpider	4590164;
EC Number	111-888-5;
PubChem CID	5489486;
CompTox Dashboard (EPA)	DTXSID70197633 ;
	InChI InChI=1S/C18H14O9/c1-6-3-10(21)8(4-19)15-11(6)18(25)27-16-9(5-20)13(22)12(17(23)24)7(2)14(16)26-15/h3-4,20-22H,5H2,1-2H3,(H,23,24) Key: VOXMONAUSQZPTP-UHFFFAOYSA-N;
	SMILES CC1=CC(=C(C2=C1C(=O)OC3=C(O2)C(=C(C(=C3CO)O)C(=O)O)C)C=O)O;
Properties
Chemical formula	C18H14O9
Molar mass	374.301 g·mol−1
Hazards
	GHS labelling:[1]
Pictograms
Signal word	Warning
Hazard statements	H317
Precautionary statements	P261, P272, P280, P302+P352, P321, P333+P317, P362+P364, P501
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Infobox references

Protocetraric acid is a chemical compound with the molecular formula C₁₈H₁₄O₉. It is a secondary metabolite produced by a variety of lichens and is classified as a depsidone.

History

In 1845 Knop and Schnedermann isolated crystalline cetraric acid from the lichen Cetraria islandica. O. Hesse proposed that cetraric acid does not exist in the lichen, but is rather the decomposition product of another acid that he called protocetraric acid, which is split up into fumaric and cetraric acids. In reviewing Hesse's work. O. Simon confirmed the statements of Knop and Schnedermann, finding cetraric acid in the plant in a free state. O. Simon did not find the protocetraric acid proposed by Hesse, but instead used that name for another acid he isolated.^[1]

Protocetraric acid was first described in the 1930s.^[2]^[3]

Rao and colleagues published the ultraviolet and infrared spectra of some lichen depsidones, including protocetraric acid, in 1967.^[4]

Properties

The molecular formula of protocetraric acid is C₁₈H₁₄O₉; it has a molecular mass of 374.29 grams per mole. In its purified crystalline form, it exists as short needles with a melting point range of 245–250 °C (473–482 °F). Its ultraviolet spectrum has three peaks of maximum absorption (λ_max) at 210, 238, and 312 nm. Its infrared spectrum has several peaks: 680, 745, 785, 814, 840, 990, 1020, 1080, 1115, 1150, 1190, 1270, 1380, 1440, 1562, 1642, 1738, 3000, and 3500 cm⁻¹.^[5] A number of ester derivatives of protocetraric acid, such as succinprotocetraric acid and fumarprotocetraric acid, have also been identified in lichens.

Preliminary research has been conducted into the potential pharmacology of protocetraric acid and related compounds. Protocetraric acid has broad spectrum antimicrobial properties against some pathogenic microbes such as Salmonella typhi.^[6] It also has weak activity against SARS-CoV-2 3C-like protease (K_i of 3.95 μM), as does the related depsidone salazinic acid, and therefore it is being studied as a scaffold for the potential discovery of more potent drugs for the treatment of COVID-19.^[7]

Biological activities

Laboratory experiments indicate that protocetraric acid has broad spectrum antimicrobial activity against some pathogenic microbes, including antibacterial activity against Salmonella typhi, and antifungal activity against Trichophyton rubrum.^[8] It also has moderate antimycobacterial activity on the growth of Mycobacterium tuberculosis.^[9]

Eponyms

Some authors have explicitly named protocetraric acid in the specific epithets of their published lichen species, thereby acknowledging the presence of this compound as an important taxonomic characteristic. These eponyms are listed here, followed by their author citation and year of publication.

Usnea hossei var. protocetrarica G.N.Stevens (1999)^[10]
Hypotrachyna protocetrarica Elix, T.H.Nash & Sipman (2009)
Karoowia protocetrarica Hale (1989)^[11]
Myriotrema protocetraricum (Hale) Hale (1980)
Ocellularia protocetrarica Hale (1978)^[12]
Opegrapha protocetrarica Seavey & J.Seavey (2014)^[13]
Oropogon protocetraricus S.D.Leav. & Essl. (2013)^[14]
Xanthoparmelia protocetrarica (Hale) G.Amo, A.Crespo, Elix & Lumbsch (2010)

Several derivatives of protocetraric acid were designed and synthesised using Diels-Alder reaction, esterification, and Friedel-Crafts alkylation of protocetraric acid with different reagents under Lewis acid. The products were tested for their α-Glucosidase inhibitory using molecular docking analysis.^[15]

Related compounds

The related chemical 9'-(O-methyl)protocetraric acid was isolated from the lichen Cladonia convoluta.^[16] Conhypoprotocetraric acid, identified from lichens Relicina cf. incongrua and Lecanora myriocarpoides, was synthesized and characterized in 1995.^[17]

Confumarprotocetraric acid^[5]
Conhyopoprotocetraric acid^[18]
Conprotocetraric acid^[19]
Consuccinprotocetraric acid^[20]
Fumarprotocetraric acid^[21]
Hypoprotocetraric acid^[22]
Malonprotocetraric acid^[23]
4-0-Methylhypoprotocetraric acid^[24]
Succinprotocetraric acid^[25]

References

^ Simon, O. (1902). "Ueber Cetrarsäure". Archiv der Pharmazie (in German). 240 (7). Wiley: 521–560. doi:10.1002/ardp.19022400705.
^ Asahina, Yasuhiko; Yanagita, Masaiti (1933). "Lichen substances. XXX. Capraric acid". Berichte der Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen. 66B: 1217–1220. doi:10.1002/cber.19330660910.
^ Asahina, Yasuhiko; Tanase, Yaichiro (1934). "Lichen substances. XXXVIII. Protocetraric acid and its alkyl ethers". Berichte der Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen. 67B: 766–773. doi:10.1002/cber.19340670514.
^ Rao, P.S.; Sarma, K.G.; Seshadri, T.R (1967). "The ultraviolet and infrared spectra of some lichen depsides and depsidones" (PDF). Proceedings of the Indian Academy of Sciences – Section A. 66: 1–14. doi:10.1007/BF03049404.
^ ^a ^b Huneck 1996, p. 317.
^ Nishanth, Kumar S.; Sreerag, R.S.; Deepa, I.; Mohandas, C.; Nambisan, Bala (2015). "Protocetraric acid: An excellent broad spectrum compound from the lichen Usnea albopunctata against medically important microbes". Natural Product Research. 29 (6): 574–577. doi:10.1080/14786419.2014.953500. PMID 25174415.
^ Fagnani, Lorenza; Nazzicone, Lisaurora; Bellio, Pierangelo; Franceschini, Nicola; Tondi, Donatella; Verri, Andrea; Petricca, Sabrina; Iorio, Roberto; Amicosante, Gianfranco; Perilli, Mariagrazia; Celenza, Giuseppe (2022). "Protocetraric and Salazinic Acids as Potential Inhibitors of SARS-CoV-2 3CL Protease: Biochemical, Cytotoxic, and Computational Characterization of Depsidones as Slow-Binding Inactivators". Pharmaceuticals. 15 (6): 714. doi:10.3390/ph15060714. PMC 9227325. PMID 35745633.
^ Nishanth, Kumar S.; Sreerag, R.S.; Deepa, I.; Mohandas, C.; Nambisan, Bala (2014). "Protocetraric acid: an excellent broad spectrum compound from the lichen Usnea albopunctata against medically important microbes". Natural Product Research. 29 (6): 574–577. doi:10.1080/14786419.2014.953500. PMID 25174415.
^ Honda, N.K.; Pavan, F.R.; Coelho, R.G.; de Andrade Leite, S.R.; Micheletti, A.C.; Lopes, T.I.B.; Misutsu, M.Y.; Beatriz, A.; Brum, R.L.; Leite, C.Q.F. (2010). "Antimycobacterial activity of lichen substances". Phytomedicine. 17 (5): 328–332. doi:10.1016/j.phymed.2009.07.018. PMID 19683421.
^ Stevens, G.N. (1999). "A Revision of the lichen family Usneaceae in Australia". Bibliotheca Lichenologica. 72: 50.
^ Hale, M.E. (1989). "A monograph of the lichen genus Karoowia Hale". Mycotaxon. 35 (1): 177–198.
^ Hale, M.E. (1978). A revision of the lichen family Thelotremataceae in Panama. Smithsonian Contributions to Botany. Vol. 38. p. 28.
^ Seavey, Frederick; Seavey, Jean; Hernández M., Jesus E.; Lücking, Robert (2014). "Three new Opegraphaspecies (Roccellaceae, Arthoniales) and several additions to the North American lichen mycota from Everglades National Park". The Bryologist. 117 (1): 62–71. doi:10.1639/0007-2745-117.1.062.
^ Leavitt, Steven D.; Esslinger, Theodore L.; Nelsen, Matthew P.; Lumbsch, H. Thorsten (2013). "Further species diversity in neotropical Oropogon (Lecanoromycetes: Parmeliaceae) in Central America". The Lichenologist. 45 (4): 553–564. Bibcode:2013ThLic..45..553L. doi:10.1017/s0024282913000212.
^ Nguyen, Huu-Hung; Duong, Thuc-Huy; Nguyen, Tran-Van-Anh; Do, Thanh-Hung; Pham, Duc-Dung; Nguyen, Ngoc-Hong; Nguyen, Huy Truong (2023). "α-Glucosidase inhibitory derivatives of protocetraric acid". Natural Product Research. 37 (12): 1935–1946. doi:10.1080/14786419.2022.2110093. PMID 35968760.
^ Bézivin, Carine; Tomasi, Sophie; Rouaud, Isabelle; Delcros, Jean-Guy; Boustie, Joël (2004). "Cytotoxic activity of compounds from the lichen: Cladonia convoluta". Planta Medica (in German). 70 (9): 874–877. doi:10.1055/s-2004-827240. PMID 15386197.
^ Elix, John A.; Lumbsch, H. Thorsten; Wardlaw, Judith H. (1995). "Conhypoprotocetraric acid, a new lichen β-orcinol depsidone". Australian Journal of Chemistry. 48 (8): 1479. doi:10.1071/ch9951479.
^ Huneck 1996, p. 318.
^ Huneck 1996, p. 319.
^ Huneck 1996, p. 320.
^ Huneck 1996, p. 327.
^ Huneck 1996, p. 331.
^ Huneck 1996, p. 336.
^ Huneck 1996, p. 339.
^ Huneck 1996, pp. 350–351.

Cited literature

Huneck, Siegfried (1996). Identification of Lichen Substances. Berlin, Heidelberg: Springer Berlin Heidelberg. ISBN 978-3-642-85245-9. OCLC 851387266.

[Simon_1902-1] Simon, O. (1902). "Ueber Cetrarsäure". Archiv der Pharmazie (in German). 240 (7). Wiley: 521–560. doi:10.1002/ardp.19022400705.

[2] Asahina, Yasuhiko; Yanagita, Masaiti (1933). "Lichen substances. XXX. Capraric acid". Berichte der Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen. 66B: 1217–1220. doi:10.1002/cber.19330660910.

[3] Asahina, Yasuhiko; Tanase, Yaichiro (1934). "Lichen substances. XXXVIII. Protocetraric acid and its alkyl ethers". Berichte der Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen. 67B: 766–773. doi:10.1002/cber.19340670514.

[Rao_et_al._1967-4] Rao, P.S.; Sarma, K.G.; Seshadri, T.R (1967). "The ultraviolet and infrared spectra of some lichen depsides and depsidones" (PDF). Proceedings of the Indian Academy of Sciences – Section A. 66: 1–14. doi:10.1007/BF03049404.

[FOOTNOTEHuneck1996317-5] Huneck 1996, p. 317.

[6] Nishanth, Kumar S.; Sreerag, R.S.; Deepa, I.; Mohandas, C.; Nambisan, Bala (2015). "Protocetraric acid: An excellent broad spectrum compound from the lichen Usnea albopunctata against medically important microbes". Natural Product Research. 29 (6): 574–577. doi:10.1080/14786419.2014.953500. PMID 25174415.

[7] Fagnani, Lorenza; Nazzicone, Lisaurora; Bellio, Pierangelo; Franceschini, Nicola; Tondi, Donatella; Verri, Andrea; Petricca, Sabrina; Iorio, Roberto; Amicosante, Gianfranco; Perilli, Mariagrazia; Celenza, Giuseppe (2022). "Protocetraric and Salazinic Acids as Potential Inhibitors of SARS-CoV-2 3CL Protease: Biochemical, Cytotoxic, and Computational Characterization of Depsidones as Slow-Binding Inactivators". Pharmaceuticals. 15 (6): 714. doi:10.3390/ph15060714. PMC 9227325. PMID 35745633.

[Nishanth_et_al._2014-8] Nishanth, Kumar S.; Sreerag, R.S.; Deepa, I.; Mohandas, C.; Nambisan, Bala (2014). "Protocetraric acid: an excellent broad spectrum compound from the lichen Usnea albopunctata against medically important microbes". Natural Product Research. 29 (6): 574–577. doi:10.1080/14786419.2014.953500. PMID 25174415.

[Honda_et_al._2010-9] Honda, N.K.; Pavan, F.R.; Coelho, R.G.; de Andrade Leite, S.R.; Micheletti, A.C.; Lopes, T.I.B.; Misutsu, M.Y.; Beatriz, A.; Brum, R.L.; Leite, C.Q.F. (2010). "Antimycobacterial activity of lichen substances". Phytomedicine. 17 (5): 328–332. doi:10.1016/j.phymed.2009.07.018. PMID 19683421.

[Stevens_1999-10] Stevens, G.N. (1999). "A Revision of the lichen family Usneaceae in Australia". Bibliotheca Lichenologica. 72: 50.

[Hale_1989-11] Hale, M.E. (1989). "A monograph of the lichen genus Karoowia Hale". Mycotaxon. 35 (1): 177–198.

[Hale_1978-12] Hale, M.E. (1978). A revision of the lichen family Thelotremataceae in Panama. Smithsonian Contributions to Botany. Vol. 38. p. 28.

[Seavey_et_al._2014-13] Seavey, Frederick; Seavey, Jean; Hernández M., Jesus E.; Lücking, Robert (2014). "Three new Opegraphaspecies (Roccellaceae, Arthoniales) and several additions to the North American lichen mycota from Everglades National Park". The Bryologist. 117 (1): 62–71. doi:10.1639/0007-2745-117.1.062.

[Leavitt_et_al._2013-14] Leavitt, Steven D.; Esslinger, Theodore L.; Nelsen, Matthew P.; Lumbsch, H. Thorsten (2013). "Further species diversity in neotropical Oropogon (Lecanoromycetes: Parmeliaceae) in Central America". The Lichenologist. 45 (4): 553–564. Bibcode:2013ThLic..45..553L. doi:10.1017/s0024282913000212.

[Nguyen_et_al._2022-15] Nguyen, Huu-Hung; Duong, Thuc-Huy; Nguyen, Tran-Van-Anh; Do, Thanh-Hung; Pham, Duc-Dung; Nguyen, Ngoc-Hong; Nguyen, Huy Truong (2023). "α-Glucosidase inhibitory derivatives of protocetraric acid". Natural Product Research. 37 (12): 1935–1946. doi:10.1080/14786419.2022.2110093. PMID 35968760.

[Bézivinet_al._2004-16] Bézivin, Carine; Tomasi, Sophie; Rouaud, Isabelle; Delcros, Jean-Guy; Boustie, Joël (2004). "Cytotoxic activity of compounds from the lichen: Cladonia convoluta". Planta Medica (in German). 70 (9): 874–877. doi:10.1055/s-2004-827240. PMID 15386197.

[Elix_et_al._1995-17] Elix, John A.; Lumbsch, H. Thorsten; Wardlaw, Judith H. (1995). "Conhypoprotocetraric acid, a new lichen β-orcinol depsidone". Australian Journal of Chemistry. 48 (8): 1479. doi:10.1071/ch9951479.

[FOOTNOTEHuneck1996318-18] Huneck 1996, p. 318.

[FOOTNOTEHuneck1996319-19] Huneck 1996, p. 319.

[FOOTNOTEHuneck1996320-20] Huneck 1996, p. 320.

[FOOTNOTEHuneck1996327-21] Huneck 1996, p. 327.

[FOOTNOTEHuneck1996331-22] Huneck 1996, p. 331.

[FOOTNOTEHuneck1996336-23] Huneck 1996, p. 336.

[FOOTNOTEHuneck1996339-24] Huneck 1996, p. 339.

[FOOTNOTEHuneck1996350–351-25] Huneck 1996, pp. 350–351.

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