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{{orphan|date=August 2009}} |
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| ImageFile = Botrydial.png |
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| verifiedrevid = 403359608 |
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| ImageFile = Avarol.png |
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| PIN = (1''R'',2''S'',4''a''S'',8''a''S'')-1,2,4''a'',5-tetramethyl-2,3,4,7,8,8''a''-hexahydronaphthalen-1-yl]methyl]benzene-1,4-diol |
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| IUPACName = [(1S,3aR,4S,6R,7S,7aS)-1,7-diformyl-7a-hydroxy-1,3,3,6-tetramethyl-2,3a, |
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4,5,6,7-hexahydroinden-4-yl] acetate |
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| Section1 = {{Chembox Identifiers |
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|Section1={{Chembox Identifiers |
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| CASNo = 54986-75-3 |
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| CASNo = 55303-98-5 |
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| PubChem = 185781 |
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| EINECS = 611-252-1 |
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| UNII = KZX416VN2B |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL = 476877 |
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| PubChem = 72185 |
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| SMILES = |
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| ChEMBL = 459814 |
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| ChemSpiderID = 65156 |
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| SMILES = C1CC2((1(C)CC3=C(C=CC(=C3)O)O)CCC=C2C)C |
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| Section2 = {{Chembox Properties |
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|Section2={{Chembox Properties |
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| Formula = C<sub>17</sub>H<sub>26</sub>O<sub>5</sub> |
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| Formula = C<sub>21</sub>H<sub>30</sub>O<sub>2</sub> |
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| MolarMass = 310.38534 g/mol |
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| MolarMass = 314.22458 g/mol |
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'''Avarol''' is a ] first isolated from the Mediterranean ] Dysidea avara 1974 <ref>Tetrahedron Letters No. 38, pp 3401 - 3404, 1974</ref> Avarol represented the first ] with a rearranged ] skeleton and its structure was established by standard analytical methods, chemical degradation and later by ]. Intrigued by the wide range of biological activities of this ], Avarol has inspired the development of many synthetic derivatives and the study of their applications. |
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'''Botrydial''' is a ] ] ] secreted by the fungus ]. Botrydial was first isolated and described in 1974<ref>Lindner, H.J.; von Groose, B. Chem. Ber. 1974, 107, 3332-3336</ref>. Botrytis Cinerea is the causal agents of gray mold disease and is known to attack a wide range of plants (over 200 species) producing leaf-spot diseases and mildews on lettuces and tomatoes as well as rotting berries<ref>Collado, I.G.; Hernandez-Galan, R.; Duran-Patron, R.; Cantoral, J.M. Phytochemistry. 1995, 38, 647-650</ref>. For this reason botrydial, as well as other Botrytis Cinerea originated sesquiterpene metabolites, represent a economically important disease for ornamental and agriculturally important crops<ref>(a) Williamson, B.; Tudzynski, B.; Tudzynski, P.; van Kan, J. A. Mol. Plant Pathol. 2007, 8, 561–580. (b) Choquer, M.; Fournier, E.; Kunz, C.; Levis, C.; Pradier, J. M.; Simon, A.; Viaud, M. FEMS Microbiol. Lett. 2007, 277, 1–10</ref>. From all the metabolites produced by this fungus, Botrydial exhibits the highest phytotoxic activity.<ref>Colmenares, A. J.; Aleu, J., Duran-Patron, R.; Collado, I. G.; Hernandez-Galan, R. J. Chem. Ecol. 2002, 28, 997-1005</ref> |
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==Biological activity== |
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== Biosynthesis == |
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Botrydial originates from the BcBOT2 ('''B'''otrytis'''c'''inerea '''BOT'''rydial biosynthesis) mediated cyclization of farnesyl diphosphate (FPP) to key intermdiate tricyclic alcohol presilphiperfolan-8β-ol. Pinedo et al. demonstrated that BcBOT2 is in fact a sesquiterpene synthase by incubation of FPP with recombinant BcBOT2 protein, which yielded the expected presilphiperfolan-8-ol as the major product. ] |
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Avarol has exhibited a wide range of biological activities, including: antitumor, antimicrobial, antiviral, etc. Proven both in vitro and in vivo, at a concentration of 3.5 μg/mL, avarol inhibited at 71% ] cancer cell growth of cells derived from a patient with primary and metastatic malignant glioblastoma tumour.<ref>Molecules. 2006 Jan; 11(1): 1–33</ref> It was reported that avarol can penetrate the blood–brain barrier while showing a low ] on rat brain synaptosomes.<ref>Andjus RK, Ćirković T, Marjanović M, Gašić MJ, Dogović N, Sladić D. 1986. Synaptosome inhibition by cytostatically and/or antibiotically active substances of marine invertebrate origin; modeling of dose-response patterns. Period Biol. 88:99–101.</ref> Colon HT-29 tumour cells were also sensitive towards this organic compound (IC50 < 7 mM).<ref>Boris Pejin, Carmine Iodice, Vesna Kojic, Dimitar Jakimov, Milica Lazovic & Giuseppina Tommonaro (2016) In vitro evaluation of cytotoxic and mutagenic activity of avarol, Natural Product Research, 30:11, 1293-1296</ref> so further studies on avarol scaffolds may contribute to development of new drug-like molecules targeting human colon tumour. |
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4 other genes are then involved in the biosynthesis of botrydial: 3 genes that encode for a P450 monooxygenase (BcBOT3, BcBOT1,BcBOT4) and a BcBOT5 gene whose amino acid sequence showed high homology to known acetyl transferases. ] This brought Pinedo et al. to the conclusion that BcBOT5 is probably responsible for introducing the acetyl group on C-4. They also concluded from quantitative reverse transcription-PCR (qRT-PCR) analysis that the five consecutive genes are co-regulated by the same BCG1-calcineurim transduction pathway.<ref name="Pinedo, C. 2008">Pinedo, C.; Wang, C. M.; Pradier, J. M.; Dalmais, B.; Choquer, M.; Le Pecheur, P.; Morgant, G.; Collado, I. G.; Cane, D. E.; Viaud, M. ACS Chem. Biol. 2008, 3, 791-801.</ref> |
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Antibacterial activity of avarol on four selected pathogenic bacteria associated with psoriasis exhibited moderate activity where minimum inhibitory and minimum bactericidal concentrations ranged from 0.78-1.56 and 3.12-18.75 μg/mL, respectively. It also proved to be more effective against '']'' in comparison to both positive controls applied, ] and ].<ref>Asian Journal of Chemistry; Vol. 26, No. 23 (2014), 8255-8256</ref> |
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== Mechanism of enzymatic formation of presilphiperfolan-8β-ol == |
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Recently in an ASAP article in The Journal of the American Chemistry Society, Cane et al. confirmed experimentally, using deuterium labeling and NMR spectroscopy, the mechanism by which FPP cyclizes into presilphiperfolan-8β-ol. The mechanism consist of elimination of the diphosphate group followed by carbocation mediated cyclizations and rearrangements.<ref>Wang, C.; Hopson, R.; Lin, X.; Cane, D.E. J. Am. Chem. Soc. 2009, ASAP, doi:10.1021/ja9021649</ref> |
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It was found to inhibit various activities of the human immunodeficiency virus (HIV). Avarol completely blocks the synthesis of glutamine transfer tRNA, which is crucial for synthesis of a viral protease required for the virus’ proliferation.<ref>Sagar, S.; Kaur, M.; Minneman, K. P. Antiviral Lead Compounds from Marine Sponges. Marine Drugs 2010, 8 (10), 2619–2638</ref> This compound also inhibits other important biological targets including the virus’ reverse transcriptase and the inhibition of cyclooxygenase and 5′-lipoxygenase.<ref>Gordaliza, M. Cytotoxic Terpene Quinones from Marine Sponges. Marine Drugs 2010, 8 (12), 2849–2870</ref> Avarol’s potent activity, low toxicity and its ability to cross the blood-brain barrier makes this compound an optimum candidate for structural transformations aimed at improving its antiviral activity.<ref>Sladic, D.; Gasic, M. Reactivity and Biological Activity of the Marine Sesquiterpene Hydroquinone Avarol and Related Compounds from Sponges of the Order Dictyoceratida. Molecules 2006, 11 (1), 1–33</ref> |
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==Biosynthesis== |
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After the formation of presilphiperfolan-8β-ol, BcBOT5 gives way to acetylation of C-4 position, then hydroxilation of the probotryane skeleton occurs in a two-step process followed by oxidative cleavage of the new formed diol to yield botrydial.<ref>Duran-Patron, R.; Colmenares, A.J.; Hernandez-Galan, R.; Collado, I.G. Tetrahedron. 2001, 57, 1929-1933</ref> |
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Terpenoid hydrocarbons, like the ones seen in Avarol's structure, are biosynthesised by the coupling of isoprene units in the form of isopentenyl pyrophosphate (IPP) to give polyenyl pyrophosphates. These are then transformed to the terpenes by terpene synthases. Coupling of two IPP molecules gives geranyl pyrophosphate (GPP) which is the precursor to all monoterpenes and the addition of another isoprene unit to gives farnesyl pyrophosphate (FPP), from which all sesquiterpenes are derived.<ref>Org. Biomol. Chem., 2005, |
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3, 57–64</ref> The cyclization of farnesyl pyrophosphate (FPP) takes place by an initial electrophilic attack at the head position of FPP giving rise to a concerted process leading to a bicyclic carbocationic intermediate from which the final products, drimane or 4,9-friedodrimane structural types are formed <ref>Molecules 2006, 11, 1–33</ref> |
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== Mechanism of action == |
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== References == |
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Botrydial is produced by Botrytis Cinerea when the host plant is infected. As a result, botrydial induces chlorosis and cell collapse.<ref>Deighton, N.; Muckenschnabel, I.; Colmenares, A. J., Collado, I. G.; Williamson, B. Phytochemistry 2001 57, 689-692</ref> Additionally, aggressive strains of the fungus secrets polyketides such as botcinic acid that exhibit phytotoxic and antifungal activity.<ref name="Pinedo, C. 2008"/> |
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== Notes == |
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