Betaenone B

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Betaenone B
250px
Systematic (IUPAC) name
[ IUPAC: (2S,3R,4R,4aS,5R,7R,8aS)-3-sec-butyl-2,7-dihydroxy-4-(3-hydroxypropanoyl)-2,4,5,7-tetramethyloctahydronaphthalen-1(2H)-one
Pharmacokinetic data
Excretion ~
Identifiers
CAS Number 85269-23-4
ATC code none
PubChem CID 158750
Chemical data
Formula C21H36O5
Molar mass 368.26 g/mol[[Script error: No such module "String".]]
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Betaenone B (as well as Betaenone A and C) is a secondary metabolite isolated from the fungus Phoma betae Frank.[1] Its phytotoxic properties have been shown to cause sugar beet leaf spots[1][2][3] , which is characterized by black, pcynidia containing, concentric circles eventually leading to necrosis of the leaf tissue[4]. Of the seven phytotoxins isolated in fungal leaf spots from sugar beet (Beta vulgaris l.), betaenone B showed the least amount of phytotoxicity showing only 8% inhibition of growth while betaenone A and C showed 73% and 89% growth inhibition, respectively[5]. Betaenone B is therefore not considered toxic to the plant, but will produce leaf spots when present in high concentrations (0.33 µg/µL)[5]. While the mechanism of action of betaenone B has yet to be elucidaed, betaenone C has been shown to inhibit RNA and protein synthesis[5]. Most of the major work on betaenone B, including the initial structure elucidation of Betaenone A, B and C as well as the partial elucidation mechanism of biosynthesis, was presented in three short papers published between 1983-88 by Sadao Sakamura et al.[1][2][3]. Recently, two novel betaenones were isolated from the marine sponge Aplysina aerophoba by Brauers et al.[6] Following isolation, the authors tested the compounds for protein inhibition and found they inhibited a variety of protein kinases signifying a possible role in cancer treatment.[7]

File:Betaenone leaf.jpg
Phoma betae Frank induced leaf spots on a sugar beet plant. The dark concentric circles contain pcynidia (fungal spores) and eventually will cause necrosis of the leaf tissue.

Molecular structures of betaenone A, B and C.

The structure of betaenone B was determined via NMR, CD and ORD measurements by Ichihara et al.[1] While they also showed that that betaenone B could be converted to betaenone A by oxidation by PCC followed by exposure to base,[1] it wasn't until 1988 that a semi-complete total synthesis was also reported by Pratt and Hopkins.[8] Using 1,3-butadiene as a starting material, they were able to achieve a stereoselective synthesis of (+/-)-4-De(3'-hydroxypropionyl) betanenone B in a 24 step synthesis. Bioactivity of this synthetic product was not tested and no further work on total synthesis of betaenones have been published since.

Biosynthesis

Very little work has been done to elucidate the biosynthetic pathways of betaenones with almost no literature references published on the subject since 1988. Their low phytotoxicity and lack of biological significance in human physiology has provoked a fairly small amount of interest in these compounds. The backbone carbon units of betaenone B are known to be synthesized via the polyketide synthesis (PKS) pathway. The backbone is synthesized through the addition of two carbon units via addition of acetate units from acetyl-CoA.[2] The 5 methyl groups are added via S-adenosyl methionine (SAM) methylation, as opposed to incorporation of propionate (instead of acetate) to the growing compound during biosynthesis.[2] The following internal cyclization proceeds through a Diels-Alder mechanism catalyzed by an unknown enzyme. The origin of the subsequent oxidations at positions 1, 2 and 8 have yet to be characterized, but they have been shown not to originate from acetate.[3] It has been theorized that cytochrome P-450 is responsible for the oxidation at these three positions since its inhibition produces probetaenone 1, the non-oxidized form of betaenone B.

While a complete de novo synthesis of Betaenone B has yet to be reported, Daniel Pratt and Paul Hopkins in 1988 proposed a method for synthesizing a precursor of Betaenone B from methoxybenzoquinone and 1,3-butadiene via Diels-Alder and Claisen chemistry.[8]

Biosynthesis of betaenone B as proposed by Oikawa et al.

References

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  1. ↑ 1.0 1.1 1.2 1.3 1.4 Ichihara A.; Oikawa, Hideaki; Hayashi, Kazuko; Sakamura, Sadao; Furusaki, Akio; Matsumoto, Takeshi (1983). "Structures of Betaenones A and B, Novel Phytotoxins from Phoma betae Fr". J. Am. Chem. Soc. 105: 2907–2908. doi:10.1021/ja00347a070. 
  2. ↑ 2.0 2.1 2.2 2.3 Oikawa H. (1984). "Biosynthesis of Betaenone B, Phytotoxins of Phoma betae Fr". J. Chem. Soc. Chem. Commun.: 814–815.  line feed character in |journal= at position 20 (help)
  3. ↑ 3.0 3.1 3.2 Oikawa H. (1988). "Biosynthetic Study of Betaenone B: Origin of the Oxygen Atoms and Accumulation of Deoxygenated Intermediate using P-450 Inhibitor". J. Chem. Soc. Chem. Commun.: 600–602. 
  4. ↑ Afonin, A.N. (2008). "Interactive Agricultural Ecological Atlas of Russia and Neighboring Countries. Economic Plants and their Diseases, Pests and Weeds Online". 
  5. ↑ 5.0 5.1 5.2 Haraguchi, T.; Oguro, Mieko; Nagano, Hiroshi; Ichihara, Akitami; Sakamura, Sadao (1983). "Specific inhibitors of eukaryotic DNA synthesis and DNA polymerase α, 3-deoxyaphidicolin and aphidicolin-17-monoacetate". Nucleic Acid Res. 11: 1197–2000. doi:10.1093/nar/11.4.1197. 
  6. ↑ Brauers, G. (2000). "Anthraquinones and Betaenone Derivatives from the Sponge-Associated Fungus Microsphaeropsis Species: Novel Inhibitors of Protein Kinases". Journal of Natural Products. 93: 739–745. 
  7. ↑ Patrick, D.; Heimbrook, D (1996). "Protein kinase inhibitors for the treatment of cancer". Drug Discovery Today. 1: 325–330. doi:10.1016/1359-6446(96)10030-1. 
  8. ↑ 8.0 8.1 Pratt, D.; Hopkins, Paul B. (1988). "Synthesis of (.+-.)-4-De(3-hydroxypropionyl)betaenone B, an advanced model for the betaenones and stamphyloxin I". The Journal of Organic Chemistry. 53: 5885–5894. doi:10.1021/jo00260a017. 
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