Rhizoxin

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ImageFile = Rhizoxin.svg
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CASNo = 90996-54-6
PubChem = 11969567
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Formula = C₃₅H₄₇NO₉
MolarMass = 625.749 g/mol
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Rhizoxin is an antimitotic agent with anti-tumor activity. [Tsuro, T., "et al"., "Rhizoxin, a macrocyclic lactone antibiotic, as a new antitumor agent against human and murine tumor cells and their vincristine resistant sublines". Cancer Res., 46, 381-385 (1986).] [Ikubo, S., "et al"., "In vitro evaluation of antimicrotubule agents in human small-cell lung cancer cell lines". Anticancer Res., 19, 3985-3988 (1999).] It is isolated from a pathogenic plant fungus ("Rhizopus microsporus") which causes rice seedling blight.

Biosynthesis

Rhizoxin is biosynthesised by "Burkholderia rhizoxina", an endosymbiotic bacteria of the fungus "Rhizopus microsporus". [Laila, P., "et al"., "Pathogenic fungus harbours endosymbiotic bacteria for toxin production"., Nature 437, 884-888., (2005).] It is one of a large group of rhizoxin-like compounds produced by the bacteria.Scherlach, K., "et al"., "Antimitotic Rhizoxin Derivatives from a Cultured Bacterial Endosymbiont of the Rice Pathogenic Fungus Rhizopus microsporus". J. Am. Chem. Soc. 128 (35) 11529 - 11536., (2006).] The bacterial endosymbiote can be grown independently in culture. This may allow easy harvesting of rhizoxin and the related compounds avoiding total chemical synthesis, although total chemical synthesis is possible [Mitchell, I.S., "et al"., "A total synthesis of the antitumour macrolide rhizoxin D". Org. Biomol. Chem. 24 4412-31 (2005).] .

Cytotoxic function

Rhizoxin binds beta tubulin in eukaryotic cells disrupting microtubule formation. This, in turn, prevents formation of the mitotic spindle inhibiting cell division. Additionally rhizoxin can depolymerise assembled microtubules. [Takahashi, M., "et al"., "Studies on macrocyclic lactone antibiotics. XI. Anti-mitotic and anti-tubulin activity of new antitumor antibiotics, rhizoxin and its homologues." J. Antibiot. (Tokyo)., 40 (1), 66-72. (1987). Erratum in J. Antibiot. (Tokyo)., 40 (4), following 565. (1987).] The function of rhizoxin is similar to "Vinca" alkaloids.

Rhizoxin has undergone clinical trials as an anti-cancer drug [McLeod, H.L., "et al"., "Multicentre phase II pharmacological evaluation of rhizoxin. Eortc early clinical studies (ECSG)/pharmacology and molecular mechanisms (PAMM) groups"., Br. J. Cancer. 74 (12) 1944-8., (1996).] although, unfortunately, did not reach later stages of clinical trials due to low activity "in vivo". Related compounds to rhizoxin may have improved biological activity.

tructure

Rhizoxin is a 16-member lactone ring connected to an oxazole ring by a long unsaturated chain. [Iwasaki, S., "et al"., "Studies on macrocyclic lactone antibiotics. VII. Structure of a phytotoxin "rhizoxin" produced by Rhizopus chinensis."J. Antibiot. (Tokyo). 37 (4), 354-62 (1984).]

References