Rhizoxin

Rhizoxin

Identifiers
CAS Number	90996-54-6
ChEMBL	ChEMBL379989
Jmol interactive 3D	Image
PubChem	11969567
SMILES O=C1C[C@@](C[C@H]3[C@H]2O3)([H])C[C@@]([C@H](C)/C=C/[C@@H](O4)[C@]4(C)[C@@H](O)C[C@]([C@H](C)[C@@H](OC)/C(C)=C/C=C/C(C)=C/C5=COC(C)=N5)([H])OC2=O)([H])O1
Properties
Chemical formula	C35H47NO9
Molar mass	625.749 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Rhizoxin is an antimitotic agent with anti-tumor activity.^[1][2] It is isolated from a pathogenic plant fungus (Rhizopus microsporus) which causes rice seedling blight.

Biosynthesis

Rhizoxin is biosynthesised by Burkholderia rhizoxinica, a bacterial endosymbiont of the fungus Rhizopus microsporus.^[3] It is one of a large group of rhizoxin-like compounds produced by the bacteria.^[4] The bacterial endosymbiont 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.^[5]

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.^[6] The function of rhizoxin is similar to Vinca alkaloids.

Rhizoxin has undergone clinical trials as an anti-cancer drug^[7] although it did not reach later stages of clinical trials due to low activity in vivo. Related compounds to rhizoxin may have improved biological activity.^[4]

Structure

Rhizoxin is a 16-membered lactone ring connected to an oxazole ring by a long unsaturated chain.^[8]

References

1. Tsuro, T.; et al. (1986). "Rhizoxin, a macrocyclic lactone antibiotic, as a new antitumor agent against human and murine tumor cells and their vincristine resistant sublines". Cancer Res. 46 (1): 381–385. PMID 3753552.
2. Ikubo, S., et al., (1999). "In vitro evaluation of antimicrotubule agents in human small-cell lung cancer cell lines". Anticancer Res. 19 (5B): 3985–3988. PMID 10628341.
3. Laila, P. & Hertweck, C. (2005). "Pathogenic fungus harbours endosymbiotic bacteria for toxin production". Nature 437 (7060): 884–888. doi:10.1038/nature03997. PMID 16208371.
4. Scherlach, K., Partida-Martinez, L.P., Dahse, H.M. & Hertweck, C. (2006). "Antimitotic Rhizoxin Derivatives from a Cultured Bacterial Endosymbiont of the Rice Pathogenic Fungus Rhizopus microsporus". J. Am. Chem. Soc. 128 (35): 11529–11536. doi:10.1021/ja062953o. PMID 16939276.
5. Mitchell, I.S.; et al. (2005). "A total synthesis of the antitumour macrolide rhizoxin D". Org. Biomol. Chem. 24 (24): 4412–31. doi:10.1039/b507570j. PMID 16327903.
6. Takahashi, M.; et al. (1987). "Studies on macrocyclic lactone antibiotics. XI. Anti-mitotic and anti-tubulin activity of new antitumor antibiotics, rhizoxin and its homologues". J. Antibiot. 40 (1): 66–72. doi:10.7164/antibiotics.40.66. PMID 3606749. Erratum in J. Antibiot. (Tokyo)., 40 (4), following 565. (1987).
7. McLeod, H.L.; et al. (1996). "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. PMC 2074819. PMID 8980394.
8. Iwasaki, S., et al., (1984). "Studies on macrocyclic lactone antibiotics. VII. Structure of a phytotoxin "rhizoxin" produced by Rhizopus chinensis". J. Antibiot. (Tokyo) 37 (4): 354–62. doi:10.7164/antibiotics.37.354.