Rhizoxin

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.

Rhizoxin
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
UNII
  • InChI=1S/C35H47NO9/c1-19(13-25-18-41-23(5)36-25)9-8-10-21(3)32(40-7)22(4)27-17-29(37)35(6)30(45-35)12-11-20(2)26-14-24(16-31(38)42-26)15-28-33(43-28)34(39)44-27/h8-13,18,20,22,24,26-30,32-33,37H,14-17H2,1-7H3/b9-8+,12-11+,19-13+,21-10+/t20-,22+,24+,26-,27+,28+,29+,30-,32+,33-,35-/m1/s1
    Key: OWPCHSCAPHNHAV-QIPOKPRISA-N
  • 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
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

Biosynthesis

Rhizoxin is biosynthesised by Paraburkholderia 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. Tsuruo T, Oh-hara T, Iida H, Tsukagoshi S, Sato Z, Matsuda I, et al. (January 1986). "Rhizoxin, a macrocyclic lactone antibiotic, as a new antitumor agent against human and murine tumor cells and their vincristine-resistant sublines". Cancer Research. 46 (1): 381–385. PMID 3753552.
  2. Ikubo S, Takigawa N, Ueoka H, Kiura K, Tabata M, Shibayama T, et al. (1999). "In vitro evaluation of antimicrotubule agents in human small-cell lung cancer cell lines". Anticancer Research. 19 (5B): 3985–8. PMID 10628341.
  3. Partida-Martinez LP, Hertweck C (October 2005). "Pathogenic fungus harbours endosymbiotic bacteria for toxin production". Nature. 437 (7060): 884–8. Bibcode:2005Natur.437..884P. doi:10.1038/nature03997. PMID 16208371. S2CID 4416437.
  4. Scherlach K, Partida-Martinez LP, Dahse HM, Hertweck C (September 2006). "Antimitotic rhizoxin derivatives from a cultured bacterial endosymbiont of the rice pathogenic fungus Rhizopus microsporus". Journal of the American Chemical Society. 128 (35): 11529–36. 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. 3 (24): 4412–31. doi:10.1039/b507570j. PMID 16327903.
  6. Takahashi M, Iwasaki S, Kobayashi H, Okuda S, Murai T, Sato Y, et al. (January 1987). "Studies on macrocyclic lactone antibiotics. XI. Anti-mitotic and anti-tubulin activity of new antitumor antibiotics, rhizoxin and its homologues". The Journal of Antibiotics. 40 (1): 66–72. doi:10.7164/antibiotics.40.66. PMID 3606749.Erratum in J. Antibiot. (Tokyo)., 40 (4), following 565. (1987)
  7. McLeod HL, Murray LS, Wanders J, Setanoians A, Graham MA, Pavlidis N, et al. (December 1996). "Multicentre phase II pharmacological evaluation of rhizoxin. Eortc early clinical studies (ECSG)/pharmacology and molecular mechanisms (PAMM) groups". British Journal of Cancer. 74 (12): 1944–8. doi:10.1038/bjc.1996.657. PMC 2074819. PMID 8980394.
  8. Iwasaki S, Kobayashi H, Furukawa J, Namikoshi M, Okuda S, Sato Z, et al. (April 1984). "Studies on macrocyclic lactone antibiotics. VII. Structure of a phytotoxin "rhizoxin" produced by Rhizopus chinensis". The Journal of Antibiotics. 37 (4): 354–62. doi:10.7164/antibiotics.37.354. PMID 6547134.
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