Rhizoxin Explained

Rhizoxin is an antimitotic agent with anti-tumor activity.^{[1] [2]} It is isolated from the fungus Rhizopus microsporus which causes rice seedling blight.

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 have improved biological activity (E.G Mertansine) .

Structure

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

Notes and References

1. Tsuruo T, Oh-hara T, Iida H, Tsukagoshi S, Sato Z, Matsuda I, Iwasaki S, Okuda S, Shimizu F, Sasagawa K. 6 . 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 . January 1986 . 3753552 .
2. Ikubo S, Takigawa N, Ueoka H, Kiura K, Tabata M, Shibayama T, Chikamori M, Aoe K, Matsushita A, Harada M . 6. In vitro evaluation of antimicrotubule agents in human small-cell lung cancer cell lines . Anticancer Research . 19 . 5B . 3985–8 . 1999 . 10628341 .
3. Partida-Martinez LP, Hertweck C . Pathogenic fungus harbours endosymbiotic bacteria for toxin production . Nature . 437 . 7060 . 884–8 . October 2005 . 16208371 . 10.1038/nature03997 . 2005Natur.437..884P . 4416437 .
4. Scherlach K, Partida-Martinez LP, Dahse HM, Hertweck C . 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 . September 2006 . 16939276 . 10.1021/ja062953o .
5. Mitchell, I.S.. A total synthesis of the antitumour macrolide rhizoxin D . Org. Biomol. Chem. . 3 . 4412–31 . 2005 . 10.1039/b507570j . 16327903 . 24. etal.
6. Takahashi M, Iwasaki S, Kobayashi H, Okuda S, Murai T, Sato Y, Haraguchi-Hiraoka T, Nagano H . 6. 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 . January 1987 . 3606749 . 10.7164/antibiotics.40.66 . free. Erratum in J. Antibiot. (Tokyo)., 40 (4), following 565. (1987)
7. McLeod HL, Murray LS, Wanders J, Setanoians A, Graham MA, Pavlidis N, Heinrich B, ten Bokkel Huinink WW, Wagener DJ, Aamdal S, Verweij J . 6. 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 . December 1996 . 8980394 . 2074819 . 10.1038/bjc.1996.657 .
8. Iwasaki S, Kobayashi H, Furukawa J, Namikoshi M, Okuda S, Sato Z, Matsuda I, Noda T. 6 . Studies on macrocyclic lactone antibiotics. VII. Structure of a phytotoxin "rhizoxin" produced by Rhizopus chinensis . The Journal of Antibiotics . 37 . 4 . 354–62 . April 1984 . 6547134 . 10.7164/antibiotics.37.354 . free .