Antiproliferative Effects of Ester- and Amide-Functionalized Rhizoxin Derivatives

摘要

The 16-membered macrolide rhizoxin (1, Figure 1) is a highly potent antiproliferative agent that destabilizes microtubules by binding to the β-tubulin subunit and thus inhibits mitosis.It was first isolated from the rice seedling blight fungus Rhizopus chinensis, where it has been implicated as virulence factor. Due to its potential as an antitumor therapeutic, 1 was evaluated in phase I and II clinical trials. However, in vivo hydrolysis of the epoxide moieties of 1 is likely to be the reason for its short elimination half-life. In the course of biosynthetic studies we discovered that rhizoxin (1) is not produced by the fungus but by the bacterial endosymbiont Burkholderia rhizox-inica, which lives within the fungal cytosol. We found that the endosymbiont uses a giant PKS-NRPS assembly line to produce the more stable 2,3-desepoxy derivatives such as rhizoxin S2 (2) and methyl ester M2 (3). Furthermore, in endosymbiont fermentations rhizoxins are produced in notably higher amounts. We have shown that semisynthetic methyl esters inhibit tubulin polymerization and display significantly stronger antiproliferative effects against K-562 cells than 1.