Abstract
A Rhizopus sp. culture containing an endosymbiont partner (Burkholderia sp.) was obtained through a citizen-science-based soil-collection program. An extract prepared from the pair of organisms exhibited strong inhibition of Ewing sarcoma cells and was selected for bioassay-guided fractionation. This led to the purification of rhizoxin (1), a potent antimitotic agent that inhibited microtubule polymerization, along with several new (2-5) and known (6) analogues of 1. The structures of 2-6 were established using a combination of NMR data analysis, while the configurations of the new stereocenters were determined using ROESY spectroscopy and comparison of GIAO-derived and experimental data for NMR chemical shift and 3JHH coupling values. Whereas compound 1 showed modest selectivity for Ewing sarcoma cell lines carrying the EWSR1/FLI1 fusion gene, the other compounds were determined to be inactive. Chemically, compound 2 stands out from other rhizoxin analogues because it is the first member of this class that is reported to contain a one-carbon-smaller 15-membered macrolactone system. Through a combination of experimental and computational tests, we determined that 2 is likely formed via an acid-catalyzed Meinwald rearrangement from 1 because of the mild acidic culture environment created by the Rhizopus sp. isolate and its symbiont.
Original language | English (US) |
---|---|
Pages (from-to) | 886-894 |
Number of pages | 9 |
Journal | Journal of Natural Products |
Volume | 82 |
Issue number | 4 |
DOIs | |
State | Published - Apr 26 2019 |
ASJC Scopus subject areas
- Analytical Chemistry
- Molecular Medicine
- Pharmacology
- Pharmaceutical Science
- Drug Discovery
- Complementary and alternative medicine
- Organic Chemistry