In situ ring contraction and transformation of the rhizoxin macrocycle through an abiotic pathway

Adam C. Carter, Cora L. Petersen, Karen L. Wendt, Sara K. Helff, April L Risinger, Susan L Mooberry, Robert H. Cichewicz

Research output: Contribution to journalArticle

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 3 J HH 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 languageEnglish (US)
JournalJournal of Natural Products
DOIs
StatePublished - Jan 1 2019

ASJC Scopus subject areas

  • Analytical Chemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine
  • Organic Chemistry

Fingerprint Dive into the research topics of 'In situ ring contraction and transformation of the rhizoxin macrocycle through an abiotic pathway'. Together they form a unique fingerprint.

  • Cite this