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 journalArticlepeer-review

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 languageEnglish (US)
Pages (from-to)886-894
Number of pages9
JournalJournal of Natural Products
Volume82
Issue number4
DOIs
StatePublished - Apr 26 2019

ASJC Scopus subject areas

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

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