In Situ Ring Contraction and Transformation of the Rhizoxin Macrocycle through an Abiotic Pathway.
J Nat Prod
; 82(4): 886-894, 2019 04 26.
Article
em En
| MEDLINE
| ID: mdl-30865445
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 JHH 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Estresse Fisiológico
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Macrolídeos
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Compostos Macrocíclicos
Limite:
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article