21859-98-3Relevant articles and documents
GenoChemetic Strategy for Derivatization of the Violacein Natural Product Scaffold
Lai, Hung-En,Obled, Alan M. C.,Chee, Soo Mei,Morgan, Rhodri M.,Lynch, Rosemary,Sharma, Sunil V.,Moore, Simon J.,Polizzi, Karen M.,Goss, Rebecca J. M.,Freemont, Paul S.
, p. 2116 - 2123 (2021/11/03)
Natural products and their analogues are often challenging to synthesize due to their complex scaffolds and embedded functional groups. Solely relying on engineering the biosynthesis of natural products may lead to limited compound diversity. Integrating synthetic biology with synthetic chemistry allows rapid access to much more diverse portfolios of xenobiotic compounds, which may accelerate the discovery of new therapeutics. As a proof-of-concept, by supplementing an Escherichia coli strain expressing the violacein biosynthesis pathway with 5-bromo-tryptophan in vitro or tryptophan 7-halogenase RebH in vivo, six halogenated analogues of violacein or deoxyviolacein were generated, demonstrating the promiscuity of the violacein biosynthesis pathway. Furthermore, 20 new derivatives were generated from 5-brominated violacein analogues via the Suzuki-Miyaura cross-coupling reaction directly using the crude extract without prior purification. Herein we demonstrate a flexible and rapid approach to access a diverse chemical space that can be applied to a wide range of natural product scaffolds.
Structure-Activity Relationship Refinement and Further Assessment of Indole-3-glyoxylamides as a Lead Series against Prion Disease
Thompson, Mark J.,Louth, Jennifer C.,Ferrara, Steven,Sorrell, Fiona J.,Irving, Benjamin J.,Cochrane, Edward J.,Meijer, Anthony J. H. M.,Chen, Beining
, p. 115 - 130 (2013/01/09)
Structure-activity relationships within the indole-3-glyoxylamide series of antiprion agents have been explored further, resulting in discovery of several new compounds demonstrating excellent activity in a cell line model of prion disease (EC50 10 nM). After examining a range of substituents at the para-position of the N-phenylglyoxylamide moiety, five-membered heterocycles containing at least two heteroatoms were found to be optimal for the antiprion effect. A number of modifications were made to probe the importance of the glyoxylamide substructure, although none were well tolerated. The most potent compounds did, however, prove largely stable towards microsomal metabolism, and the most active library member cured scrapie-infected cells indefinitely on administration of a single treatment. The present results thereby confirm the indole-3-glyoxylamides as a promising lead series for continuing in vitro and in vivo evaluation against prion disease.Making mad cows a myth! The indole-3-glyoxylamide series of antiprion agents has been further optimised, and characteristics contributing to their activity have been identified by computational studies. Varying the glyoxylamide motif or introducing substitution at N-1 gave analogues with lower efficacy.
