Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 52, Issue 8, Pages 2515-2530Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm801661m
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Funding
- National Institutes of Health [CA112314-01]
- GIcNAc and GaINAc synthesis and evaluation [AR054005-01]
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This study investigates the breadth of cellular responses engendered by short chain fatty acid (SCFA)-hexosamine hybrid molecules, a class of compounds long used in metabolic glycoengineering that are now emerging as drug candidates. First, a mix and match strategy showed that different SCFA (n-butyrate and acetate) appended to the same core sugar altered biological activity, complementing previous results [Campbell et al. J. Med. Chem. 2008, 51, 8135-8147] where a single type of SCFA elicited distinct responses. Microarray profiling then compared transcriptional responses engendered by regioisomerically modified ManNAc, GlcNAc, and GalNAc analogues in MDA-MB-231 cells. These data, which were validated by qRT-PCR or Western analysis for IDI, TP53, HPSE, NQO1, EGR1, and VEGFA, showed a two-pronged response where a core set of genes was coordinately regulated by all analogues while each analogue simultaneously uniquely regulated a larger number of genes. Finally, AutoDock modeling supported a mechanism where the analogues directly interact with elements of the NF-kappa B pathway. Together, these results establish the SCFA-hexosamine template as a versatile platform for modulating biological activity and developing new therapeutics.
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