Hexosamine Template. A Platform for Modulating Gene Expression and for Sugar-Based Drug Discovery

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• 作者：Noha Elmouelhi ; Udayanath Aich ; Venkata D. P. Paruchuri ; M. Adam Meledeo ; Christopher T. Campbell ; Jean J. Wang ; Raja Srinivas ; Hargun S. Khanna ; Kevin J. Yarema
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：April 23, 2009
• 年：2009
• 卷：52
• 期：8
• 页码：2515-2530
• 全文大小：848K
• 年卷期：v.52,no.8(April 23, 2009)
• ISSN：1520-4804

文摘

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 ID1, 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-κB pathway. Together, these results establish the SCFA−hexosamine template as a versatile platform for modulating biological activity and developing new therapeutics.