Hexosamine Template. A Platform for Modulating Gene Expression and for Sugar-Based Drug Discovery
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-...
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| Veröffentlicht in: | Journal of medicinal chemistry 2009-04, Vol.52 (8), p.2515-2530 |
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| container_title | Journal of medicinal chemistry |
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| creator | Elmouelhi, Noha Aich, Udayanath Paruchuri, Venkata D. P Meledeo, M. Adam Campbell, Christopher T Wang, Jean J Srinivas, Raja Khanna, Hargun S Yarema, Kevin J |
| description | 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. |
| doi_str_mv | 10.1021/jm801661m |
| format | Article |
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A Platform for Modulating Gene Expression and for Sugar-Based Drug Discovery</title><source>MEDLINE</source><source>American Chemical Society Journals</source><creator>Elmouelhi, Noha ; Aich, Udayanath ; Paruchuri, Venkata D. P ; Meledeo, M. Adam ; Campbell, Christopher T ; Wang, Jean J ; Srinivas, Raja ; Khanna, Hargun S ; Yarema, Kevin J</creator><creatorcontrib>Elmouelhi, Noha ; Aich, Udayanath ; Paruchuri, Venkata D. P ; Meledeo, M. Adam ; Campbell, Christopher T ; Wang, Jean J ; Srinivas, Raja ; Khanna, Hargun S ; Yarema, Kevin J</creatorcontrib><description>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.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm801661m</identifier><identifier>PMID: 19326913</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Acylation ; Apoptosis ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Drug Discovery ; Early Growth Response Protein 1 - biosynthesis ; Early Growth Response Protein 1 - genetics ; Fatty Acids, Volatile - chemical synthesis ; Fatty Acids, Volatile - chemistry ; Fatty Acids, Volatile - pharmacology ; Gene Expression - drug effects ; Gene Expression Profiling ; Glucuronidase - biosynthesis ; Glucuronidase - genetics ; Hexosamines - chemical synthesis ; Hexosamines - chemistry ; Hexosamines - pharmacology ; Humans ; Models, Molecular ; Mucin-1 - biosynthesis ; N-Acetylneuraminic Acid - biosynthesis ; NF-kappa B - biosynthesis ; NF-kappa B - genetics ; Oligonucleotide Array Sequence Analysis ; Oncogenes ; Signal Transduction ; Structure-Activity Relationship ; Transcription, Genetic ; Tumor Suppressor Protein p53 - biosynthesis ; Tumor Suppressor Protein p53 - genetics</subject><ispartof>Journal of medicinal chemistry, 2009-04, Vol.52 (8), p.2515-2530</ispartof><rights>Copyright © 2009 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a403t-303059034aeb3fef20ab963157507477d70c883c11e9178a8540b4ec2a02e7e3</citedby><cites>FETCH-LOGICAL-a403t-303059034aeb3fef20ab963157507477d70c883c11e9178a8540b4ec2a02e7e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm801661m$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm801661m$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,776,780,881,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19326913$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Elmouelhi, Noha</creatorcontrib><creatorcontrib>Aich, Udayanath</creatorcontrib><creatorcontrib>Paruchuri, Venkata D. P</creatorcontrib><creatorcontrib>Meledeo, M. Adam</creatorcontrib><creatorcontrib>Campbell, Christopher T</creatorcontrib><creatorcontrib>Wang, Jean J</creatorcontrib><creatorcontrib>Srinivas, Raja</creatorcontrib><creatorcontrib>Khanna, Hargun S</creatorcontrib><creatorcontrib>Yarema, Kevin J</creatorcontrib><title>Hexosamine Template. A Platform for Modulating Gene Expression and for Sugar-Based Drug Discovery</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>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.</description><subject>Acylation</subject><subject>Apoptosis</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Drug Discovery</subject><subject>Early Growth Response Protein 1 - biosynthesis</subject><subject>Early Growth Response Protein 1 - genetics</subject><subject>Fatty Acids, Volatile - chemical synthesis</subject><subject>Fatty Acids, Volatile - chemistry</subject><subject>Fatty Acids, Volatile - pharmacology</subject><subject>Gene Expression - drug effects</subject><subject>Gene Expression Profiling</subject><subject>Glucuronidase - biosynthesis</subject><subject>Glucuronidase - genetics</subject><subject>Hexosamines - chemical synthesis</subject><subject>Hexosamines - chemistry</subject><subject>Hexosamines - pharmacology</subject><subject>Humans</subject><subject>Models, Molecular</subject><subject>Mucin-1 - biosynthesis</subject><subject>N-Acetylneuraminic Acid - biosynthesis</subject><subject>NF-kappa B - biosynthesis</subject><subject>NF-kappa B - genetics</subject><subject>Oligonucleotide Array Sequence Analysis</subject><subject>Oncogenes</subject><subject>Signal Transduction</subject><subject>Structure-Activity Relationship</subject><subject>Transcription, Genetic</subject><subject>Tumor Suppressor Protein p53 - biosynthesis</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkE1PwkAQhjdGI4ge_ANmLx48FGd32257MUFAMMFoIvdm206xhHabXUrg37sKQU28zEfmmXcyLyHXDPoMOLtfVhGwMGTVCemygIPnR-Cfki4A5x4PueiQC2uXACAYF-ekw2LBw5iJLlFT3GqrqrJGOseqWak19umAvrmi0KaiLtAXnbeuL-sFnaADx9vGoLWlrqmq82_kvV0o4z0qizkdmXZBR6XN9AbN7pKcFWpl8eqQe2T-NJ4Pp97sdfI8HMw85YNYewIEBDEIX2EqCiw4qDQOBQtkANKXMpeQRZHIGMOYyUhFgQ-pjxlXwFGi6JGHvWzTphXmGdZro1ZJY8pKmV2iVZn8ndTlR7LQm4RLztwVJ3C3F8iMttZgcdxlkHzZnBxtduzN72M_5MFXB9zuAZXZZKlbU7vX_xH6BHVUhK4</recordid><startdate>20090423</startdate><enddate>20090423</enddate><creator>Elmouelhi, Noha</creator><creator>Aich, Udayanath</creator><creator>Paruchuri, Venkata D. P</creator><creator>Meledeo, M. Adam</creator><creator>Campbell, Christopher T</creator><creator>Wang, Jean J</creator><creator>Srinivas, Raja</creator><creator>Khanna, Hargun S</creator><creator>Yarema, Kevin J</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>20090423</creationdate><title>Hexosamine Template. A Platform for Modulating Gene Expression and for Sugar-Based Drug Discovery</title><author>Elmouelhi, Noha ; Aich, Udayanath ; Paruchuri, Venkata D. P ; Meledeo, M. Adam ; Campbell, Christopher T ; Wang, Jean J ; Srinivas, Raja ; Khanna, Hargun S ; Yarema, Kevin J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a403t-303059034aeb3fef20ab963157507477d70c883c11e9178a8540b4ec2a02e7e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Acylation</topic><topic>Apoptosis</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Drug Discovery</topic><topic>Early Growth Response Protein 1 - biosynthesis</topic><topic>Early Growth Response Protein 1 - genetics</topic><topic>Fatty Acids, Volatile - chemical synthesis</topic><topic>Fatty Acids, Volatile - chemistry</topic><topic>Fatty Acids, Volatile - pharmacology</topic><topic>Gene Expression - drug effects</topic><topic>Gene Expression Profiling</topic><topic>Glucuronidase - biosynthesis</topic><topic>Glucuronidase - genetics</topic><topic>Hexosamines - chemical synthesis</topic><topic>Hexosamines - chemistry</topic><topic>Hexosamines - pharmacology</topic><topic>Humans</topic><topic>Models, Molecular</topic><topic>Mucin-1 - biosynthesis</topic><topic>N-Acetylneuraminic Acid - biosynthesis</topic><topic>NF-kappa B - biosynthesis</topic><topic>NF-kappa B - genetics</topic><topic>Oligonucleotide Array Sequence Analysis</topic><topic>Oncogenes</topic><topic>Signal Transduction</topic><topic>Structure-Activity Relationship</topic><topic>Transcription, Genetic</topic><topic>Tumor Suppressor Protein p53 - biosynthesis</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Elmouelhi, Noha</creatorcontrib><creatorcontrib>Aich, Udayanath</creatorcontrib><creatorcontrib>Paruchuri, Venkata D. P</creatorcontrib><creatorcontrib>Meledeo, M. Adam</creatorcontrib><creatorcontrib>Campbell, Christopher T</creatorcontrib><creatorcontrib>Wang, Jean J</creatorcontrib><creatorcontrib>Srinivas, Raja</creatorcontrib><creatorcontrib>Khanna, Hargun S</creatorcontrib><creatorcontrib>Yarema, Kevin J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Elmouelhi, Noha</au><au>Aich, Udayanath</au><au>Paruchuri, Venkata D. P</au><au>Meledeo, M. Adam</au><au>Campbell, Christopher T</au><au>Wang, Jean J</au><au>Srinivas, Raja</au><au>Khanna, Hargun S</au><au>Yarema, Kevin J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hexosamine Template. A Platform for Modulating Gene Expression and for Sugar-Based Drug Discovery</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2009-04-23</date><risdate>2009</risdate><volume>52</volume><issue>8</issue><spage>2515</spage><epage>2530</epage><pages>2515-2530</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>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.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>19326913</pmid><doi>10.1021/jm801661m</doi><tpages>16</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2009-04, Vol.52 (8), p.2515-2530 |
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| source | MEDLINE; American Chemical Society Journals |
| subjects | Acylation Apoptosis Cell Line, Tumor Cell Proliferation - drug effects Drug Discovery Early Growth Response Protein 1 - biosynthesis Early Growth Response Protein 1 - genetics Fatty Acids, Volatile - chemical synthesis Fatty Acids, Volatile - chemistry Fatty Acids, Volatile - pharmacology Gene Expression - drug effects Gene Expression Profiling Glucuronidase - biosynthesis Glucuronidase - genetics Hexosamines - chemical synthesis Hexosamines - chemistry Hexosamines - pharmacology Humans Models, Molecular Mucin-1 - biosynthesis N-Acetylneuraminic Acid - biosynthesis NF-kappa B - biosynthesis NF-kappa B - genetics Oligonucleotide Array Sequence Analysis Oncogenes Signal Transduction Structure-Activity Relationship Transcription, Genetic Tumor Suppressor Protein p53 - biosynthesis Tumor Suppressor Protein p53 - genetics |
| title | Hexosamine Template. A Platform for Modulating Gene Expression and for Sugar-Based Drug Discovery |
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