A novel HDAC inhibitor with a hydroxy-pyrimidine scaffold
Histone deacetylases (HDACs) are enzymes involved in many important biological functions. They have been linked to a variety of cancers, psychiatric disorders, and other diseases. Since small molecules can serve as probes to study the relevant biological roles of HDACs, novel scaffolds are necessary...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2011-07, Vol.21 (14), p.4164-4169 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Kemp, Melissa M. Wang, Qiu Fuller, Jason H. West, Nathan Martinez, Nicole M. Morse, Elizabeth M. Weïwer, Michel Schreiber, Stuart L. Bradner, James E. Koehler, Angela N. |
| description | Histone deacetylases (HDACs) are enzymes involved in many important biological functions. They have been linked to a variety of cancers, psychiatric disorders, and other diseases. Since small molecules can serve as probes to study the relevant biological roles of HDACs, novel scaffolds are necessary to develop more efficient, selective drug candidates. Screening libraries of molecules may yield structurally diverse probes that bind these enzymes and modulate their functions in cells. Here we report a small molecule with a novel hydroxy-pyrimidine scaffold that inhibits multiple HDAC enzymes and modulates acetylation levels in cells. Analogs were synthesized in an effort to evaluate structure–activity relationships. |
| doi_str_mv | 10.1016/j.bmcl.2011.05.098 |
| format | Article |
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They have been linked to a variety of cancers, psychiatric disorders, and other diseases. Since small molecules can serve as probes to study the relevant biological roles of HDACs, novel scaffolds are necessary to develop more efficient, selective drug candidates. Screening libraries of molecules may yield structurally diverse probes that bind these enzymes and modulate their functions in cells. Here we report a small molecule with a novel hydroxy-pyrimidine scaffold that inhibits multiple HDAC enzymes and modulates acetylation levels in cells. 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Drug treatments ; Pyrimidines - chemical synthesis ; Pyrimidines - chemistry ; Pyrimidines - pharmacology ; SAR studies ; screening ; Structure-Activity Relationship ; structure-activity relationships</subject><ispartof>Bioorganic & medicinal chemistry letters, 2011-07, Vol.21 (14), p.4164-4169</ispartof><rights>2011 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2011 Elsevier Ltd. All rights reserved.</rights><rights>2011 Elsevier Ltd. All rights reserved. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c540t-9aac8c7eecb5c60390cac7c22e8cd3d1d2208d001c35d9f13f37e090f79a036b3</citedby><cites>FETCH-LOGICAL-c540t-9aac8c7eecb5c60390cac7c22e8cd3d1d2208d001c35d9f13f37e090f79a036b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2011.05.098$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3548,27923,27924,45994</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24343606$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21696956$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kemp, Melissa M.</creatorcontrib><creatorcontrib>Wang, Qiu</creatorcontrib><creatorcontrib>Fuller, Jason H.</creatorcontrib><creatorcontrib>West, Nathan</creatorcontrib><creatorcontrib>Martinez, Nicole M.</creatorcontrib><creatorcontrib>Morse, Elizabeth M.</creatorcontrib><creatorcontrib>Weïwer, Michel</creatorcontrib><creatorcontrib>Schreiber, Stuart L.</creatorcontrib><creatorcontrib>Bradner, James E.</creatorcontrib><creatorcontrib>Koehler, Angela N.</creatorcontrib><title>A novel HDAC inhibitor with a hydroxy-pyrimidine scaffold</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Histone deacetylases (HDACs) are enzymes involved in many important biological functions. They have been linked to a variety of cancers, psychiatric disorders, and other diseases. Since small molecules can serve as probes to study the relevant biological roles of HDACs, novel scaffolds are necessary to develop more efficient, selective drug candidates. Screening libraries of molecules may yield structurally diverse probes that bind these enzymes and modulate their functions in cells. Here we report a small molecule with a novel hydroxy-pyrimidine scaffold that inhibits multiple HDAC enzymes and modulates acetylation levels in cells. Analogs were synthesized in an effort to evaluate structure–activity relationships.</description><subject>Acetylation</subject><subject>Analytical, structural and metabolic biochemistry</subject><subject>Biological and medical sciences</subject><subject>drugs</subject><subject>Enzymes and enzyme inhibitors</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Histone deacetylase</subject><subject>Histone Deacetylase Inhibitors - chemical synthesis</subject><subject>Histone Deacetylase Inhibitors - chemistry</subject><subject>Histone Deacetylase Inhibitors - pharmacology</subject><subject>Histone Deacetylases - chemistry</subject><subject>Histone Deacetylases - metabolism</subject><subject>Humans</subject><subject>Hydrolases</subject><subject>Hydroxy-pyrimidine</subject><subject>Medical sciences</subject><subject>Miscellaneous</subject><subject>neoplasms</subject><subject>Non-selective inhibitor</subject><subject>Pharmacology. Drug treatments</subject><subject>Pyrimidines - chemical synthesis</subject><subject>Pyrimidines - chemistry</subject><subject>Pyrimidines - pharmacology</subject><subject>SAR studies</subject><subject>screening</subject><subject>Structure-Activity Relationship</subject><subject>structure-activity relationships</subject><issn>0960-894X</issn><issn>1464-3405</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc2O0zAURi0EYsrAC7CAbBCrhOvYcWwJIVXlZ5BGYgEjsbOca2fqKo2LnRb69jhqGWADKy987ufP9xDylEJFgYpXm6rb4lDVQGkFTQVK3iMLygUvGYfmPlmAElBKxb9ekEcpbQAoB84fkouaCiVUIxZELYsxHNxQXL1drgo_rn3npxCL735aF6ZYH20MP47l7hj91ls_uiKh6fsw2MfkQW-G5J6cz0ty8_7dl9VVef3pw8fV8rrEhsNUKmNQYuscdg0KYArQYIt17SRaZqmta5A2V0PWWNVT1rPWgYK-VQaY6NgleXPK3e27rbPoximaQe9yIROPOhiv_74Z_VrfhoNmNZetbHPAy3NADN_2Lk166xO6YTCjC_ukpWS5lmT1_8mW50gKM1mfSIwhpej6uz4U9CxHb_QsR89yNDQ6y8lDz_78yd3ILxsZeHEGTN7y0Eczok-_Oc44EzBzz09cb4I2tzEzN5_zS01eI2tA8Ey8PhEumzl4F3VC70Z01keHk7bB_6vpTwd2tps</recordid><startdate>20110715</startdate><enddate>20110715</enddate><creator>Kemp, Melissa M.</creator><creator>Wang, Qiu</creator><creator>Fuller, Jason H.</creator><creator>West, Nathan</creator><creator>Martinez, Nicole M.</creator><creator>Morse, Elizabeth M.</creator><creator>Weïwer, Michel</creator><creator>Schreiber, Stuart L.</creator><creator>Bradner, James E.</creator><creator>Koehler, Angela N.</creator><general>Elsevier Ltd</general><general>Elsevier</general><scope>FBQ</scope><scope>IQODW</scope><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>7X8</scope><scope>7QO</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>5PM</scope></search><sort><creationdate>20110715</creationdate><title>A novel HDAC inhibitor with a hydroxy-pyrimidine scaffold</title><author>Kemp, Melissa M. ; Wang, Qiu ; Fuller, Jason H. ; West, Nathan ; Martinez, Nicole M. ; Morse, Elizabeth M. ; Weïwer, Michel ; Schreiber, Stuart L. ; Bradner, James E. ; Koehler, Angela N.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c540t-9aac8c7eecb5c60390cac7c22e8cd3d1d2208d001c35d9f13f37e090f79a036b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Acetylation</topic><topic>Analytical, structural and metabolic biochemistry</topic><topic>Biological and medical sciences</topic><topic>drugs</topic><topic>Enzymes and enzyme inhibitors</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Histone deacetylase</topic><topic>Histone Deacetylase Inhibitors - chemical synthesis</topic><topic>Histone Deacetylase Inhibitors - chemistry</topic><topic>Histone Deacetylase Inhibitors - pharmacology</topic><topic>Histone Deacetylases - chemistry</topic><topic>Histone Deacetylases - metabolism</topic><topic>Humans</topic><topic>Hydrolases</topic><topic>Hydroxy-pyrimidine</topic><topic>Medical sciences</topic><topic>Miscellaneous</topic><topic>neoplasms</topic><topic>Non-selective inhibitor</topic><topic>Pharmacology. 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| subjects | Acetylation Analytical, structural and metabolic biochemistry Biological and medical sciences drugs Enzymes and enzyme inhibitors Fundamental and applied biological sciences. Psychology Histone deacetylase Histone Deacetylase Inhibitors - chemical synthesis Histone Deacetylase Inhibitors - chemistry Histone Deacetylase Inhibitors - pharmacology Histone Deacetylases - chemistry Histone Deacetylases - metabolism Humans Hydrolases Hydroxy-pyrimidine Medical sciences Miscellaneous neoplasms Non-selective inhibitor Pharmacology. Drug treatments Pyrimidines - chemical synthesis Pyrimidines - chemistry Pyrimidines - pharmacology SAR studies screening Structure-Activity Relationship structure-activity relationships |
| title | A novel HDAC inhibitor with a hydroxy-pyrimidine scaffold |
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