Non-Peptide Macrocyclic Histone Deacetylase Inhibitors Derived from Tricyclic Ketolide Skeleton
Inhibition of histone deacetylase (HDAC) function is a validated therapeutic strategy for cancer treatment. Of the several structurally distinct small molecule histone deacetylase inhibitors (HDACi) reported, macrocyclic depsipeptides possess the most complex cap groups and have demonstrated excelle...
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| Veröffentlicht in: | Journal of medicinal chemistry 2010-08, Vol.53 (16), p.6100-6111 |
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| container_title | Journal of medicinal chemistry |
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| creator | Mwakwari, Sandra C Guerrant, William Patil, Vishal Khan, Shabana I Tekwani, Babu L Gurard-Levin, Zachary A Mrksich, Milan Oyelere, Adegboyega K |
| description | Inhibition of histone deacetylase (HDAC) function is a validated therapeutic strategy for cancer treatment. Of the several structurally distinct small molecule histone deacetylase inhibitors (HDACi) reported, macrocyclic depsipeptides possess the most complex cap groups and have demonstrated excellent HDAC inhibition potency and isoform selectivity. Unfortunately, the development of macrocyclic depsipeptides has been hampered in part because of development problems characteristic of large peptides and the complex reaction schemes required for their synthesis. Herein we report that tricyclic ketolide TE-802 is an excellent mimetic for the peptide backbone of macrocyclic HDACi. Compounds derived from this template are particularly selective against HDACs 1 and 2 with nanomolar inhibitory activity. Interrogation of the association between a subset of these compounds and key HDAC isoforms, using AutoDock, enables a molecular description of the interaction between the HDAC enzyme’s outer rim and the inhibitors’ macrocyclic cap group that are responsible for compound affinity and presumably isoform selectivity. |
| doi_str_mv | 10.1021/jm100507q |
| format | Article |
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Of the several structurally distinct small molecule histone deacetylase inhibitors (HDACi) reported, macrocyclic depsipeptides possess the most complex cap groups and have demonstrated excellent HDAC inhibition potency and isoform selectivity. Unfortunately, the development of macrocyclic depsipeptides has been hampered in part because of development problems characteristic of large peptides and the complex reaction schemes required for their synthesis. Herein we report that tricyclic ketolide TE-802 is an excellent mimetic for the peptide backbone of macrocyclic HDACi. Compounds derived from this template are particularly selective against HDACs 1 and 2 with nanomolar inhibitory activity. 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Med. Chem</addtitle><description>Inhibition of histone deacetylase (HDAC) function is a validated therapeutic strategy for cancer treatment. Of the several structurally distinct small molecule histone deacetylase inhibitors (HDACi) reported, macrocyclic depsipeptides possess the most complex cap groups and have demonstrated excellent HDAC inhibition potency and isoform selectivity. Unfortunately, the development of macrocyclic depsipeptides has been hampered in part because of development problems characteristic of large peptides and the complex reaction schemes required for their synthesis. Herein we report that tricyclic ketolide TE-802 is an excellent mimetic for the peptide backbone of macrocyclic HDACi. Compounds derived from this template are particularly selective against HDACs 1 and 2 with nanomolar inhibitory activity. Interrogation of the association between a subset of these compounds and key HDAC isoforms, using AutoDock, enables a molecular description of the interaction between the HDAC enzyme’s outer rim and the inhibitors’ macrocyclic cap group that are responsible for compound affinity and presumably isoform selectivity.</description><subject>Antimalarials - chemical synthesis</subject><subject>Antimalarials - chemistry</subject><subject>Antimalarials - pharmacology</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Cell Line, Tumor</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Histone Deacetylase Inhibitors - chemical synthesis</subject><subject>Histone Deacetylase Inhibitors - chemistry</subject><subject>Histone Deacetylase Inhibitors - pharmacology</subject><subject>Humans</subject><subject>Hydrophobic and Hydrophilic Interactions</subject><subject>Isoenzymes - antagonists & inhibitors</subject><subject>Ketolides - chemical synthesis</subject><subject>Ketolides - chemistry</subject><subject>Ketolides - pharmacology</subject><subject>Leishmania donovani - drug effects</subject><subject>Models, Molecular</subject><subject>Parasitic Sensitivity Tests</subject><subject>Plasmodium falciparum - drug effects</subject><subject>Structure-Activity Relationship</subject><subject>Trypanocidal Agents - chemical synthesis</subject><subject>Trypanocidal Agents - chemistry</subject><subject>Trypanocidal Agents - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkE1PAjEQhhujEUQP_gGzFw8eVqftdj8uJgY_IOJHIp6bbtuV4rLFdiHh31sCEk08zWTmnWdmXoROMVxiIPhqOsMADLKvPdTFjECc5JDsoy4AITFJCe2gI--nAEAxoYeoQyBNiyIjXcSfbRO_6nlrlI6ehHRWrmRtZDQwvrWNjm61kLpd1cLraNhMTGla63woO7PUKqqcnUVjZ7ZTj7q19Rr19qnrkDfH6KAStdcn29hD7_d34_4gHr08DPs3o1gkGbSxLrOMUCgwqYpcMQxYsBzC6VJXQBVLFYFS6YJihgngRFCKIWcyAVWphBW0h6433PminGklddM6UfO5MzPhVtwKw_92GjPhH3bJSUGShOEAuNgAggXeO13tZjHwtct853LQnv1etlP-2BoE5xuBkJ5P7cI14fd_QN_DOYTh</recordid><startdate>20100826</startdate><enddate>20100826</enddate><creator>Mwakwari, Sandra C</creator><creator>Guerrant, William</creator><creator>Patil, Vishal</creator><creator>Khan, Shabana I</creator><creator>Tekwani, Babu L</creator><creator>Gurard-Levin, Zachary A</creator><creator>Mrksich, Milan</creator><creator>Oyelere, Adegboyega K</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>20100826</creationdate><title>Non-Peptide Macrocyclic Histone Deacetylase Inhibitors Derived from Tricyclic Ketolide Skeleton</title><author>Mwakwari, Sandra C ; 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Med. Chem</addtitle><date>2010-08-26</date><risdate>2010</risdate><volume>53</volume><issue>16</issue><spage>6100</spage><epage>6111</epage><pages>6100-6111</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Inhibition of histone deacetylase (HDAC) function is a validated therapeutic strategy for cancer treatment. Of the several structurally distinct small molecule histone deacetylase inhibitors (HDACi) reported, macrocyclic depsipeptides possess the most complex cap groups and have demonstrated excellent HDAC inhibition potency and isoform selectivity. Unfortunately, the development of macrocyclic depsipeptides has been hampered in part because of development problems characteristic of large peptides and the complex reaction schemes required for their synthesis. Herein we report that tricyclic ketolide TE-802 is an excellent mimetic for the peptide backbone of macrocyclic HDACi. 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| subjects | Antimalarials - chemical synthesis Antimalarials - chemistry Antimalarials - pharmacology Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Cell Line, Tumor Drug Screening Assays, Antitumor Histone Deacetylase Inhibitors - chemical synthesis Histone Deacetylase Inhibitors - chemistry Histone Deacetylase Inhibitors - pharmacology Humans Hydrophobic and Hydrophilic Interactions Isoenzymes - antagonists & inhibitors Ketolides - chemical synthesis Ketolides - chemistry Ketolides - pharmacology Leishmania donovani - drug effects Models, Molecular Parasitic Sensitivity Tests Plasmodium falciparum - drug effects Structure-Activity Relationship Trypanocidal Agents - chemical synthesis Trypanocidal Agents - chemistry Trypanocidal Agents - pharmacology |
| title | Non-Peptide Macrocyclic Histone Deacetylase Inhibitors Derived from Tricyclic Ketolide Skeleton |
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