Benzimidazole and imidazole inhibitors of histone deacetylases: Synthesis and biological activity
A series of imidazole and benzimidazole compounds were designed, synthesized, and found to be nanomolar inhibitors of human histone deacetylases, displaying activity in cellular and xenograft models. A series of N-hydroxy-3-[3-(1-substituted-1 H-benzoimidazol-2-yl)-phenyl]-acrylamides ( 5a– 5ab) and...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2010-05, Vol.20 (10), p.3138-3141 |
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| creator | Bressi, Jerome C. Jong, Ron de Wu, Yiqin Jennings, Andy J. Brown, Jason W. O’Connell, Shawn Tari, Leslie W. Skene, Robert J. Vu, Phong Navre, Marc Cao, Xiaodong Gangloff, Anthony R. |
| description | A series of imidazole and benzimidazole compounds were designed, synthesized, and found to be nanomolar inhibitors of human histone deacetylases, displaying activity in cellular and xenograft models.
A series of
N-hydroxy-3-[3-(1-substituted-1
H-benzoimidazol-2-yl)-phenyl]-acrylamides (
5a–
5ab) and
N-hydroxy-3-[3-(1,4,5-trisubstituted-1
H-imidazol-2-yl)-phenyl]-acrylamides (
12a–
s) were designed, synthesized, and found to be nanomolar inhibitors of human histone deacetylases. Multiple compounds bearing an
N1-piperidine demonstrate EC
50s of 20–100
nM in human A549, HL60, and PC3 cells, in vitro and in vivo hyperacetylation of histones H3 and H4, and induction of p21
waf. Compound
5x displays efficacy in human tumor xenograft models. |
| doi_str_mv | 10.1016/j.bmcl.2010.03.092 |
| format | Article |
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A series of
N-hydroxy-3-[3-(1-substituted-1
H-benzoimidazol-2-yl)-phenyl]-acrylamides (
5a–
5ab) and
N-hydroxy-3-[3-(1,4,5-trisubstituted-1
H-imidazol-2-yl)-phenyl]-acrylamides (
12a–
s) were designed, synthesized, and found to be nanomolar inhibitors of human histone deacetylases. Multiple compounds bearing an
N1-piperidine demonstrate EC
50s of 20–100
nM in human A549, HL60, and PC3 cells, in vitro and in vivo hyperacetylation of histones H3 and H4, and induction of p21
waf. Compound
5x displays efficacy in human tumor xenograft models.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2010.03.092</identifier><identifier>PMID: 20392637</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>Acetylation ; Animals ; Antineoplastic agents ; Benzimidazoles - chemical synthesis ; Benzimidazoles - chemistry ; Benzimidazoles - pharmacology ; Biological and medical sciences ; Cell Line, Tumor ; General aspects ; HDAC ; Histone deacetylase inhibitors ; Histone Deacetylase Inhibitors - chemical synthesis ; Histone Deacetylase Inhibitors - chemistry ; Histone Deacetylase Inhibitors - pharmacology ; Histone Deacetylases - chemistry ; Histone Deacetylases - metabolism ; HL-60 Cells ; Humans ; Imidazoles - chemical synthesis ; Imidazoles - chemistry ; Imidazoles - pharmacology ; Medical sciences ; Mice ; Mice, Nude ; Oncology ; Pharmacology. Drug treatments ; Structure-Activity Relationship ; Xenograft Model Antitumor Assays</subject><ispartof>Bioorganic & medicinal chemistry letters, 2010-05, Vol.20 (10), p.3138-3141</ispartof><rights>2010 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright 2010 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c417t-283f3f7a8fd2732972fa77314233f57b5d762a3d722f854daa7a9a8e0275de43</citedby><cites>FETCH-LOGICAL-c417t-283f3f7a8fd2732972fa77314233f57b5d762a3d722f854daa7a9a8e0275de43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X10004336$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22896322$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20392637$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bressi, Jerome C.</creatorcontrib><creatorcontrib>Jong, Ron de</creatorcontrib><creatorcontrib>Wu, Yiqin</creatorcontrib><creatorcontrib>Jennings, Andy J.</creatorcontrib><creatorcontrib>Brown, Jason W.</creatorcontrib><creatorcontrib>O’Connell, Shawn</creatorcontrib><creatorcontrib>Tari, Leslie W.</creatorcontrib><creatorcontrib>Skene, Robert J.</creatorcontrib><creatorcontrib>Vu, Phong</creatorcontrib><creatorcontrib>Navre, Marc</creatorcontrib><creatorcontrib>Cao, Xiaodong</creatorcontrib><creatorcontrib>Gangloff, Anthony R.</creatorcontrib><title>Benzimidazole and imidazole inhibitors of histone deacetylases: Synthesis and biological activity</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>A series of imidazole and benzimidazole compounds were designed, synthesized, and found to be nanomolar inhibitors of human histone deacetylases, displaying activity in cellular and xenograft models.
A series of
N-hydroxy-3-[3-(1-substituted-1
H-benzoimidazol-2-yl)-phenyl]-acrylamides (
5a–
5ab) and
N-hydroxy-3-[3-(1,4,5-trisubstituted-1
H-imidazol-2-yl)-phenyl]-acrylamides (
12a–
s) were designed, synthesized, and found to be nanomolar inhibitors of human histone deacetylases. Multiple compounds bearing an
N1-piperidine demonstrate EC
50s of 20–100
nM in human A549, HL60, and PC3 cells, in vitro and in vivo hyperacetylation of histones H3 and H4, and induction of p21
waf. Compound
5x displays efficacy in human tumor xenograft models.</description><subject>Acetylation</subject><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Benzimidazoles - chemical synthesis</subject><subject>Benzimidazoles - chemistry</subject><subject>Benzimidazoles - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Cell Line, Tumor</subject><subject>General aspects</subject><subject>HDAC</subject><subject>Histone deacetylase inhibitors</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>HL-60 Cells</subject><subject>Humans</subject><subject>Imidazoles - chemical synthesis</subject><subject>Imidazoles - chemistry</subject><subject>Imidazoles - pharmacology</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Oncology</subject><subject>Pharmacology. Drug treatments</subject><subject>Structure-Activity Relationship</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU9v1DAQxS0EokvhC3BAuSBOWRzbiWPEpVT8kypxoAdu1sQes7NK4mJ7K20_PdnuQm9wssb6vTej9xh72fB1w5vu7XY9TG5cC758cLnmRjxiq0Z1qpaKt4_ZipuO171RP87Ys5y3nDeKK_WUnQkujeikXjH4gPMdTeThLo5Yweyrh4nmDQ1UYspVDNWGcokzVh7BYdmPkDG_q77v57LBTPleO1Ac409yMFbgCt1S2T9nTwKMGV-c3nN2_enj9eWX-urb56-XF1e1U40utehlkEFDH7zQUhgtAmgtGyWkDK0eWq87AdJrIULfKg-gwUCPXOjWo5Ln7M3R9ibFXzvMxU6UHY4jzBh32WrVmqPbf0kpjZKdEAspjqRLMeeEwd4kmiDtbcPtoQK7tYcK7KECy6VdKlhEr072u2FC_1fyJ_MFeH0CIC9BhQSzo_zAid508n77-yOHS2q3hMlmRzg79JTQFesj_euO3wXYpUU</recordid><startdate>20100515</startdate><enddate>20100515</enddate><creator>Bressi, Jerome C.</creator><creator>Jong, Ron de</creator><creator>Wu, Yiqin</creator><creator>Jennings, Andy J.</creator><creator>Brown, Jason W.</creator><creator>O’Connell, Shawn</creator><creator>Tari, Leslie W.</creator><creator>Skene, Robert J.</creator><creator>Vu, Phong</creator><creator>Navre, Marc</creator><creator>Cao, Xiaodong</creator><creator>Gangloff, Anthony R.</creator><general>Elsevier Ltd</general><general>Elsevier</general><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></search><sort><creationdate>20100515</creationdate><title>Benzimidazole and imidazole inhibitors of histone deacetylases: Synthesis and biological activity</title><author>Bressi, Jerome C. ; Jong, Ron de ; Wu, Yiqin ; Jennings, Andy J. ; Brown, Jason W. ; O’Connell, Shawn ; Tari, Leslie W. ; Skene, Robert J. ; Vu, Phong ; Navre, Marc ; Cao, Xiaodong ; Gangloff, Anthony R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c417t-283f3f7a8fd2732972fa77314233f57b5d762a3d722f854daa7a9a8e0275de43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Acetylation</topic><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Benzimidazoles - chemical synthesis</topic><topic>Benzimidazoles - chemistry</topic><topic>Benzimidazoles - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Cell Line, Tumor</topic><topic>General aspects</topic><topic>HDAC</topic><topic>Histone deacetylase inhibitors</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>HL-60 Cells</topic><topic>Humans</topic><topic>Imidazoles - chemical synthesis</topic><topic>Imidazoles - chemistry</topic><topic>Imidazoles - pharmacology</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Oncology</topic><topic>Pharmacology. 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A series of
N-hydroxy-3-[3-(1-substituted-1
H-benzoimidazol-2-yl)-phenyl]-acrylamides (
5a–
5ab) and
N-hydroxy-3-[3-(1,4,5-trisubstituted-1
H-imidazol-2-yl)-phenyl]-acrylamides (
12a–
s) were designed, synthesized, and found to be nanomolar inhibitors of human histone deacetylases. Multiple compounds bearing an
N1-piperidine demonstrate EC
50s of 20–100
nM in human A549, HL60, and PC3 cells, in vitro and in vivo hyperacetylation of histones H3 and H4, and induction of p21
waf. Compound
5x displays efficacy in human tumor xenograft models.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>20392637</pmid><doi>10.1016/j.bmcl.2010.03.092</doi><tpages>4</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2010-05, Vol.20 (10), p.3138-3141 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Acetylation Animals Antineoplastic agents Benzimidazoles - chemical synthesis Benzimidazoles - chemistry Benzimidazoles - pharmacology Biological and medical sciences Cell Line, Tumor General aspects HDAC Histone deacetylase inhibitors Histone Deacetylase Inhibitors - chemical synthesis Histone Deacetylase Inhibitors - chemistry Histone Deacetylase Inhibitors - pharmacology Histone Deacetylases - chemistry Histone Deacetylases - metabolism HL-60 Cells Humans Imidazoles - chemical synthesis Imidazoles - chemistry Imidazoles - pharmacology Medical sciences Mice Mice, Nude Oncology Pharmacology. Drug treatments Structure-Activity Relationship Xenograft Model Antitumor Assays |
| title | Benzimidazole and imidazole inhibitors of histone deacetylases: Synthesis and biological activity |
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