Selective non-zinc binding MMP-2 inhibitors: Novel benzamide Ilomastat analogs with anti-tumor metastasis
[Display omitted] Novel Ilomastat analogs with substituted benzamide groups, instead of hydroxamic acid groups, were designed, synthesized and evaluated against MMP-2 and MMP-9. Among these analogs, the most potent compound 10a exhibited potent inhibitory activity against MMP-2 with IC50 value of 0....
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2016-05, Vol.26 (9), p.2174-2178 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Song, Jiao Peng, Peng Chang, Jun Liu, Ming-Ming Yu, Jian-Ming Zhou, Lu Sun, Xun |
| description | [Display omitted]
Novel Ilomastat analogs with substituted benzamide groups, instead of hydroxamic acid groups, were designed, synthesized and evaluated against MMP-2 and MMP-9. Among these analogs, the most potent compound 10a exhibited potent inhibitory activity against MMP-2 with IC50 value of 0.19nM, which is 5 times more potent than that of Ilomastat (IC50=0.94nM). Importantly, 10a exhibited more than 8300 fold selectivity for MMP-2 versus MMP-9 (IC50=1.58μM). Molecular docking studies showed that 10a bond to the catalytic active pocket of MMP-2 by a non-zinc-chelating mechanism which was different from that of Ilomastat. Furthermore, the invasion assay showed that 10a was effective in reducing HEY cells invasion at 84.6% in 50μM concentration. For 10a, the pharmacokinetic properties had been improved and especially the more desirable t1/2z was achieved compared with these of the lead compound Ilomastat. |
| doi_str_mv | 10.1016/j.bmcl.2016.03.064 |
| format | Article |
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Novel Ilomastat analogs with substituted benzamide groups, instead of hydroxamic acid groups, were designed, synthesized and evaluated against MMP-2 and MMP-9. Among these analogs, the most potent compound 10a exhibited potent inhibitory activity against MMP-2 with IC50 value of 0.19nM, which is 5 times more potent than that of Ilomastat (IC50=0.94nM). Importantly, 10a exhibited more than 8300 fold selectivity for MMP-2 versus MMP-9 (IC50=1.58μM). Molecular docking studies showed that 10a bond to the catalytic active pocket of MMP-2 by a non-zinc-chelating mechanism which was different from that of Ilomastat. Furthermore, the invasion assay showed that 10a was effective in reducing HEY cells invasion at 84.6% in 50μM concentration. For 10a, the pharmacokinetic properties had been improved and especially the more desirable t1/2z was achieved compared with these of the lead compound Ilomastat.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2016.03.064</identifier><identifier>PMID: 27038494</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Anilides - chemical synthesis ; Anilides - pharmacokinetics ; Anilides - pharmacology ; Animals ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - pharmacology ; Benzamide groups ; Binding Sites ; Cell Line, Tumor ; Drug Screening Assays, Antitumor ; Enzyme inhibition ; HEY cell invasion ; Humans ; Hydrogen Bonding ; Hydroxamic Acids - chemical synthesis ; Hydroxamic Acids - pharmacokinetics ; Hydroxamic Acids - pharmacology ; Ilomastat analogs ; Indoles - chemical synthesis ; Indoles - pharmacokinetics ; Indoles - pharmacology ; Matrix Metalloproteinase 2 - metabolism ; Matrix Metalloproteinase 9 - metabolism ; Matrix Metalloproteinase Inhibitors - chemical synthesis ; Matrix Metalloproteinase Inhibitors - pharmacokinetics ; Matrix Metalloproteinase Inhibitors - pharmacology ; MMP-2 and MMP-9 ; Molecular Docking Simulation ; Neoplasm Invasiveness - pathology ; Neoplasm Metastasis ; Non-zinc binding ; Rats ; Rats, Sprague-Dawley</subject><ispartof>Bioorganic & medicinal chemistry letters, 2016-05, Vol.26 (9), p.2174-2178</ispartof><rights>2016 Elsevier Ltd</rights><rights>Copyright © 2016 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c389t-817d0438c5f938a00a257bcb9072f61fb4ae3ce241b02e09c5400625761b04f73</citedby><cites>FETCH-LOGICAL-c389t-817d0438c5f938a00a257bcb9072f61fb4ae3ce241b02e09c5400625761b04f73</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.2016.03.064$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27038494$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Song, Jiao</creatorcontrib><creatorcontrib>Peng, Peng</creatorcontrib><creatorcontrib>Chang, Jun</creatorcontrib><creatorcontrib>Liu, Ming-Ming</creatorcontrib><creatorcontrib>Yu, Jian-Ming</creatorcontrib><creatorcontrib>Zhou, Lu</creatorcontrib><creatorcontrib>Sun, Xun</creatorcontrib><title>Selective non-zinc binding MMP-2 inhibitors: Novel benzamide Ilomastat analogs with anti-tumor metastasis</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
Novel Ilomastat analogs with substituted benzamide groups, instead of hydroxamic acid groups, were designed, synthesized and evaluated against MMP-2 and MMP-9. Among these analogs, the most potent compound 10a exhibited potent inhibitory activity against MMP-2 with IC50 value of 0.19nM, which is 5 times more potent than that of Ilomastat (IC50=0.94nM). Importantly, 10a exhibited more than 8300 fold selectivity for MMP-2 versus MMP-9 (IC50=1.58μM). Molecular docking studies showed that 10a bond to the catalytic active pocket of MMP-2 by a non-zinc-chelating mechanism which was different from that of Ilomastat. Furthermore, the invasion assay showed that 10a was effective in reducing HEY cells invasion at 84.6% in 50μM concentration. For 10a, the pharmacokinetic properties had been improved and especially the more desirable t1/2z was achieved compared with these of the lead compound Ilomastat.</description><subject>Anilides - chemical synthesis</subject><subject>Anilides - pharmacokinetics</subject><subject>Anilides - pharmacology</subject><subject>Animals</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - pharmacokinetics</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Benzamide groups</subject><subject>Binding Sites</subject><subject>Cell Line, Tumor</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Enzyme inhibition</subject><subject>HEY cell invasion</subject><subject>Humans</subject><subject>Hydrogen Bonding</subject><subject>Hydroxamic Acids - chemical synthesis</subject><subject>Hydroxamic Acids - pharmacokinetics</subject><subject>Hydroxamic Acids - pharmacology</subject><subject>Ilomastat analogs</subject><subject>Indoles - chemical synthesis</subject><subject>Indoles - pharmacokinetics</subject><subject>Indoles - pharmacology</subject><subject>Matrix Metalloproteinase 2 - metabolism</subject><subject>Matrix Metalloproteinase 9 - metabolism</subject><subject>Matrix Metalloproteinase Inhibitors - chemical synthesis</subject><subject>Matrix Metalloproteinase Inhibitors - pharmacokinetics</subject><subject>Matrix Metalloproteinase Inhibitors - pharmacology</subject><subject>MMP-2 and MMP-9</subject><subject>Molecular Docking Simulation</subject><subject>Neoplasm Invasiveness - pathology</subject><subject>Neoplasm Metastasis</subject><subject>Non-zinc binding</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkU1v1DAQhi0EokvhD3BAPnJJGMeOEyMuqCpQqQUkQOJm2c6k9Sqxi-1dRH89Xm3hiDjNh555D_MQ8pxBy4DJV9vWrm5pu9q3wFuQ4gHZMCFFwwX0D8kGlIRmVOL7CXmS8xaACRDiMTnpBuCjUGJD_Bdc0BW_RxpiaO58cNT6MPlwTa-uPjcd9eHGW19iyq_px7jHhVoMd2b1E9KLJa4mF1OoCWaJ15n-9OWmDsU3ZbfGRFcsByD7_JQ8ms2S8dl9PSXf3p1_PfvQXH56f3H29rJxfFSlGdkwgeCj62fFRwNgun6wzioYulmy2QqD3GEnmIUOQbleAMjKyLoQ88BPyctj7m2KP3aYi159drgsJmDcZc0GBaqXPfD_QEfWcyl7VdHuiLoUc04469vkV5N-aQb6YENv9cGGPtjQwHW1UY9e3Ofv7IrT35M_76_AmyOA9SF7j0ln5zE4nHyqVvQU_b_yfwNyx5rn</recordid><startdate>20160501</startdate><enddate>20160501</enddate><creator>Song, Jiao</creator><creator>Peng, Peng</creator><creator>Chang, Jun</creator><creator>Liu, Ming-Ming</creator><creator>Yu, Jian-Ming</creator><creator>Zhou, Lu</creator><creator>Sun, Xun</creator><general>Elsevier Ltd</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>7X8</scope><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20160501</creationdate><title>Selective non-zinc binding MMP-2 inhibitors: Novel benzamide Ilomastat analogs with anti-tumor metastasis</title><author>Song, Jiao ; Peng, Peng ; Chang, Jun ; Liu, Ming-Ming ; Yu, Jian-Ming ; Zhou, Lu ; Sun, Xun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c389t-817d0438c5f938a00a257bcb9072f61fb4ae3ce241b02e09c5400625761b04f73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Anilides - chemical synthesis</topic><topic>Anilides - pharmacokinetics</topic><topic>Anilides - pharmacology</topic><topic>Animals</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - pharmacokinetics</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Benzamide groups</topic><topic>Binding Sites</topic><topic>Cell Line, Tumor</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Enzyme inhibition</topic><topic>HEY cell invasion</topic><topic>Humans</topic><topic>Hydrogen Bonding</topic><topic>Hydroxamic Acids - chemical synthesis</topic><topic>Hydroxamic Acids - pharmacokinetics</topic><topic>Hydroxamic Acids - pharmacology</topic><topic>Ilomastat analogs</topic><topic>Indoles - chemical synthesis</topic><topic>Indoles - pharmacokinetics</topic><topic>Indoles - pharmacology</topic><topic>Matrix Metalloproteinase 2 - metabolism</topic><topic>Matrix Metalloproteinase 9 - metabolism</topic><topic>Matrix Metalloproteinase Inhibitors - chemical synthesis</topic><topic>Matrix Metalloproteinase Inhibitors - pharmacokinetics</topic><topic>Matrix Metalloproteinase Inhibitors - pharmacology</topic><topic>MMP-2 and MMP-9</topic><topic>Molecular Docking Simulation</topic><topic>Neoplasm Invasiveness - pathology</topic><topic>Neoplasm Metastasis</topic><topic>Non-zinc binding</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Song, Jiao</creatorcontrib><creatorcontrib>Peng, Peng</creatorcontrib><creatorcontrib>Chang, Jun</creatorcontrib><creatorcontrib>Liu, Ming-Ming</creatorcontrib><creatorcontrib>Yu, Jian-Ming</creatorcontrib><creatorcontrib>Zhou, Lu</creatorcontrib><creatorcontrib>Sun, Xun</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Song, Jiao</au><au>Peng, Peng</au><au>Chang, Jun</au><au>Liu, Ming-Ming</au><au>Yu, Jian-Ming</au><au>Zhou, Lu</au><au>Sun, Xun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Selective non-zinc binding MMP-2 inhibitors: Novel benzamide Ilomastat analogs with anti-tumor metastasis</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2016-05-01</date><risdate>2016</risdate><volume>26</volume><issue>9</issue><spage>2174</spage><epage>2178</epage><pages>2174-2178</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
Novel Ilomastat analogs with substituted benzamide groups, instead of hydroxamic acid groups, were designed, synthesized and evaluated against MMP-2 and MMP-9. Among these analogs, the most potent compound 10a exhibited potent inhibitory activity against MMP-2 with IC50 value of 0.19nM, which is 5 times more potent than that of Ilomastat (IC50=0.94nM). Importantly, 10a exhibited more than 8300 fold selectivity for MMP-2 versus MMP-9 (IC50=1.58μM). Molecular docking studies showed that 10a bond to the catalytic active pocket of MMP-2 by a non-zinc-chelating mechanism which was different from that of Ilomastat. Furthermore, the invasion assay showed that 10a was effective in reducing HEY cells invasion at 84.6% in 50μM concentration. For 10a, the pharmacokinetic properties had been improved and especially the more desirable t1/2z was achieved compared with these of the lead compound Ilomastat.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>27038494</pmid><doi>10.1016/j.bmcl.2016.03.064</doi><tpages>5</tpages></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2016-05, Vol.26 (9), p.2174-2178 |
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| source | MEDLINE; ScienceDirect Journals (5 years ago - present) |
| subjects | Anilides - chemical synthesis Anilides - pharmacokinetics Anilides - pharmacology Animals Antineoplastic Agents - chemical synthesis Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - pharmacology Benzamide groups Binding Sites Cell Line, Tumor Drug Screening Assays, Antitumor Enzyme inhibition HEY cell invasion Humans Hydrogen Bonding Hydroxamic Acids - chemical synthesis Hydroxamic Acids - pharmacokinetics Hydroxamic Acids - pharmacology Ilomastat analogs Indoles - chemical synthesis Indoles - pharmacokinetics Indoles - pharmacology Matrix Metalloproteinase 2 - metabolism Matrix Metalloproteinase 9 - metabolism Matrix Metalloproteinase Inhibitors - chemical synthesis Matrix Metalloproteinase Inhibitors - pharmacokinetics Matrix Metalloproteinase Inhibitors - pharmacology MMP-2 and MMP-9 Molecular Docking Simulation Neoplasm Invasiveness - pathology Neoplasm Metastasis Non-zinc binding Rats Rats, Sprague-Dawley |
| title | Selective non-zinc binding MMP-2 inhibitors: Novel benzamide Ilomastat analogs with anti-tumor metastasis |
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