Dual-tail approach to discovery of novel carbonic anhydrase IX inhibitors by simultaneously matching the hydrophobic and hydrophilic halves of the active site
Dual-tail approach was employed to design novel Carbonic Anhydrase (CA) IX inhibitors by simultaneously matching the hydrophobic and hydrophilic halves of the active site, which also contains a zinc ion as part of the catalytic center. The classic sulfanilamide moiety was used as the zinc binding gr...
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Veröffentlicht in: | European journal of medicinal chemistry 2017-05, Vol.132, p.1-10 |
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container_title | European journal of medicinal chemistry |
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creator | Hou, Zhuang Lin, Bin Bao, Yu Yan, Hai-ning Zhang, Miao Chang, Xiao-wei Zhang, Xin-xin Wang, Zi-jie Wei, Gao-fei Cheng, Mao-sheng Liu, Yang Guo, Chun |
description | Dual-tail approach was employed to design novel Carbonic Anhydrase (CA) IX inhibitors by simultaneously matching the hydrophobic and hydrophilic halves of the active site, which also contains a zinc ion as part of the catalytic center. The classic sulfanilamide moiety was used as the zinc binding group. An amino glucosamine fragment was chosen as the hydrophilic part and a cinnamamide fragment as the hydrophobic part in order to draw favorable interactions with the corresponding halves of the active site. In comparison with sulfanilamide which is largely devoid of the hydrophilic and hydrophobic interactions with the two halves of the active site, the compounds so designed and synthesized in this study showed 1000-fold improvement in binding affinity. Most of the compounds inhibited the CA effectively with IC50 values in the range of 7–152 nM. Compound 14e (IC50: 7 nM) was more effective than the reference drug acetazolamide (IC50: 30 nM). The results proved that the dual-tail approach to simultaneously matching the hydrophobic and hydrophilic halves of the active site by linking hydrophobic and hydrophilic fragments was useful for designing novel CA inhibitors. The effectiveness of those compounds was elucidated by both the experimental data and molecular docking simulations. This work laid a solid foundation for further development of novel CA IX inhibitors for cancer treatment.
[Display omitted]
•Novel dual-tail approach was employed to design Carbonic Anhydrase inhibitors.•Compounds 14a-14g showed better antitumor activity under hypoxic conditions.•Compound 14e (IC50: 7 nM) was more effective than the reference drug acetazolamide.•Compound 14e significantly inhibits acidification of the extracellular pH of cancer cells. |
doi_str_mv | 10.1016/j.ejmech.2017.03.023 |
format | Article |
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[Display omitted]
•Novel dual-tail approach was employed to design Carbonic Anhydrase inhibitors.•Compounds 14a-14g showed better antitumor activity under hypoxic conditions.•Compound 14e (IC50: 7 nM) was more effective than the reference drug acetazolamide.•Compound 14e significantly inhibits acidification of the extracellular pH of cancer cells.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2017.03.023</identifier><identifier>PMID: 28334643</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>Antineoplastic Agents - chemistry ; Binding Sites ; CA inhibitors ; Carbonic anhydrase ; Carbonic Anhydrase Inhibitors - chemistry ; Carbonic Anhydrase Inhibitors - pharmacology ; Carbonic Anhydrase IX - antagonists & inhibitors ; Cinnamates - chemistry ; Drug Design ; Dual-tail approach ; Glucosamine - chemistry ; Humans ; Hydrophilic half ; Hydrophobic and Hydrophilic Interactions ; Hydrophobic half ; Inhibitory Concentration 50 ; Molecular Docking Simulation ; Protein Binding ; Structure-Activity Relationship</subject><ispartof>European journal of medicinal chemistry, 2017-05, Vol.132, p.1-10</ispartof><rights>2017 Elsevier Masson SAS</rights><rights>Copyright © 2017 Elsevier Masson SAS. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c362t-c1874300a54d2ffdc833390d2b4cd9be209d6cc8066f976ac151d18b8def8c6d3</citedby><cites>FETCH-LOGICAL-c362t-c1874300a54d2ffdc833390d2b4cd9be209d6cc8066f976ac151d18b8def8c6d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ejmech.2017.03.023$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>315,781,785,3551,27929,27930,46000</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28334643$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hou, Zhuang</creatorcontrib><creatorcontrib>Lin, Bin</creatorcontrib><creatorcontrib>Bao, Yu</creatorcontrib><creatorcontrib>Yan, Hai-ning</creatorcontrib><creatorcontrib>Zhang, Miao</creatorcontrib><creatorcontrib>Chang, Xiao-wei</creatorcontrib><creatorcontrib>Zhang, Xin-xin</creatorcontrib><creatorcontrib>Wang, Zi-jie</creatorcontrib><creatorcontrib>Wei, Gao-fei</creatorcontrib><creatorcontrib>Cheng, Mao-sheng</creatorcontrib><creatorcontrib>Liu, Yang</creatorcontrib><creatorcontrib>Guo, Chun</creatorcontrib><title>Dual-tail approach to discovery of novel carbonic anhydrase IX inhibitors by simultaneously matching the hydrophobic and hydrophilic halves of the active site</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>Dual-tail approach was employed to design novel Carbonic Anhydrase (CA) IX inhibitors by simultaneously matching the hydrophobic and hydrophilic halves of the active site, which also contains a zinc ion as part of the catalytic center. The classic sulfanilamide moiety was used as the zinc binding group. An amino glucosamine fragment was chosen as the hydrophilic part and a cinnamamide fragment as the hydrophobic part in order to draw favorable interactions with the corresponding halves of the active site. In comparison with sulfanilamide which is largely devoid of the hydrophilic and hydrophobic interactions with the two halves of the active site, the compounds so designed and synthesized in this study showed 1000-fold improvement in binding affinity. Most of the compounds inhibited the CA effectively with IC50 values in the range of 7–152 nM. Compound 14e (IC50: 7 nM) was more effective than the reference drug acetazolamide (IC50: 30 nM). The results proved that the dual-tail approach to simultaneously matching the hydrophobic and hydrophilic halves of the active site by linking hydrophobic and hydrophilic fragments was useful for designing novel CA inhibitors. The effectiveness of those compounds was elucidated by both the experimental data and molecular docking simulations. This work laid a solid foundation for further development of novel CA IX inhibitors for cancer treatment.
[Display omitted]
•Novel dual-tail approach was employed to design Carbonic Anhydrase inhibitors.•Compounds 14a-14g showed better antitumor activity under hypoxic conditions.•Compound 14e (IC50: 7 nM) was more effective than the reference drug acetazolamide.•Compound 14e significantly inhibits acidification of the extracellular pH of cancer cells.</description><subject>Antineoplastic Agents - chemistry</subject><subject>Binding Sites</subject><subject>CA inhibitors</subject><subject>Carbonic anhydrase</subject><subject>Carbonic Anhydrase Inhibitors - chemistry</subject><subject>Carbonic Anhydrase Inhibitors - pharmacology</subject><subject>Carbonic Anhydrase IX - antagonists & inhibitors</subject><subject>Cinnamates - chemistry</subject><subject>Drug Design</subject><subject>Dual-tail approach</subject><subject>Glucosamine - chemistry</subject><subject>Humans</subject><subject>Hydrophilic half</subject><subject>Hydrophobic and Hydrophilic Interactions</subject><subject>Hydrophobic half</subject><subject>Inhibitory Concentration 50</subject><subject>Molecular Docking Simulation</subject><subject>Protein Binding</subject><subject>Structure-Activity Relationship</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9Uctu1DAUtRAVHQp_gJCXbBL8SDyeDRJqeVSq1E0rsbMc-4Z45MSD7YyUn-FbcUjLktW9VzoPnXsQekdJTQkVH481HEcwQ80I3deE14TxF2hH90JWnLXNS7QjjPGqZby5RK9TOhJCWkHIK3TJJOeNaPgO_b6Zta-ydh7r0ykGbQacA7YumXCGuODQ46lsHhsduzA5g_U0LDbqBPj2B3bT4DqXQ0y4W3By4-yzniDMyS941NkMbvqJ8wB4JYXTELq_Evb5dr7cg_ZnSKvXitQmuzMUsQxv0EWvfYK3T_MKPX798nD9vbq7_3Z7_fmuMlywXBkq9w0nRLeNZX1vTcnHD8SyrjH20AEjByuMkUSI_rAX2tCWWio7aaGXRlh-hT5suuUFv2ZIWY3lA-D9lkVRKSkTjAlZoM0GNTGkFKFXp-hGHRdFiVqbUUe1NaPWZhThqjRTaO-fHOZuBPuP9FxFAXzaAFBynh1ElYyDyYB1EUxWNrj_O_wB1SelJw</recordid><startdate>20170526</startdate><enddate>20170526</enddate><creator>Hou, Zhuang</creator><creator>Lin, Bin</creator><creator>Bao, Yu</creator><creator>Yan, Hai-ning</creator><creator>Zhang, Miao</creator><creator>Chang, Xiao-wei</creator><creator>Zhang, Xin-xin</creator><creator>Wang, Zi-jie</creator><creator>Wei, Gao-fei</creator><creator>Cheng, Mao-sheng</creator><creator>Liu, Yang</creator><creator>Guo, Chun</creator><general>Elsevier Masson SAS</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></search><sort><creationdate>20170526</creationdate><title>Dual-tail approach to discovery of novel carbonic anhydrase IX inhibitors by simultaneously matching the hydrophobic and hydrophilic halves of the active site</title><author>Hou, Zhuang ; Lin, Bin ; Bao, Yu ; Yan, Hai-ning ; Zhang, Miao ; Chang, Xiao-wei ; Zhang, Xin-xin ; Wang, Zi-jie ; Wei, Gao-fei ; Cheng, Mao-sheng ; Liu, Yang ; Guo, Chun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c362t-c1874300a54d2ffdc833390d2b4cd9be209d6cc8066f976ac151d18b8def8c6d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Antineoplastic Agents - chemistry</topic><topic>Binding Sites</topic><topic>CA inhibitors</topic><topic>Carbonic anhydrase</topic><topic>Carbonic Anhydrase Inhibitors - chemistry</topic><topic>Carbonic Anhydrase Inhibitors - pharmacology</topic><topic>Carbonic Anhydrase IX - antagonists & inhibitors</topic><topic>Cinnamates - chemistry</topic><topic>Drug Design</topic><topic>Dual-tail approach</topic><topic>Glucosamine - chemistry</topic><topic>Humans</topic><topic>Hydrophilic half</topic><topic>Hydrophobic and Hydrophilic Interactions</topic><topic>Hydrophobic half</topic><topic>Inhibitory Concentration 50</topic><topic>Molecular Docking Simulation</topic><topic>Protein Binding</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hou, Zhuang</creatorcontrib><creatorcontrib>Lin, Bin</creatorcontrib><creatorcontrib>Bao, Yu</creatorcontrib><creatorcontrib>Yan, Hai-ning</creatorcontrib><creatorcontrib>Zhang, Miao</creatorcontrib><creatorcontrib>Chang, Xiao-wei</creatorcontrib><creatorcontrib>Zhang, Xin-xin</creatorcontrib><creatorcontrib>Wang, Zi-jie</creatorcontrib><creatorcontrib>Wei, Gao-fei</creatorcontrib><creatorcontrib>Cheng, Mao-sheng</creatorcontrib><creatorcontrib>Liu, Yang</creatorcontrib><creatorcontrib>Guo, Chun</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><jtitle>European journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hou, Zhuang</au><au>Lin, Bin</au><au>Bao, Yu</au><au>Yan, Hai-ning</au><au>Zhang, Miao</au><au>Chang, Xiao-wei</au><au>Zhang, Xin-xin</au><au>Wang, Zi-jie</au><au>Wei, Gao-fei</au><au>Cheng, Mao-sheng</au><au>Liu, Yang</au><au>Guo, Chun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Dual-tail approach to discovery of novel carbonic anhydrase IX inhibitors by simultaneously matching the hydrophobic and hydrophilic halves of the active site</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2017-05-26</date><risdate>2017</risdate><volume>132</volume><spage>1</spage><epage>10</epage><pages>1-10</pages><issn>0223-5234</issn><eissn>1768-3254</eissn><abstract>Dual-tail approach was employed to design novel Carbonic Anhydrase (CA) IX inhibitors by simultaneously matching the hydrophobic and hydrophilic halves of the active site, which also contains a zinc ion as part of the catalytic center. The classic sulfanilamide moiety was used as the zinc binding group. An amino glucosamine fragment was chosen as the hydrophilic part and a cinnamamide fragment as the hydrophobic part in order to draw favorable interactions with the corresponding halves of the active site. In comparison with sulfanilamide which is largely devoid of the hydrophilic and hydrophobic interactions with the two halves of the active site, the compounds so designed and synthesized in this study showed 1000-fold improvement in binding affinity. Most of the compounds inhibited the CA effectively with IC50 values in the range of 7–152 nM. Compound 14e (IC50: 7 nM) was more effective than the reference drug acetazolamide (IC50: 30 nM). The results proved that the dual-tail approach to simultaneously matching the hydrophobic and hydrophilic halves of the active site by linking hydrophobic and hydrophilic fragments was useful for designing novel CA inhibitors. The effectiveness of those compounds was elucidated by both the experimental data and molecular docking simulations. This work laid a solid foundation for further development of novel CA IX inhibitors for cancer treatment.
[Display omitted]
•Novel dual-tail approach was employed to design Carbonic Anhydrase inhibitors.•Compounds 14a-14g showed better antitumor activity under hypoxic conditions.•Compound 14e (IC50: 7 nM) was more effective than the reference drug acetazolamide.•Compound 14e significantly inhibits acidification of the extracellular pH of cancer cells.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>28334643</pmid><doi>10.1016/j.ejmech.2017.03.023</doi><tpages>10</tpages></addata></record> |
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subjects | Antineoplastic Agents - chemistry Binding Sites CA inhibitors Carbonic anhydrase Carbonic Anhydrase Inhibitors - chemistry Carbonic Anhydrase Inhibitors - pharmacology Carbonic Anhydrase IX - antagonists & inhibitors Cinnamates - chemistry Drug Design Dual-tail approach Glucosamine - chemistry Humans Hydrophilic half Hydrophobic and Hydrophilic Interactions Hydrophobic half Inhibitory Concentration 50 Molecular Docking Simulation Protein Binding Structure-Activity Relationship |
title | Dual-tail approach to discovery of novel carbonic anhydrase IX inhibitors by simultaneously matching the hydrophobic and hydrophilic halves of the active site |
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