Evaluation of the Influence of Compound Structure on Stacked-Dimer Formation in the DNA Minor Groove

The Human Genome Project as well as sequencing of the genomes of other organisms offers a wealth of DNA targets for both therapeutic and diagnostic applications, and it is important to develop additional DNA binding motifs to fully exploit the potential of this new information. We have recently foun...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Biochemistry (Easton) 2001-02, Vol.40 (8), p.2511-2521
Hauptverfasser: Wang, Lei, Carrasco, Carolina, Kumar, Arvind, Stephens, Chad E, Bailly, Christian, Boykin, David W, Wilson, W. David
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 2521
container_issue 8
container_start_page 2511
container_title Biochemistry (Easton)
container_volume 40
creator Wang, Lei
Carrasco, Carolina
Kumar, Arvind
Stephens, Chad E
Bailly, Christian
Boykin, David W
Wilson, W. David
description The Human Genome Project as well as sequencing of the genomes of other organisms offers a wealth of DNA targets for both therapeutic and diagnostic applications, and it is important to develop additional DNA binding motifs to fully exploit the potential of this new information. We have recently found that an aromatic dication, DB293, with an amidine-phenyl-furan-benzimidazole-amidine structure can recognize specific sequences of DNA by binding in the minor groove as a dimer [Wang, L., Bailly, C., Kumar, A., Ding, D., Bajic, M., Boykin, D. W., and Wilson, W. D. (2000) Proc. Natl. Acad. Sci. U.S.A. 97, 12−16]. The dimer binding is strong, highly cooperative and, in contrast to many closely related heterocyclic dications, has both GC and AT base pairs in the minor groove binding site. The aromatic heterocycle stacked dimer is quite different in structure from the polyamide-lexitropsin type compounds, and it is a dication while all lexitropsin dimers are monocations. The heterocyclic dimer represents only the second small molecule class that can recognize mixed sequences of DNA. To test the structural limits on the new type of complex, it is important to probe the influence of compound charge, chemical groups, and structural features. The effects of these compound molecular variations on DNA complex formation with several DNA sequences were evaluated by DNase I footprinting, CD and UV spectroscopy, thermal melting, and quantitative analysis with surface plasmon resonance biosensor methods. Conversion of the amidines to guanidinium groups does permit the cooperative dimer to form but removal of one amidine or addition of an alkyl group to the amidine strongly inhibited dimer formation. Changing the phenyl of DB293 to a benzimidazole or the benzimidazole to a phenyl or benzofuran also inhibited dimer formation. The results show that formation of the minor groove stacked−dimer complex is very sensitive to compound structure. The discovery of the aromatic dimer mode offers new opportunities to enhance the specificity and expand the range of applications of the compounds that target DNA.
doi_str_mv 10.1021/bi002301r
format Article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_70824890</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>17866667</sourcerecordid><originalsourceid>FETCH-LOGICAL-a380t-77c002cda4ea766069f564bc97e9c3ffe590ddeff7a556d09dcd2db8d65890f03</originalsourceid><addsrcrecordid>eNqFkE1P3DAQhi3UCrbAgT9Q5VKkHtKOk9iOj2j5lJYCWrhwsbz-UAOJvdgxgn-PaVb0UqlzGc3Mo_fVvAgdYPiBocI_Vx1AVQMOW2iGSQVlwzn5hGYAQMuKU9hBX2J8yGMDrNlGOxjXFWtZPUP65Fn2SY6dd4W3xfjbFBfO9sk4Zd4Xcz-sfXK6WI4hqTGFvHV5kOrR6PK4G0woTn0YJoXO_VE4_nVUXHbOh-IseP9s9tBnK_to9jd9F92dntzOz8vF1dnF_GhRyrqFsWRM5T-Ulo2RjFKg3BLarBRnhqvaWkM4aG2sZZIQqoFrpSu9ajUlLQcL9S46nHTXwT8lE0cxdFGZvpfO-BQFg7ZqMvpfELOW5mIZ_D6BKvgYg7FiHbpBhleBQbxnLz6yz-zXjWhaDUb_JTdhZ6CcgC6O5uXjLsOjyFaMiNvrpVjAzSW5r87FMvPfJl6qKB58Ci6H9w_jN8I7mgM</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>17866667</pqid></control><display><type>article</type><title>Evaluation of the Influence of Compound Structure on Stacked-Dimer Formation in the DNA Minor Groove</title><source>MEDLINE</source><source>American Chemical Society Journals</source><creator>Wang, Lei ; Carrasco, Carolina ; Kumar, Arvind ; Stephens, Chad E ; Bailly, Christian ; Boykin, David W ; Wilson, W. David</creator><creatorcontrib>Wang, Lei ; Carrasco, Carolina ; Kumar, Arvind ; Stephens, Chad E ; Bailly, Christian ; Boykin, David W ; Wilson, W. David</creatorcontrib><description>The Human Genome Project as well as sequencing of the genomes of other organisms offers a wealth of DNA targets for both therapeutic and diagnostic applications, and it is important to develop additional DNA binding motifs to fully exploit the potential of this new information. We have recently found that an aromatic dication, DB293, with an amidine-phenyl-furan-benzimidazole-amidine structure can recognize specific sequences of DNA by binding in the minor groove as a dimer [Wang, L., Bailly, C., Kumar, A., Ding, D., Bajic, M., Boykin, D. W., and Wilson, W. D. (2000) Proc. Natl. Acad. Sci. U.S.A. 97, 12−16]. The dimer binding is strong, highly cooperative and, in contrast to many closely related heterocyclic dications, has both GC and AT base pairs in the minor groove binding site. The aromatic heterocycle stacked dimer is quite different in structure from the polyamide-lexitropsin type compounds, and it is a dication while all lexitropsin dimers are monocations. The heterocyclic dimer represents only the second small molecule class that can recognize mixed sequences of DNA. To test the structural limits on the new type of complex, it is important to probe the influence of compound charge, chemical groups, and structural features. The effects of these compound molecular variations on DNA complex formation with several DNA sequences were evaluated by DNase I footprinting, CD and UV spectroscopy, thermal melting, and quantitative analysis with surface plasmon resonance biosensor methods. Conversion of the amidines to guanidinium groups does permit the cooperative dimer to form but removal of one amidine or addition of an alkyl group to the amidine strongly inhibited dimer formation. Changing the phenyl of DB293 to a benzimidazole or the benzimidazole to a phenyl or benzofuran also inhibited dimer formation. The results show that formation of the minor groove stacked−dimer complex is very sensitive to compound structure. The discovery of the aromatic dimer mode offers new opportunities to enhance the specificity and expand the range of applications of the compounds that target DNA.</description><identifier>ISSN: 0006-2960</identifier><identifier>EISSN: 1520-4995</identifier><identifier>DOI: 10.1021/bi002301r</identifier><identifier>PMID: 11327873</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Amidines - chemical synthesis ; Amidines - chemistry ; Base Pairing ; Benzimidazoles - chemical synthesis ; Binding Sites ; Carbazoles - chemical synthesis ; Cations - chemistry ; Circular Dichroism ; DB293 ; DNA - chemistry ; DNA Footprinting ; Furans - chemical synthesis ; Guanidine - analogs &amp; derivatives ; Guanidine - chemical synthesis ; Human Genome Project ; lexitropsin ; Netropsin - analogs &amp; derivatives ; Netropsin - chemistry ; Nucleic Acid Conformation ; Nucleic Acid Denaturation ; Oligonucleotides - chemical synthesis ; Pyrimidine Dimers - chemistry ; Spectrophotometry, Ultraviolet ; Surface Plasmon Resonance</subject><ispartof>Biochemistry (Easton), 2001-02, Vol.40 (8), p.2511-2521</ispartof><rights>Copyright © 2001 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a380t-77c002cda4ea766069f564bc97e9c3ffe590ddeff7a556d09dcd2db8d65890f03</citedby><cites>FETCH-LOGICAL-a380t-77c002cda4ea766069f564bc97e9c3ffe590ddeff7a556d09dcd2db8d65890f03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/bi002301r$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/bi002301r$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11327873$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Lei</creatorcontrib><creatorcontrib>Carrasco, Carolina</creatorcontrib><creatorcontrib>Kumar, Arvind</creatorcontrib><creatorcontrib>Stephens, Chad E</creatorcontrib><creatorcontrib>Bailly, Christian</creatorcontrib><creatorcontrib>Boykin, David W</creatorcontrib><creatorcontrib>Wilson, W. David</creatorcontrib><title>Evaluation of the Influence of Compound Structure on Stacked-Dimer Formation in the DNA Minor Groove</title><title>Biochemistry (Easton)</title><addtitle>Biochemistry</addtitle><description>The Human Genome Project as well as sequencing of the genomes of other organisms offers a wealth of DNA targets for both therapeutic and diagnostic applications, and it is important to develop additional DNA binding motifs to fully exploit the potential of this new information. We have recently found that an aromatic dication, DB293, with an amidine-phenyl-furan-benzimidazole-amidine structure can recognize specific sequences of DNA by binding in the minor groove as a dimer [Wang, L., Bailly, C., Kumar, A., Ding, D., Bajic, M., Boykin, D. W., and Wilson, W. D. (2000) Proc. Natl. Acad. Sci. U.S.A. 97, 12−16]. The dimer binding is strong, highly cooperative and, in contrast to many closely related heterocyclic dications, has both GC and AT base pairs in the minor groove binding site. The aromatic heterocycle stacked dimer is quite different in structure from the polyamide-lexitropsin type compounds, and it is a dication while all lexitropsin dimers are monocations. The heterocyclic dimer represents only the second small molecule class that can recognize mixed sequences of DNA. To test the structural limits on the new type of complex, it is important to probe the influence of compound charge, chemical groups, and structural features. The effects of these compound molecular variations on DNA complex formation with several DNA sequences were evaluated by DNase I footprinting, CD and UV spectroscopy, thermal melting, and quantitative analysis with surface plasmon resonance biosensor methods. Conversion of the amidines to guanidinium groups does permit the cooperative dimer to form but removal of one amidine or addition of an alkyl group to the amidine strongly inhibited dimer formation. Changing the phenyl of DB293 to a benzimidazole or the benzimidazole to a phenyl or benzofuran also inhibited dimer formation. The results show that formation of the minor groove stacked−dimer complex is very sensitive to compound structure. The discovery of the aromatic dimer mode offers new opportunities to enhance the specificity and expand the range of applications of the compounds that target DNA.</description><subject>Amidines - chemical synthesis</subject><subject>Amidines - chemistry</subject><subject>Base Pairing</subject><subject>Benzimidazoles - chemical synthesis</subject><subject>Binding Sites</subject><subject>Carbazoles - chemical synthesis</subject><subject>Cations - chemistry</subject><subject>Circular Dichroism</subject><subject>DB293</subject><subject>DNA - chemistry</subject><subject>DNA Footprinting</subject><subject>Furans - chemical synthesis</subject><subject>Guanidine - analogs &amp; derivatives</subject><subject>Guanidine - chemical synthesis</subject><subject>Human Genome Project</subject><subject>lexitropsin</subject><subject>Netropsin - analogs &amp; derivatives</subject><subject>Netropsin - chemistry</subject><subject>Nucleic Acid Conformation</subject><subject>Nucleic Acid Denaturation</subject><subject>Oligonucleotides - chemical synthesis</subject><subject>Pyrimidine Dimers - chemistry</subject><subject>Spectrophotometry, Ultraviolet</subject><subject>Surface Plasmon Resonance</subject><issn>0006-2960</issn><issn>1520-4995</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkE1P3DAQhi3UCrbAgT9Q5VKkHtKOk9iOj2j5lJYCWrhwsbz-UAOJvdgxgn-PaVb0UqlzGc3Mo_fVvAgdYPiBocI_Vx1AVQMOW2iGSQVlwzn5hGYAQMuKU9hBX2J8yGMDrNlGOxjXFWtZPUP65Fn2SY6dd4W3xfjbFBfO9sk4Zd4Xcz-sfXK6WI4hqTGFvHV5kOrR6PK4G0woTn0YJoXO_VE4_nVUXHbOh-IseP9s9tBnK_to9jd9F92dntzOz8vF1dnF_GhRyrqFsWRM5T-Ulo2RjFKg3BLarBRnhqvaWkM4aG2sZZIQqoFrpSu9ajUlLQcL9S46nHTXwT8lE0cxdFGZvpfO-BQFg7ZqMvpfELOW5mIZ_D6BKvgYg7FiHbpBhleBQbxnLz6yz-zXjWhaDUb_JTdhZ6CcgC6O5uXjLsOjyFaMiNvrpVjAzSW5r87FMvPfJl6qKB58Ci6H9w_jN8I7mgM</recordid><startdate>20010227</startdate><enddate>20010227</enddate><creator>Wang, Lei</creator><creator>Carrasco, Carolina</creator><creator>Kumar, Arvind</creator><creator>Stephens, Chad E</creator><creator>Bailly, Christian</creator><creator>Boykin, David W</creator><creator>Wilson, W. David</creator><general>American Chemical Society</general><scope>BSCLL</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>7TM</scope><scope>7X8</scope></search><sort><creationdate>20010227</creationdate><title>Evaluation of the Influence of Compound Structure on Stacked-Dimer Formation in the DNA Minor Groove</title><author>Wang, Lei ; Carrasco, Carolina ; Kumar, Arvind ; Stephens, Chad E ; Bailly, Christian ; Boykin, David W ; Wilson, W. David</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a380t-77c002cda4ea766069f564bc97e9c3ffe590ddeff7a556d09dcd2db8d65890f03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Amidines - chemical synthesis</topic><topic>Amidines - chemistry</topic><topic>Base Pairing</topic><topic>Benzimidazoles - chemical synthesis</topic><topic>Binding Sites</topic><topic>Carbazoles - chemical synthesis</topic><topic>Cations - chemistry</topic><topic>Circular Dichroism</topic><topic>DB293</topic><topic>DNA - chemistry</topic><topic>DNA Footprinting</topic><topic>Furans - chemical synthesis</topic><topic>Guanidine - analogs &amp; derivatives</topic><topic>Guanidine - chemical synthesis</topic><topic>Human Genome Project</topic><topic>lexitropsin</topic><topic>Netropsin - analogs &amp; derivatives</topic><topic>Netropsin - chemistry</topic><topic>Nucleic Acid Conformation</topic><topic>Nucleic Acid Denaturation</topic><topic>Oligonucleotides - chemical synthesis</topic><topic>Pyrimidine Dimers - chemistry</topic><topic>Spectrophotometry, Ultraviolet</topic><topic>Surface Plasmon Resonance</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Lei</creatorcontrib><creatorcontrib>Carrasco, Carolina</creatorcontrib><creatorcontrib>Kumar, Arvind</creatorcontrib><creatorcontrib>Stephens, Chad E</creatorcontrib><creatorcontrib>Bailly, Christian</creatorcontrib><creatorcontrib>Boykin, David W</creatorcontrib><creatorcontrib>Wilson, W. David</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Biochemistry (Easton)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Lei</au><au>Carrasco, Carolina</au><au>Kumar, Arvind</au><au>Stephens, Chad E</au><au>Bailly, Christian</au><au>Boykin, David W</au><au>Wilson, W. David</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Evaluation of the Influence of Compound Structure on Stacked-Dimer Formation in the DNA Minor Groove</atitle><jtitle>Biochemistry (Easton)</jtitle><addtitle>Biochemistry</addtitle><date>2001-02-27</date><risdate>2001</risdate><volume>40</volume><issue>8</issue><spage>2511</spage><epage>2521</epage><pages>2511-2521</pages><issn>0006-2960</issn><eissn>1520-4995</eissn><abstract>The Human Genome Project as well as sequencing of the genomes of other organisms offers a wealth of DNA targets for both therapeutic and diagnostic applications, and it is important to develop additional DNA binding motifs to fully exploit the potential of this new information. We have recently found that an aromatic dication, DB293, with an amidine-phenyl-furan-benzimidazole-amidine structure can recognize specific sequences of DNA by binding in the minor groove as a dimer [Wang, L., Bailly, C., Kumar, A., Ding, D., Bajic, M., Boykin, D. W., and Wilson, W. D. (2000) Proc. Natl. Acad. Sci. U.S.A. 97, 12−16]. The dimer binding is strong, highly cooperative and, in contrast to many closely related heterocyclic dications, has both GC and AT base pairs in the minor groove binding site. The aromatic heterocycle stacked dimer is quite different in structure from the polyamide-lexitropsin type compounds, and it is a dication while all lexitropsin dimers are monocations. The heterocyclic dimer represents only the second small molecule class that can recognize mixed sequences of DNA. To test the structural limits on the new type of complex, it is important to probe the influence of compound charge, chemical groups, and structural features. The effects of these compound molecular variations on DNA complex formation with several DNA sequences were evaluated by DNase I footprinting, CD and UV spectroscopy, thermal melting, and quantitative analysis with surface plasmon resonance biosensor methods. Conversion of the amidines to guanidinium groups does permit the cooperative dimer to form but removal of one amidine or addition of an alkyl group to the amidine strongly inhibited dimer formation. Changing the phenyl of DB293 to a benzimidazole or the benzimidazole to a phenyl or benzofuran also inhibited dimer formation. The results show that formation of the minor groove stacked−dimer complex is very sensitive to compound structure. The discovery of the aromatic dimer mode offers new opportunities to enhance the specificity and expand the range of applications of the compounds that target DNA.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>11327873</pmid><doi>10.1021/bi002301r</doi><tpages>11</tpages></addata></record>
fulltext fulltext
identifier ISSN: 0006-2960
ispartof Biochemistry (Easton), 2001-02, Vol.40 (8), p.2511-2521
issn 0006-2960
1520-4995
language eng
recordid cdi_proquest_miscellaneous_70824890
source MEDLINE; American Chemical Society Journals
subjects Amidines - chemical synthesis
Amidines - chemistry
Base Pairing
Benzimidazoles - chemical synthesis
Binding Sites
Carbazoles - chemical synthesis
Cations - chemistry
Circular Dichroism
DB293
DNA - chemistry
DNA Footprinting
Furans - chemical synthesis
Guanidine - analogs & derivatives
Guanidine - chemical synthesis
Human Genome Project
lexitropsin
Netropsin - analogs & derivatives
Netropsin - chemistry
Nucleic Acid Conformation
Nucleic Acid Denaturation
Oligonucleotides - chemical synthesis
Pyrimidine Dimers - chemistry
Spectrophotometry, Ultraviolet
Surface Plasmon Resonance
title Evaluation of the Influence of Compound Structure on Stacked-Dimer Formation in the DNA Minor Groove
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-19T10%3A44%3A45IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Evaluation%20of%20the%20Influence%20of%20Compound%20Structure%20on%20Stacked-Dimer%20Formation%20in%20the%20DNA%20Minor%20Groove&rft.jtitle=Biochemistry%20(Easton)&rft.au=Wang,%20Lei&rft.date=2001-02-27&rft.volume=40&rft.issue=8&rft.spage=2511&rft.epage=2521&rft.pages=2511-2521&rft.issn=0006-2960&rft.eissn=1520-4995&rft_id=info:doi/10.1021/bi002301r&rft_dat=%3Cproquest_cross%3E17866667%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=17866667&rft_id=info:pmid/11327873&rfr_iscdi=true