Definition of the Effect and Role of the Bleomycin A2 Valerate Substituents:  Preorganization of a Rigid, Compact Conformation Implicated in Sequence-Selective DNA Cleavage

The synthesis and a comparative study of deglycobleomycin A2 analogues containing key modifications in the valerate subunit are described in efforts that define the role of the linker length and its substituents. In addition to demonstrating that the C3-hydroxy group exhibits only a modest effect (1...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Journal of the American Chemical Society 1998-09, Vol.120 (36), p.9149-9158
Hauptverfasser: Boger, Dale L, Ramsey, Timothy M, Cai, Hui, Hoehn, Silvia T, Stubbe, JoAnne
Format: Artikel
Sprache:eng
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 9158
container_issue 36
container_start_page 9149
container_title Journal of the American Chemical Society
container_volume 120
creator Boger, Dale L
Ramsey, Timothy M
Cai, Hui
Hoehn, Silvia T
Stubbe, JoAnne
description The synthesis and a comparative study of deglycobleomycin A2 analogues containing key modifications in the valerate subunit are described in efforts that define the role of the linker length and its substituents. In addition to demonstrating that the C3-hydroxy group exhibits only a modest effect (1−2×) that may be attributed to an intermolecular H-bond with DNA and that the length of the linker is important (C4 > C5 > C3 > C2), the studies illustrate that the substantial impact of the C4-methyl group is linked to the presence of the C2-methyl group, while the modest impact of the C2-methyl group itself (ca. 2×) is not coupled to the presence of the C4-methyl group. These effects may be explained by the conformational properties of the agents resulting from the substitutions and beautifully fit the models of DNA-bound Co(III)OOH bleomycin A2 and deglycobleomycin A2. The magnitude of the effects suggests that an important functional role of the linker region is to facilitate adoption of a rigid, compact conformation productive for DNA cleavage. The studies also identify a second potential site that may adopt two nearly equivalent conformations which may constitute a swivel point that permits access to a class of related bound structures adaptable to the conformational characteristics of the multiple cleavage sites or access to both strands of DNA from a common intercalation site important for both primary (single strand) and secondary (double strand) cleavage.
doi_str_mv 10.1021/ja9816640
format Article
fullrecord <record><control><sourceid>acs_istex</sourceid><recordid>TN_cdi_istex_primary_ark_67375_TPS_F31BVNPR_N</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>c479077595</sourcerecordid><originalsourceid>FETCH-LOGICAL-a136t-14119213076a572a3be2b30a9c899d1cf6ab81a48b5c46ebee180b8c0b3f00923</originalsourceid><addsrcrecordid>eNo9kc1O20AUhUeISgToom8wm-5qmDtjj-3ugvlpJJRGCWU7up5cp5PanmBPEGHVLS_DQ_VJapTS1dW5-vTpSIexTyDOQEg4X2OegdaxOGAjSKSIEpD6kI2EEDJKM62O2HHfr4cYywxG7PWSKte64HzLfcXDT-JXVUU2cGyXfO5ren9f1OSbnXUtH0t-jzV1GIgvtmUfXNhSG_qvf36_8FlHvlth657xXYp87lZu-YUXvtngoC58W_mu2QOTZlM7O7iWfHAv6GFwWYoWVA8t3CPxy-mYFzXhI67olH2osO7p4797wn5cX90V36Lb7zeTYnwbISgdIogBcglKpBqTVKIqSZZKYG6zPF-CrTSWGWCclYmNNZVEkIkys6JUlRC5VCcs2ntdH-jJbDrXYLcz2P0yOlVpYu5mC3Ot4OJ-Opub6cB_3vNoe7P2264d2hkQ5m0U838U9RfhQ4CT</addsrcrecordid><sourcetype>Publisher</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Definition of the Effect and Role of the Bleomycin A2 Valerate Substituents:  Preorganization of a Rigid, Compact Conformation Implicated in Sequence-Selective DNA Cleavage</title><source>ACS Publications</source><creator>Boger, Dale L ; Ramsey, Timothy M ; Cai, Hui ; Hoehn, Silvia T ; Stubbe, JoAnne</creator><creatorcontrib>Boger, Dale L ; Ramsey, Timothy M ; Cai, Hui ; Hoehn, Silvia T ; Stubbe, JoAnne</creatorcontrib><description>The synthesis and a comparative study of deglycobleomycin A2 analogues containing key modifications in the valerate subunit are described in efforts that define the role of the linker length and its substituents. In addition to demonstrating that the C3-hydroxy group exhibits only a modest effect (1−2×) that may be attributed to an intermolecular H-bond with DNA and that the length of the linker is important (C4 &gt; C5 &gt; C3 &gt; C2), the studies illustrate that the substantial impact of the C4-methyl group is linked to the presence of the C2-methyl group, while the modest impact of the C2-methyl group itself (ca. 2×) is not coupled to the presence of the C4-methyl group. These effects may be explained by the conformational properties of the agents resulting from the substitutions and beautifully fit the models of DNA-bound Co(III)OOH bleomycin A2 and deglycobleomycin A2. The magnitude of the effects suggests that an important functional role of the linker region is to facilitate adoption of a rigid, compact conformation productive for DNA cleavage. The studies also identify a second potential site that may adopt two nearly equivalent conformations which may constitute a swivel point that permits access to a class of related bound structures adaptable to the conformational characteristics of the multiple cleavage sites or access to both strands of DNA from a common intercalation site important for both primary (single strand) and secondary (double strand) cleavage.</description><identifier>ISSN: 0002-7863</identifier><identifier>EISSN: 1520-5126</identifier><identifier>DOI: 10.1021/ja9816640</identifier><language>eng</language><publisher>American Chemical Society</publisher><ispartof>Journal of the American Chemical Society, 1998-09, Vol.120 (36), p.9149-9158</ispartof><rights>Copyright © 1998 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/ja9816640$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/ja9816640$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,27053,27901,27902,56713,56763</link.rule.ids></links><search><creatorcontrib>Boger, Dale L</creatorcontrib><creatorcontrib>Ramsey, Timothy M</creatorcontrib><creatorcontrib>Cai, Hui</creatorcontrib><creatorcontrib>Hoehn, Silvia T</creatorcontrib><creatorcontrib>Stubbe, JoAnne</creatorcontrib><title>Definition of the Effect and Role of the Bleomycin A2 Valerate Substituents:  Preorganization of a Rigid, Compact Conformation Implicated in Sequence-Selective DNA Cleavage</title><title>Journal of the American Chemical Society</title><addtitle>J. Am. Chem. Soc</addtitle><description>The synthesis and a comparative study of deglycobleomycin A2 analogues containing key modifications in the valerate subunit are described in efforts that define the role of the linker length and its substituents. In addition to demonstrating that the C3-hydroxy group exhibits only a modest effect (1−2×) that may be attributed to an intermolecular H-bond with DNA and that the length of the linker is important (C4 &gt; C5 &gt; C3 &gt; C2), the studies illustrate that the substantial impact of the C4-methyl group is linked to the presence of the C2-methyl group, while the modest impact of the C2-methyl group itself (ca. 2×) is not coupled to the presence of the C4-methyl group. These effects may be explained by the conformational properties of the agents resulting from the substitutions and beautifully fit the models of DNA-bound Co(III)OOH bleomycin A2 and deglycobleomycin A2. The magnitude of the effects suggests that an important functional role of the linker region is to facilitate adoption of a rigid, compact conformation productive for DNA cleavage. The studies also identify a second potential site that may adopt two nearly equivalent conformations which may constitute a swivel point that permits access to a class of related bound structures adaptable to the conformational characteristics of the multiple cleavage sites or access to both strands of DNA from a common intercalation site important for both primary (single strand) and secondary (double strand) cleavage.</description><issn>0002-7863</issn><issn>1520-5126</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1998</creationdate><recordtype>article</recordtype><recordid>eNo9kc1O20AUhUeISgToom8wm-5qmDtjj-3ugvlpJJRGCWU7up5cp5PanmBPEGHVLS_DQ_VJapTS1dW5-vTpSIexTyDOQEg4X2OegdaxOGAjSKSIEpD6kI2EEDJKM62O2HHfr4cYywxG7PWSKte64HzLfcXDT-JXVUU2cGyXfO5ren9f1OSbnXUtH0t-jzV1GIgvtmUfXNhSG_qvf36_8FlHvlth657xXYp87lZu-YUXvtngoC58W_mu2QOTZlM7O7iWfHAv6GFwWYoWVA8t3CPxy-mYFzXhI67olH2osO7p4797wn5cX90V36Lb7zeTYnwbISgdIogBcglKpBqTVKIqSZZKYG6zPF-CrTSWGWCclYmNNZVEkIkys6JUlRC5VCcs2ntdH-jJbDrXYLcz2P0yOlVpYu5mC3Ot4OJ-Opub6cB_3vNoe7P2264d2hkQ5m0U838U9RfhQ4CT</recordid><startdate>19980916</startdate><enddate>19980916</enddate><creator>Boger, Dale L</creator><creator>Ramsey, Timothy M</creator><creator>Cai, Hui</creator><creator>Hoehn, Silvia T</creator><creator>Stubbe, JoAnne</creator><general>American Chemical Society</general><scope>BSCLL</scope></search><sort><creationdate>19980916</creationdate><title>Definition of the Effect and Role of the Bleomycin A2 Valerate Substituents:  Preorganization of a Rigid, Compact Conformation Implicated in Sequence-Selective DNA Cleavage</title><author>Boger, Dale L ; Ramsey, Timothy M ; Cai, Hui ; Hoehn, Silvia T ; Stubbe, JoAnne</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a136t-14119213076a572a3be2b30a9c899d1cf6ab81a48b5c46ebee180b8c0b3f00923</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1998</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Boger, Dale L</creatorcontrib><creatorcontrib>Ramsey, Timothy M</creatorcontrib><creatorcontrib>Cai, Hui</creatorcontrib><creatorcontrib>Hoehn, Silvia T</creatorcontrib><creatorcontrib>Stubbe, JoAnne</creatorcontrib><collection>Istex</collection><jtitle>Journal of the American Chemical Society</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Boger, Dale L</au><au>Ramsey, Timothy M</au><au>Cai, Hui</au><au>Hoehn, Silvia T</au><au>Stubbe, JoAnne</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Definition of the Effect and Role of the Bleomycin A2 Valerate Substituents:  Preorganization of a Rigid, Compact Conformation Implicated in Sequence-Selective DNA Cleavage</atitle><jtitle>Journal of the American Chemical Society</jtitle><addtitle>J. Am. Chem. Soc</addtitle><date>1998-09-16</date><risdate>1998</risdate><volume>120</volume><issue>36</issue><spage>9149</spage><epage>9158</epage><pages>9149-9158</pages><issn>0002-7863</issn><eissn>1520-5126</eissn><abstract>The synthesis and a comparative study of deglycobleomycin A2 analogues containing key modifications in the valerate subunit are described in efforts that define the role of the linker length and its substituents. In addition to demonstrating that the C3-hydroxy group exhibits only a modest effect (1−2×) that may be attributed to an intermolecular H-bond with DNA and that the length of the linker is important (C4 &gt; C5 &gt; C3 &gt; C2), the studies illustrate that the substantial impact of the C4-methyl group is linked to the presence of the C2-methyl group, while the modest impact of the C2-methyl group itself (ca. 2×) is not coupled to the presence of the C4-methyl group. These effects may be explained by the conformational properties of the agents resulting from the substitutions and beautifully fit the models of DNA-bound Co(III)OOH bleomycin A2 and deglycobleomycin A2. The magnitude of the effects suggests that an important functional role of the linker region is to facilitate adoption of a rigid, compact conformation productive for DNA cleavage. The studies also identify a second potential site that may adopt two nearly equivalent conformations which may constitute a swivel point that permits access to a class of related bound structures adaptable to the conformational characteristics of the multiple cleavage sites or access to both strands of DNA from a common intercalation site important for both primary (single strand) and secondary (double strand) cleavage.</abstract><pub>American Chemical Society</pub><doi>10.1021/ja9816640</doi><tpages>10</tpages></addata></record>
fulltext fulltext
identifier ISSN: 0002-7863
ispartof Journal of the American Chemical Society, 1998-09, Vol.120 (36), p.9149-9158
issn 0002-7863
1520-5126
language eng
recordid cdi_istex_primary_ark_67375_TPS_F31BVNPR_N
source ACS Publications
title Definition of the Effect and Role of the Bleomycin A2 Valerate Substituents:  Preorganization of a Rigid, Compact Conformation Implicated in Sequence-Selective DNA Cleavage
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-16T14%3A07%3A32IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-acs_istex&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Definition%20of%20the%20Effect%20and%20Role%20of%20the%20Bleomycin%20A2%20Valerate%20Substituents:%E2%80%89%20Preorganization%20of%20a%20Rigid,%20Compact%20Conformation%20Implicated%20in%20Sequence-Selective%20DNA%20Cleavage&rft.jtitle=Journal%20of%20the%20American%20Chemical%20Society&rft.au=Boger,%20Dale%20L&rft.date=1998-09-16&rft.volume=120&rft.issue=36&rft.spage=9149&rft.epage=9158&rft.pages=9149-9158&rft.issn=0002-7863&rft.eissn=1520-5126&rft_id=info:doi/10.1021/ja9816640&rft_dat=%3Cacs_istex%3Ec479077595%3C/acs_istex%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/&rfr_iscdi=true