Synthesis and in Vitro Evaluation of Biotinylated RG108: A High Affinity Compound for Studying Binding Interactions with Human DNA Methyltransferases
Small-molecule inhibitors of DNA methyltransferases such as RG108 represent promising candidates for cancer drug development. We report the synthesis and in vitro analysis of a biotinylated RG108 conjugate, 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(5-{3-[5-(2-oxo-hexahydro-thieno[3,4-d]imidazol-4-y...
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| Veröffentlicht in: | Bioconjugate chemistry 2006-03, Vol.17 (2), p.261-266 |
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| container_title | Bioconjugate chemistry |
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| creator | Schirrmacher, Esther Beck, Carmen Brueckner, Bodo Schmitges, Frank Siedlecki, Pawel Bartenstein, Peter Lyko, Frank Schirrmacher, Ralf |
| description | Small-molecule inhibitors of DNA methyltransferases such as RG108 represent promising candidates for cancer drug development. We report the synthesis and in vitro analysis of a biotinylated RG108 conjugate, 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(5-{3-[5-(2-oxo-hexahydro-thieno[3,4-d]imidazol-4-yl)pentanoylamino]propoxy}-1H-indol-3-yl)propionic acid (bio-RG108), for the evaluation of interactions with DNA methyltransferase enzymes. The structural design of the chemically modified inhibitor was aided by molecular modeling, which suggested the possibility for extensive chemical modifications at the 5-position of the tryptophan moiety in RG108. The inhibitory activity of the corresponding derivative was confirmed in a cell-free biochemical assay, where bio-RG108 showed an undiminished inhibition of DNA methyltransferase activity (IC50 = 40 nM). Bio-RG108 therefore represents a suitable bioconjugate for the elucidation of inhibitory mechanisms and for the affinity purification of RG108-associated proteins. |
| doi_str_mv | 10.1021/bc050300b |
| format | Article |
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We report the synthesis and in vitro analysis of a biotinylated RG108 conjugate, 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(5-{3-[5-(2-oxo-hexahydro-thieno[3,4-d]imidazol-4-yl)pentanoylamino]propoxy}-1H-indol-3-yl)propionic acid (bio-RG108), for the evaluation of interactions with DNA methyltransferase enzymes. The structural design of the chemically modified inhibitor was aided by molecular modeling, which suggested the possibility for extensive chemical modifications at the 5-position of the tryptophan moiety in RG108. The inhibitory activity of the corresponding derivative was confirmed in a cell-free biochemical assay, where bio-RG108 showed an undiminished inhibition of DNA methyltransferase activity (IC50 = 40 nM). Bio-RG108 therefore represents a suitable bioconjugate for the elucidation of inhibitory mechanisms and for the affinity purification of RG108-associated proteins.</description><identifier>ISSN: 1043-1802</identifier><identifier>EISSN: 1520-4812</identifier><identifier>DOI: 10.1021/bc050300b</identifier><identifier>PMID: 16536454</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Biochemistry ; Biotin - chemistry ; Biotin - metabolism ; Cell-Free System ; Deoxyribonucleic acid ; DNA ; DNA Modification Methylases - antagonists & inhibitors ; DNA Modification Methylases - metabolism ; Enzymes ; Human body ; Humans ; Indoles - chemistry ; Indoles - metabolism ; Medical research ; Molecular Structure ; Nuclear Magnetic Resonance, Biomolecular ; Phthalimides ; Prescription drugs ; Propionates - chemistry ; Propionates - metabolism ; Protein Binding ; Proteins ; Tryptophan - analogs & derivatives</subject><ispartof>Bioconjugate chemistry, 2006-03, Vol.17 (2), p.261-266</ispartof><rights>Copyright © 2006 American Chemical Society</rights><rights>Copyright American Chemical Society Mar 2006</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a409t-6e798c3b31febc727b4a274957664754f9f0fc55fc3fc30b0f737fdd5b28884f3</citedby><cites>FETCH-LOGICAL-a409t-6e798c3b31febc727b4a274957664754f9f0fc55fc3fc30b0f737fdd5b28884f3</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/bc050300b$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/bc050300b$$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/16536454$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Schirrmacher, Esther</creatorcontrib><creatorcontrib>Beck, Carmen</creatorcontrib><creatorcontrib>Brueckner, Bodo</creatorcontrib><creatorcontrib>Schmitges, Frank</creatorcontrib><creatorcontrib>Siedlecki, Pawel</creatorcontrib><creatorcontrib>Bartenstein, Peter</creatorcontrib><creatorcontrib>Lyko, Frank</creatorcontrib><creatorcontrib>Schirrmacher, Ralf</creatorcontrib><title>Synthesis and in Vitro Evaluation of Biotinylated RG108: A High Affinity Compound for Studying Binding Interactions with Human DNA Methyltransferases</title><title>Bioconjugate chemistry</title><addtitle>Bioconjugate Chem</addtitle><description>Small-molecule inhibitors of DNA methyltransferases such as RG108 represent promising candidates for cancer drug development. We report the synthesis and in vitro analysis of a biotinylated RG108 conjugate, 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(5-{3-[5-(2-oxo-hexahydro-thieno[3,4-d]imidazol-4-yl)pentanoylamino]propoxy}-1H-indol-3-yl)propionic acid (bio-RG108), for the evaluation of interactions with DNA methyltransferase enzymes. The structural design of the chemically modified inhibitor was aided by molecular modeling, which suggested the possibility for extensive chemical modifications at the 5-position of the tryptophan moiety in RG108. The inhibitory activity of the corresponding derivative was confirmed in a cell-free biochemical assay, where bio-RG108 showed an undiminished inhibition of DNA methyltransferase activity (IC50 = 40 nM). Bio-RG108 therefore represents a suitable bioconjugate for the elucidation of inhibitory mechanisms and for the affinity purification of RG108-associated proteins.</description><subject>Biochemistry</subject><subject>Biotin - chemistry</subject><subject>Biotin - metabolism</subject><subject>Cell-Free System</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA Modification Methylases - antagonists & inhibitors</subject><subject>DNA Modification Methylases - metabolism</subject><subject>Enzymes</subject><subject>Human body</subject><subject>Humans</subject><subject>Indoles - chemistry</subject><subject>Indoles - metabolism</subject><subject>Medical research</subject><subject>Molecular Structure</subject><subject>Nuclear Magnetic Resonance, Biomolecular</subject><subject>Phthalimides</subject><subject>Prescription drugs</subject><subject>Propionates - chemistry</subject><subject>Propionates - metabolism</subject><subject>Protein Binding</subject><subject>Proteins</subject><subject>Tryptophan - analogs & derivatives</subject><issn>1043-1802</issn><issn>1520-4812</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0cuO0zAUBuAIgZgLLHgBZCExEovA8SWOw66UoR1pCogOLNhETmJPPZPaxXaA7NjyBjwfT4KrVjMSLJAsHUv-_PtYJ8seYXiOgeAXTQsFUIDmTnaICwI5E5jcTXtgNMcCyEF2FMIVAFRYkPvZAeYF5axgh9mv5WjjSgUTkLQdMhZ9MtE7dPpV9oOMxlnkNHplXDR27GVUHfowwyBe_v7xE03Q3Fyu0ERrY00c0dStN25IMdp5tIxDNxp7mS7bblvPbFRettvMgL6ZuELzYS0tev12ghYqrsY-emmDTiio8CC7p2Uf1MN9Pc4-vjm9mM7z83ezs-nkPJcMqphzVVaipQ3FWjVtScqGSVKyqig5Z2XBdKVBt0WhW5oWNKBLWuquKxoihGCaHmcnu9yNd18GFWK9NqFVfS-tckOoeZnSiKD_hQQop1TgBJ_8Ba_c4G36RE0wxxUAZwk926HWuxC80vXGm7X0Y42h3g61vhlqso_3gUOzVt2t3E8xgXwHTIjq-8259NepfVoW9cX7Zc0Xn8lituA1Sf7pzss23Db378N_ACumuFQ</recordid><startdate>20060301</startdate><enddate>20060301</enddate><creator>Schirrmacher, Esther</creator><creator>Beck, Carmen</creator><creator>Brueckner, Bodo</creator><creator>Schmitges, Frank</creator><creator>Siedlecki, Pawel</creator><creator>Bartenstein, Peter</creator><creator>Lyko, Frank</creator><creator>Schirrmacher, Ralf</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>7QO</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20060301</creationdate><title>Synthesis and in Vitro Evaluation of Biotinylated RG108: A High Affinity Compound for Studying Binding Interactions with Human DNA Methyltransferases</title><author>Schirrmacher, Esther ; Beck, Carmen ; Brueckner, Bodo ; Schmitges, Frank ; Siedlecki, Pawel ; Bartenstein, Peter ; Lyko, Frank ; Schirrmacher, Ralf</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a409t-6e798c3b31febc727b4a274957664754f9f0fc55fc3fc30b0f737fdd5b28884f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Biochemistry</topic><topic>Biotin - chemistry</topic><topic>Biotin - metabolism</topic><topic>Cell-Free System</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA Modification Methylases - antagonists & inhibitors</topic><topic>DNA Modification Methylases - metabolism</topic><topic>Enzymes</topic><topic>Human body</topic><topic>Humans</topic><topic>Indoles - chemistry</topic><topic>Indoles - metabolism</topic><topic>Medical research</topic><topic>Molecular Structure</topic><topic>Nuclear Magnetic Resonance, Biomolecular</topic><topic>Phthalimides</topic><topic>Prescription drugs</topic><topic>Propionates - chemistry</topic><topic>Propionates - metabolism</topic><topic>Protein Binding</topic><topic>Proteins</topic><topic>Tryptophan - analogs & derivatives</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Schirrmacher, Esther</creatorcontrib><creatorcontrib>Beck, Carmen</creatorcontrib><creatorcontrib>Brueckner, Bodo</creatorcontrib><creatorcontrib>Schmitges, Frank</creatorcontrib><creatorcontrib>Siedlecki, Pawel</creatorcontrib><creatorcontrib>Bartenstein, Peter</creatorcontrib><creatorcontrib>Lyko, Frank</creatorcontrib><creatorcontrib>Schirrmacher, Ralf</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>Biotechnology Research Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Bioconjugate chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Schirrmacher, Esther</au><au>Beck, Carmen</au><au>Brueckner, Bodo</au><au>Schmitges, Frank</au><au>Siedlecki, Pawel</au><au>Bartenstein, Peter</au><au>Lyko, Frank</au><au>Schirrmacher, Ralf</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and in Vitro Evaluation of Biotinylated RG108: A High Affinity Compound for Studying Binding Interactions with Human DNA Methyltransferases</atitle><jtitle>Bioconjugate chemistry</jtitle><addtitle>Bioconjugate Chem</addtitle><date>2006-03-01</date><risdate>2006</risdate><volume>17</volume><issue>2</issue><spage>261</spage><epage>266</epage><pages>261-266</pages><issn>1043-1802</issn><eissn>1520-4812</eissn><abstract>Small-molecule inhibitors of DNA methyltransferases such as RG108 represent promising candidates for cancer drug development. We report the synthesis and in vitro analysis of a biotinylated RG108 conjugate, 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(5-{3-[5-(2-oxo-hexahydro-thieno[3,4-d]imidazol-4-yl)pentanoylamino]propoxy}-1H-indol-3-yl)propionic acid (bio-RG108), for the evaluation of interactions with DNA methyltransferase enzymes. The structural design of the chemically modified inhibitor was aided by molecular modeling, which suggested the possibility for extensive chemical modifications at the 5-position of the tryptophan moiety in RG108. The inhibitory activity of the corresponding derivative was confirmed in a cell-free biochemical assay, where bio-RG108 showed an undiminished inhibition of DNA methyltransferase activity (IC50 = 40 nM). Bio-RG108 therefore represents a suitable bioconjugate for the elucidation of inhibitory mechanisms and for the affinity purification of RG108-associated proteins.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>16536454</pmid><doi>10.1021/bc050300b</doi><tpages>6</tpages></addata></record> |
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| ispartof | Bioconjugate chemistry, 2006-03, Vol.17 (2), p.261-266 |
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| subjects | Biochemistry Biotin - chemistry Biotin - metabolism Cell-Free System Deoxyribonucleic acid DNA DNA Modification Methylases - antagonists & inhibitors DNA Modification Methylases - metabolism Enzymes Human body Humans Indoles - chemistry Indoles - metabolism Medical research Molecular Structure Nuclear Magnetic Resonance, Biomolecular Phthalimides Prescription drugs Propionates - chemistry Propionates - metabolism Protein Binding Proteins Tryptophan - analogs & derivatives |
| title | Synthesis and in Vitro Evaluation of Biotinylated RG108: A High Affinity Compound for Studying Binding Interactions with Human DNA Methyltransferases |
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