Synthesis and biological evaluation of sparsomycin analogs
Three series of sparsomycin analogues were prepared and examined for their ability to inhibit DNA or protein synthesis in bone marrow, P388 lymphocytic leukemia, and P815 mastocytoma cells. The compounds of series I and II, distinguished by the inclusion or exclusion of a hydroxymethyl functional gr...
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| Veröffentlicht in: | Journal of medicinal chemistry 1983-11, Vol.26 (11), p.1556-1561 |
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| container_title | Journal of medicinal chemistry |
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| creator | Duke, Scherer S Boots, Marvin R |
| description | Three series of sparsomycin analogues were prepared and examined for their ability to inhibit DNA or protein synthesis in bone marrow, P388 lymphocytic leukemia, and P815 mastocytoma cells. The compounds of series I and II, distinguished by the inclusion or exclusion of a hydroxymethyl functional group, were designed to elucidate the effect on activity of replacing the oxodithioacetal side chain of sparsomycin with 4-substituted benzyl groups. The series III analogues, which excluded the hydroxymethyl group and replaced the oxodithioacetal moiety of sparsomycin with a benzyl amide group, were designed to investigate the potential interaction of an amide oxygen in contrast to the sulfoxide oxygen of sparsomycin. Overall, the bromobenzyl-substituted analogues imparted the greatest inhibitory activity in the protein synthesis assay, while the methoxybenzyl-substituted analogues displayed the least. The methylbenzyl and the unsubstituted benzyl compounds were intermediate in inhibitory potential. The activity in the protein synthesis assay may correspond to the lipophilic and electronic characteristics of the substituents on the benzyl moiety of the analogues. All of the compounds were inactive in the DNA synthesis assay. |
| doi_str_mv | 10.1021/jm00365a003 |
| format | Article |
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The compounds of series I and II, distinguished by the inclusion or exclusion of a hydroxymethyl functional group, were designed to elucidate the effect on activity of replacing the oxodithioacetal side chain of sparsomycin with 4-substituted benzyl groups. The series III analogues, which excluded the hydroxymethyl group and replaced the oxodithioacetal moiety of sparsomycin with a benzyl amide group, were designed to investigate the potential interaction of an amide oxygen in contrast to the sulfoxide oxygen of sparsomycin. Overall, the bromobenzyl-substituted analogues imparted the greatest inhibitory activity in the protein synthesis assay, while the methoxybenzyl-substituted analogues displayed the least. The methylbenzyl and the unsubstituted benzyl compounds were intermediate in inhibitory potential. The activity in the protein synthesis assay may correspond to the lipophilic and electronic characteristics of the substituents on the benzyl moiety of the analogues. All of the compounds were inactive in the DNA synthesis assay.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00365a003</identifier><identifier>PMID: 6415284</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Antibiotics, Antineoplastic - chemical synthesis ; Biological Assay ; Bone Marrow - drug effects ; Bone Marrow - metabolism ; Chemistry ; DNA Replication - drug effects ; Drug Evaluation, Preclinical ; Exact sciences and technology ; Heterocyclic compounds ; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings ; Indicators and Reagents ; Leukemia P388 - drug therapy ; Male ; Mast-Cell Sarcoma - drug therapy ; Mice ; Mice, Inbred DBA ; Organic chemistry ; Preparations and properties ; Protein Biosynthesis - drug effects ; Sparsomycin - analogs & derivatives ; Sparsomycin - chemical synthesis ; Sparsomycin - pharmacology ; Sparsomycin - therapeutic use ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 1983-11, Vol.26 (11), p.1556-1561</ispartof><rights>1984 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a383t-55f9321504d199482bab9a710564f45c96928efb21578b172bda57448d1b01c03</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm00365a003$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00365a003$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,777,781,2753,27058,27906,27907,56720,56770</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=9348786$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/6415284$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Duke, Scherer S</creatorcontrib><creatorcontrib>Boots, Marvin R</creatorcontrib><title>Synthesis and biological evaluation of sparsomycin analogs</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Three series of sparsomycin analogues were prepared and examined for their ability to inhibit DNA or protein synthesis in bone marrow, P388 lymphocytic leukemia, and P815 mastocytoma cells. The compounds of series I and II, distinguished by the inclusion or exclusion of a hydroxymethyl functional group, were designed to elucidate the effect on activity of replacing the oxodithioacetal side chain of sparsomycin with 4-substituted benzyl groups. The series III analogues, which excluded the hydroxymethyl group and replaced the oxodithioacetal moiety of sparsomycin with a benzyl amide group, were designed to investigate the potential interaction of an amide oxygen in contrast to the sulfoxide oxygen of sparsomycin. Overall, the bromobenzyl-substituted analogues imparted the greatest inhibitory activity in the protein synthesis assay, while the methoxybenzyl-substituted analogues displayed the least. The methylbenzyl and the unsubstituted benzyl compounds were intermediate in inhibitory potential. The activity in the protein synthesis assay may correspond to the lipophilic and electronic characteristics of the substituents on the benzyl moiety of the analogues. All of the compounds were inactive in the DNA synthesis assay.</description><subject>Animals</subject><subject>Antibiotics, Antineoplastic - chemical synthesis</subject><subject>Biological Assay</subject><subject>Bone Marrow - drug effects</subject><subject>Bone Marrow - metabolism</subject><subject>Chemistry</subject><subject>DNA Replication - drug effects</subject><subject>Drug Evaluation, Preclinical</subject><subject>Exact sciences and technology</subject><subject>Heterocyclic compounds</subject><subject>Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings</subject><subject>Indicators and Reagents</subject><subject>Leukemia P388 - drug therapy</subject><subject>Male</subject><subject>Mast-Cell Sarcoma - drug therapy</subject><subject>Mice</subject><subject>Mice, Inbred DBA</subject><subject>Organic chemistry</subject><subject>Preparations and properties</subject><subject>Protein Biosynthesis - drug effects</subject><subject>Sparsomycin - analogs & derivatives</subject><subject>Sparsomycin - chemical synthesis</subject><subject>Sparsomycin - pharmacology</subject><subject>Sparsomycin - therapeutic use</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1983</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0M9L3EAUB_BBKrq1nnoWcijtQaLzMzPxVkSrsqVFLZRehpdkorNNMuu8pLj_vSO7LD14ee_w_fB4fAn5yOgJo5ydLnpKRaEgzR0yY4rTXBoq35EZpZznvOBin7xHXNAkGBd7ZK-QiRk5I2d3q2F8dOgxg6HJKh-68OBr6DL3D7oJRh-GLLQZLiFi6Fe1HxKEhPAD2W2hQ3e42Qfk1-XF_flVPv_x7fr86zwHYcSYK9WWgjNFZcPKUhpeQVWCZlQVspWqLouSG9dWiWhTMc2rBpSW0jSsoqym4oB8Xt9dxvA0ORxt77F2XQeDCxNaQzXTiuoEj9ewjgExutYuo-8hriyj9rUp-19TSR9tzk5V75qt3VST8k-bHDD10UYYao9bVgpptCkSy9fM4-ietzHEv7bQQit7__PO_r75_mde3s7tZfJf1h5qtIswxVQmvvngCxZNikQ</recordid><startdate>198311</startdate><enddate>198311</enddate><creator>Duke, Scherer S</creator><creator>Boots, Marvin R</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>IQODW</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>7X8</scope></search><sort><creationdate>198311</creationdate><title>Synthesis and biological evaluation of sparsomycin analogs</title><author>Duke, Scherer S ; Boots, Marvin R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a383t-55f9321504d199482bab9a710564f45c96928efb21578b172bda57448d1b01c03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1983</creationdate><topic>Animals</topic><topic>Antibiotics, Antineoplastic - chemical synthesis</topic><topic>Biological Assay</topic><topic>Bone Marrow - drug effects</topic><topic>Bone Marrow - metabolism</topic><topic>Chemistry</topic><topic>DNA Replication - drug effects</topic><topic>Drug Evaluation, Preclinical</topic><topic>Exact sciences and technology</topic><topic>Heterocyclic compounds</topic><topic>Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings</topic><topic>Indicators and Reagents</topic><topic>Leukemia P388 - drug therapy</topic><topic>Male</topic><topic>Mast-Cell Sarcoma - drug therapy</topic><topic>Mice</topic><topic>Mice, Inbred DBA</topic><topic>Organic chemistry</topic><topic>Preparations and properties</topic><topic>Protein Biosynthesis - drug effects</topic><topic>Sparsomycin - analogs & derivatives</topic><topic>Sparsomycin - chemical synthesis</topic><topic>Sparsomycin - pharmacology</topic><topic>Sparsomycin - therapeutic use</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Duke, Scherer S</creatorcontrib><creatorcontrib>Boots, Marvin R</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><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>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Duke, Scherer S</au><au>Boots, Marvin R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and biological evaluation of sparsomycin analogs</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1983-11</date><risdate>1983</risdate><volume>26</volume><issue>11</issue><spage>1556</spage><epage>1561</epage><pages>1556-1561</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Three series of sparsomycin analogues were prepared and examined for their ability to inhibit DNA or protein synthesis in bone marrow, P388 lymphocytic leukemia, and P815 mastocytoma cells. The compounds of series I and II, distinguished by the inclusion or exclusion of a hydroxymethyl functional group, were designed to elucidate the effect on activity of replacing the oxodithioacetal side chain of sparsomycin with 4-substituted benzyl groups. The series III analogues, which excluded the hydroxymethyl group and replaced the oxodithioacetal moiety of sparsomycin with a benzyl amide group, were designed to investigate the potential interaction of an amide oxygen in contrast to the sulfoxide oxygen of sparsomycin. Overall, the bromobenzyl-substituted analogues imparted the greatest inhibitory activity in the protein synthesis assay, while the methoxybenzyl-substituted analogues displayed the least. The methylbenzyl and the unsubstituted benzyl compounds were intermediate in inhibitory potential. The activity in the protein synthesis assay may correspond to the lipophilic and electronic characteristics of the substituents on the benzyl moiety of the analogues. All of the compounds were inactive in the DNA synthesis assay.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>6415284</pmid><doi>10.1021/jm00365a003</doi><tpages>6</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 1983-11, Vol.26 (11), p.1556-1561 |
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| language | eng |
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| source | MEDLINE; American Chemical Society Journals |
| subjects | Animals Antibiotics, Antineoplastic - chemical synthesis Biological Assay Bone Marrow - drug effects Bone Marrow - metabolism Chemistry DNA Replication - drug effects Drug Evaluation, Preclinical Exact sciences and technology Heterocyclic compounds Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings Indicators and Reagents Leukemia P388 - drug therapy Male Mast-Cell Sarcoma - drug therapy Mice Mice, Inbred DBA Organic chemistry Preparations and properties Protein Biosynthesis - drug effects Sparsomycin - analogs & derivatives Sparsomycin - chemical synthesis Sparsomycin - pharmacology Sparsomycin - therapeutic use Structure-Activity Relationship |
| title | Synthesis and biological evaluation of sparsomycin analogs |
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