Radioprotective stereostructure-activity study of cis- and trans-2-mercaptocyclobutylamine analogs and homologs of 2-mercaptoethylamine
For purposes of studying stereostructure-activity relationships at the molecular, cellular, and animal levels and probing the mechanism of 2-mercaptoethylamine (MEA) radioprotection we synthesized several conformationally constrained cyclobutyl analogs. The comparative radioprotective properties for...
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| Veröffentlicht in: | Journal of medicinal chemistry 1975-04, Vol.18 (4), p.323-331 |
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| container_title | Journal of medicinal chemistry |
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| creator | Hart, Ronald W Gibson, Ruth E Chapman, J. Donald Reuvers, Antoon P Sinha, Birandra K Griffith, Robert K Witiak, Donald T |
| description | For purposes of studying stereostructure-activity relationships at the molecular, cellular, and animal levels and probing the mechanism of 2-mercaptoethylamine (MEA) radioprotection we synthesized several conformationally constrained cyclobutyl analogs. The comparative radioprotective properties for MEA, cis- and trans-2-mercaptocyclobutylamine (2), cis- and trans-2-mercaptocyclobutylmethylamine (3), and trans-2-mercaptomethylcyclobutylamine (4) are discussed in terms of their ability to chemically reduce transient free radicals, the formation of single strand breaks in DNA, and protect Chinese hamster cells (in vitro) and mice against the lethal effects of ionizing radiation. The results are interpreted in light of current proposed mechanisms of action for MEA. No correlation exists between ability of these analogs to enhance mice survival times and their ability to protect against the induction of DNA single strand breaks and the inactivation of proliferative capacity of hamster cells growing in vitro. Analysis of two isomers (cis- and trans-3) on the repair of single strand breaks showed both isomers only marginally influenced the rate and did not influence of extent of single strand break rejoining. The results are consistent with a mode of action involving chemical repair of transient radicals and protection against DNA and critical enzymatic sites. |
| doi_str_mv | 10.1021/jm00238a001 |
| format | Article |
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Donald ; Reuvers, Antoon P ; Sinha, Birandra K ; Griffith, Robert K ; Witiak, Donald T</creator><creatorcontrib>Hart, Ronald W ; Gibson, Ruth E ; Chapman, J. Donald ; Reuvers, Antoon P ; Sinha, Birandra K ; Griffith, Robert K ; Witiak, Donald T ; Ohio State Univ., Columbus</creatorcontrib><description>For purposes of studying stereostructure-activity relationships at the molecular, cellular, and animal levels and probing the mechanism of 2-mercaptoethylamine (MEA) radioprotection we synthesized several conformationally constrained cyclobutyl analogs. The comparative radioprotective properties for MEA, cis- and trans-2-mercaptocyclobutylamine (2), cis- and trans-2-mercaptocyclobutylmethylamine (3), and trans-2-mercaptomethylcyclobutylamine (4) are discussed in terms of their ability to chemically reduce transient free radicals, the formation of single strand breaks in DNA, and protect Chinese hamster cells (in vitro) and mice against the lethal effects of ionizing radiation. The results are interpreted in light of current proposed mechanisms of action for MEA. No correlation exists between ability of these analogs to enhance mice survival times and their ability to protect against the induction of DNA single strand breaks and the inactivation of proliferative capacity of hamster cells growing in vitro. Analysis of two isomers (cis- and trans-3) on the repair of single strand breaks showed both isomers only marginally influenced the rate and did not influence of extent of single strand break rejoining. The results are consistent with a mode of action involving chemical repair of transient radicals and protection against DNA and critical enzymatic sites.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00238a001</identifier><identifier>PMID: 1120998</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>ANIMAL CELLS- BIOLOGICAL RADIATION EFFECTS ; Animals ; Cell Line ; CELL PROLIFERATION ; Cricetinae ; Cyclobutanes - chemical synthesis ; Cyclobutanes - pharmacology ; DNA - radiation effects ; DNA Repair - drug effects ; DNA Repair - radiation effects ; DNA- STRAND BREAKS ; Dose-Response Relationship, Radiation ; Female ; GAMMA RADIATION ; Gamma Rays ; HAMSTERS ; MEA- RADIOSENSITIVITY EFFECTS ; Mercaptoethylamines - chemical synthesis ; Mercaptoethylamines - pharmacology ; MICE ; Mice, Inbred ICR ; ORGANIC SULFUR COMPOUNDS- RADIOSENSITIVITY EFFECTS ; Radiation Effects ; RADIATION PROTECTION ; Radiation-Protective Agents - chemical synthesis ; Radiation-Protective Agents - pharmacology ; RADICALS ; RADIOLOGY AND NUCLEAR MEDICINE ; Stereoisomerism ; STRAND BREAKS- RADIOINDUCTION ; Structure-Activity Relationship ; Sulfhydryl Compounds - chemical synthesis ; Sulfhydryl Compounds - pharmacology ; SURVIVAL TIME</subject><ispartof>Journal of medicinal chemistry, 1975-04, Vol.18 (4), p.323-331</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a296t-849ae66dc058bc8e8c8f8ccabe7876966511850e5aaeec32fef19d6a4b7cd0763</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/jm00238a001$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00238a001$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,778,782,883,2754,27063,27911,27912,56725,56775</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/1120998$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/4127620$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Hart, Ronald W</creatorcontrib><creatorcontrib>Gibson, Ruth E</creatorcontrib><creatorcontrib>Chapman, J. Donald</creatorcontrib><creatorcontrib>Reuvers, Antoon P</creatorcontrib><creatorcontrib>Sinha, Birandra K</creatorcontrib><creatorcontrib>Griffith, Robert K</creatorcontrib><creatorcontrib>Witiak, Donald T</creatorcontrib><creatorcontrib>Ohio State Univ., Columbus</creatorcontrib><title>Radioprotective stereostructure-activity study of cis- and trans-2-mercaptocyclobutylamine analogs and homologs of 2-mercaptoethylamine</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>For purposes of studying stereostructure-activity relationships at the molecular, cellular, and animal levels and probing the mechanism of 2-mercaptoethylamine (MEA) radioprotection we synthesized several conformationally constrained cyclobutyl analogs. The comparative radioprotective properties for MEA, cis- and trans-2-mercaptocyclobutylamine (2), cis- and trans-2-mercaptocyclobutylmethylamine (3), and trans-2-mercaptomethylcyclobutylamine (4) are discussed in terms of their ability to chemically reduce transient free radicals, the formation of single strand breaks in DNA, and protect Chinese hamster cells (in vitro) and mice against the lethal effects of ionizing radiation. The results are interpreted in light of current proposed mechanisms of action for MEA. No correlation exists between ability of these analogs to enhance mice survival times and their ability to protect against the induction of DNA single strand breaks and the inactivation of proliferative capacity of hamster cells growing in vitro. Analysis of two isomers (cis- and trans-3) on the repair of single strand breaks showed both isomers only marginally influenced the rate and did not influence of extent of single strand break rejoining. The results are consistent with a mode of action involving chemical repair of transient radicals and protection against DNA and critical enzymatic sites.</description><subject>ANIMAL CELLS- BIOLOGICAL RADIATION EFFECTS</subject><subject>Animals</subject><subject>Cell Line</subject><subject>CELL PROLIFERATION</subject><subject>Cricetinae</subject><subject>Cyclobutanes - chemical synthesis</subject><subject>Cyclobutanes - pharmacology</subject><subject>DNA - radiation effects</subject><subject>DNA Repair - drug effects</subject><subject>DNA Repair - radiation effects</subject><subject>DNA- STRAND BREAKS</subject><subject>Dose-Response Relationship, Radiation</subject><subject>Female</subject><subject>GAMMA RADIATION</subject><subject>Gamma Rays</subject><subject>HAMSTERS</subject><subject>MEA- RADIOSENSITIVITY EFFECTS</subject><subject>Mercaptoethylamines - chemical synthesis</subject><subject>Mercaptoethylamines - pharmacology</subject><subject>MICE</subject><subject>Mice, Inbred ICR</subject><subject>ORGANIC SULFUR COMPOUNDS- RADIOSENSITIVITY EFFECTS</subject><subject>Radiation Effects</subject><subject>RADIATION PROTECTION</subject><subject>Radiation-Protective Agents - chemical synthesis</subject><subject>Radiation-Protective Agents - pharmacology</subject><subject>RADICALS</subject><subject>RADIOLOGY AND NUCLEAR MEDICINE</subject><subject>Stereoisomerism</subject><subject>STRAND BREAKS- RADIOINDUCTION</subject><subject>Structure-Activity Relationship</subject><subject>Sulfhydryl Compounds - chemical synthesis</subject><subject>Sulfhydryl Compounds - pharmacology</subject><subject>SURVIVAL TIME</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1975</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkMFu1DAQhi0EKtvCiTNSxIUDMoydxHGOqCoUVIkC5dKLNXEmrJdNvLIdRJ6A18ZtKsqBk-X5P4_1f4w9E_BagBRvdiOALDUCiAdsI2oJvNJQPWSbPJdcKlk-Zscx7gCgFLI8YkdCSGhbvWG_v2Dv_CH4RDa5n1TERIF8TGG2aQ7E8Wbs0pKDuV8KPxTWRV7g1Bcp4BS55CMFi4fk7WL3vpvTssfRTZQZ3Pvv8Zbd-tHfXvKC-xeUtnfwE_ZowH2kp3fnCfv27uzq9JxffHr_4fTtBUfZqsR11SIp1VuodWc1aasHbS121OhGtUrVQugaqEYksqUcaBBtr7DqGttDo8oT9mLdmys6E63LvbfWT1OubyohGyUhQ69WyAYfY6DBHIIbMSxGgLlRbv5RnunnK32Yu5H6e3Z1nHO-5i67_fU3xvDDqKZsanN1-dVcy-vPl3Xz0bSZf7nyaKPZ-TlkjfG_P_8BiWyblg</recordid><startdate>19750401</startdate><enddate>19750401</enddate><creator>Hart, Ronald W</creator><creator>Gibson, Ruth E</creator><creator>Chapman, J. Donald</creator><creator>Reuvers, Antoon P</creator><creator>Sinha, Birandra K</creator><creator>Griffith, Robert K</creator><creator>Witiak, Donald T</creator><general>American Chemical Society</general><general>American Chemical Society (ACS)</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>OTOTI</scope></search><sort><creationdate>19750401</creationdate><title>Radioprotective stereostructure-activity study of cis- and trans-2-mercaptocyclobutylamine analogs and homologs of 2-mercaptoethylamine</title><author>Hart, Ronald W ; Gibson, Ruth E ; Chapman, J. Donald ; Reuvers, Antoon P ; Sinha, Birandra K ; Griffith, Robert K ; Witiak, Donald T</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a296t-849ae66dc058bc8e8c8f8ccabe7876966511850e5aaeec32fef19d6a4b7cd0763</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1975</creationdate><topic>ANIMAL CELLS- BIOLOGICAL RADIATION EFFECTS</topic><topic>Animals</topic><topic>Cell Line</topic><topic>CELL PROLIFERATION</topic><topic>Cricetinae</topic><topic>Cyclobutanes - chemical synthesis</topic><topic>Cyclobutanes - pharmacology</topic><topic>DNA - radiation effects</topic><topic>DNA Repair - drug effects</topic><topic>DNA Repair - radiation effects</topic><topic>DNA- STRAND BREAKS</topic><topic>Dose-Response Relationship, Radiation</topic><topic>Female</topic><topic>GAMMA RADIATION</topic><topic>Gamma Rays</topic><topic>HAMSTERS</topic><topic>MEA- RADIOSENSITIVITY EFFECTS</topic><topic>Mercaptoethylamines - chemical synthesis</topic><topic>Mercaptoethylamines - pharmacology</topic><topic>MICE</topic><topic>Mice, Inbred ICR</topic><topic>ORGANIC SULFUR COMPOUNDS- RADIOSENSITIVITY EFFECTS</topic><topic>Radiation Effects</topic><topic>RADIATION PROTECTION</topic><topic>Radiation-Protective Agents - chemical synthesis</topic><topic>Radiation-Protective Agents - pharmacology</topic><topic>RADICALS</topic><topic>RADIOLOGY AND NUCLEAR MEDICINE</topic><topic>Stereoisomerism</topic><topic>STRAND BREAKS- RADIOINDUCTION</topic><topic>Structure-Activity Relationship</topic><topic>Sulfhydryl Compounds - chemical synthesis</topic><topic>Sulfhydryl Compounds - pharmacology</topic><topic>SURVIVAL TIME</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hart, Ronald W</creatorcontrib><creatorcontrib>Gibson, Ruth E</creatorcontrib><creatorcontrib>Chapman, J. Donald</creatorcontrib><creatorcontrib>Reuvers, Antoon P</creatorcontrib><creatorcontrib>Sinha, Birandra K</creatorcontrib><creatorcontrib>Griffith, Robert K</creatorcontrib><creatorcontrib>Witiak, Donald T</creatorcontrib><creatorcontrib>Ohio State Univ., Columbus</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>OSTI.GOV</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hart, Ronald W</au><au>Gibson, Ruth E</au><au>Chapman, J. Donald</au><au>Reuvers, Antoon P</au><au>Sinha, Birandra K</au><au>Griffith, Robert K</au><au>Witiak, Donald T</au><aucorp>Ohio State Univ., Columbus</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Radioprotective stereostructure-activity study of cis- and trans-2-mercaptocyclobutylamine analogs and homologs of 2-mercaptoethylamine</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1975-04-01</date><risdate>1975</risdate><volume>18</volume><issue>4</issue><spage>323</spage><epage>331</epage><pages>323-331</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>For purposes of studying stereostructure-activity relationships at the molecular, cellular, and animal levels and probing the mechanism of 2-mercaptoethylamine (MEA) radioprotection we synthesized several conformationally constrained cyclobutyl analogs. The comparative radioprotective properties for MEA, cis- and trans-2-mercaptocyclobutylamine (2), cis- and trans-2-mercaptocyclobutylmethylamine (3), and trans-2-mercaptomethylcyclobutylamine (4) are discussed in terms of their ability to chemically reduce transient free radicals, the formation of single strand breaks in DNA, and protect Chinese hamster cells (in vitro) and mice against the lethal effects of ionizing radiation. The results are interpreted in light of current proposed mechanisms of action for MEA. No correlation exists between ability of these analogs to enhance mice survival times and their ability to protect against the induction of DNA single strand breaks and the inactivation of proliferative capacity of hamster cells growing in vitro. Analysis of two isomers (cis- and trans-3) on the repair of single strand breaks showed both isomers only marginally influenced the rate and did not influence of extent of single strand break rejoining. The results are consistent with a mode of action involving chemical repair of transient radicals and protection against DNA and critical enzymatic sites.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>1120998</pmid><doi>10.1021/jm00238a001</doi><tpages>9</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 1975-04, Vol.18 (4), p.323-331 |
| issn | 0022-2623 1520-4804 |
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| source | MEDLINE; American Chemical Society Journals |
| subjects | ANIMAL CELLS- BIOLOGICAL RADIATION EFFECTS Animals Cell Line CELL PROLIFERATION Cricetinae Cyclobutanes - chemical synthesis Cyclobutanes - pharmacology DNA - radiation effects DNA Repair - drug effects DNA Repair - radiation effects DNA- STRAND BREAKS Dose-Response Relationship, Radiation Female GAMMA RADIATION Gamma Rays HAMSTERS MEA- RADIOSENSITIVITY EFFECTS Mercaptoethylamines - chemical synthesis Mercaptoethylamines - pharmacology MICE Mice, Inbred ICR ORGANIC SULFUR COMPOUNDS- RADIOSENSITIVITY EFFECTS Radiation Effects RADIATION PROTECTION Radiation-Protective Agents - chemical synthesis Radiation-Protective Agents - pharmacology RADICALS RADIOLOGY AND NUCLEAR MEDICINE Stereoisomerism STRAND BREAKS- RADIOINDUCTION Structure-Activity Relationship Sulfhydryl Compounds - chemical synthesis Sulfhydryl Compounds - pharmacology SURVIVAL TIME |
| title | Radioprotective stereostructure-activity study of cis- and trans-2-mercaptocyclobutylamine analogs and homologs of 2-mercaptoethylamine |
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