Rational design and molecular effects of a new topoisomerase II inhibitor azatoxin
Azatoxin [NSC 640737-M; 5.R,11aS-1H,6H,3-one-5,4,11,11a-tetrahydro-5-(3,5-dimethoxy-4-hydr oxyphenyl) oxazolo (3',4':1,6)pyrido-(3,4-b)indole] was rationally designed from a model for the pharmacophore of drugs with topoisomerase II inhibition activity. This pharmacophore has at least 2 do...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 1992-08, Vol.52 (16), p.4478-4483 |
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| container_title | Cancer research (Chicago, Ill.) |
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| creator | LETEURTRE, F MADALENGOITIA, J ORR, A CUZI, T. J LEHNERT, E MACDONALD, T POMMIER, Y |
| description | Azatoxin [NSC 640737-M; 5.R,11aS-1H,6H,3-one-5,4,11,11a-tetrahydro-5-(3,5-dimethoxy-4-hydr oxyphenyl) oxazolo (3',4':1,6)pyrido-(3,4-b)indole] was rationally designed from a model for the pharmacophore of drugs with topoisomerase II inhibition activity. This pharmacophore has at least 2 domains: a quasiplanar polycyclic ring system proposed to bind between the DNA base pairs and a pendant substituent proposed to interact with the enzyme and/or to the DNA grooves. The present study shows that, in cell free systems, azatoxin induces a large number of double strand-breaks in linear Simian virus 40 and human c-myc DNA. These breaks yield cleavage patterns that are different from those of well established topoisomerase II inhibitors (epipodophyllotoxins, amsacrine, mitoxantrone). Azatoxin also inhibits the catalytic activity of purified topoisomerase II, and is a nonintercalator. The structure-activity relationship of 3 isomers and 6 derivatives of azatoxin shows a stringent stereochemical requirement for activity. The effects of azatoxin pendant ring substitution on topoisomerase II mediated DNA cleavage activity were similar to the relationship observed for etoposide. |
| format | Article |
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J ; LEHNERT, E ; MACDONALD, T ; POMMIER, Y</creator><creatorcontrib>LETEURTRE, F ; MADALENGOITIA, J ; ORR, A ; CUZI, T. J ; LEHNERT, E ; MACDONALD, T ; POMMIER, Y</creatorcontrib><description>Azatoxin [NSC 640737-M; 5.R,11aS-1H,6H,3-one-5,4,11,11a-tetrahydro-5-(3,5-dimethoxy-4-hydr oxyphenyl) oxazolo (3',4':1,6)pyrido-(3,4-b)indole] was rationally designed from a model for the pharmacophore of drugs with topoisomerase II inhibition activity. This pharmacophore has at least 2 domains: a quasiplanar polycyclic ring system proposed to bind between the DNA base pairs and a pendant substituent proposed to interact with the enzyme and/or to the DNA grooves. The present study shows that, in cell free systems, azatoxin induces a large number of double strand-breaks in linear Simian virus 40 and human c-myc DNA. These breaks yield cleavage patterns that are different from those of well established topoisomerase II inhibitors (epipodophyllotoxins, amsacrine, mitoxantrone). Azatoxin also inhibits the catalytic activity of purified topoisomerase II, and is a nonintercalator. The structure-activity relationship of 3 isomers and 6 derivatives of azatoxin shows a stringent stereochemical requirement for activity. The effects of azatoxin pendant ring substitution on topoisomerase II mediated DNA cleavage activity were similar to the relationship observed for etoposide.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>PMID: 1322792</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Antineoplastic agents ; Biological and medical sciences ; DNA - drug effects ; DNA Damage ; DNA Topoisomerases, Type I - pharmacology ; DNA, Superhelical - drug effects ; DNA, Viral - drug effects ; Drug Design ; General aspects ; Humans ; Indoles - chemistry ; Indoles - pharmacology ; Medical sciences ; Pharmacology. Drug treatments ; Podophyllotoxin - analogs & derivatives ; Podophyllotoxin - pharmacology ; Simian virus 40 - genetics ; Topoisomerase II Inhibitors</subject><ispartof>Cancer research (Chicago, Ill.), 1992-08, Vol.52 (16), p.4478-4483</ispartof><rights>1992 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,778,782</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=5465122$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/1322792$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>LETEURTRE, F</creatorcontrib><creatorcontrib>MADALENGOITIA, J</creatorcontrib><creatorcontrib>ORR, A</creatorcontrib><creatorcontrib>CUZI, T. J</creatorcontrib><creatorcontrib>LEHNERT, E</creatorcontrib><creatorcontrib>MACDONALD, T</creatorcontrib><creatorcontrib>POMMIER, Y</creatorcontrib><title>Rational design and molecular effects of a new topoisomerase II inhibitor azatoxin</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>Azatoxin [NSC 640737-M; 5.R,11aS-1H,6H,3-one-5,4,11,11a-tetrahydro-5-(3,5-dimethoxy-4-hydr oxyphenyl) oxazolo (3',4':1,6)pyrido-(3,4-b)indole] was rationally designed from a model for the pharmacophore of drugs with topoisomerase II inhibition activity. This pharmacophore has at least 2 domains: a quasiplanar polycyclic ring system proposed to bind between the DNA base pairs and a pendant substituent proposed to interact with the enzyme and/or to the DNA grooves. The present study shows that, in cell free systems, azatoxin induces a large number of double strand-breaks in linear Simian virus 40 and human c-myc DNA. These breaks yield cleavage patterns that are different from those of well established topoisomerase II inhibitors (epipodophyllotoxins, amsacrine, mitoxantrone). Azatoxin also inhibits the catalytic activity of purified topoisomerase II, and is a nonintercalator. The structure-activity relationship of 3 isomers and 6 derivatives of azatoxin shows a stringent stereochemical requirement for activity. The effects of azatoxin pendant ring substitution on topoisomerase II mediated DNA cleavage activity were similar to the relationship observed for etoposide.</description><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>DNA - drug effects</subject><subject>DNA Damage</subject><subject>DNA Topoisomerases, Type I - pharmacology</subject><subject>DNA, Superhelical - drug effects</subject><subject>DNA, Viral - drug effects</subject><subject>Drug Design</subject><subject>General aspects</subject><subject>Humans</subject><subject>Indoles - chemistry</subject><subject>Indoles - pharmacology</subject><subject>Medical sciences</subject><subject>Pharmacology. Drug treatments</subject><subject>Podophyllotoxin - analogs & derivatives</subject><subject>Podophyllotoxin - pharmacology</subject><subject>Simian virus 40 - genetics</subject><subject>Topoisomerase II Inhibitors</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1992</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kEtLxDAUhYMo4zj6E4QsxF0hz6ZdyuCjMCAMui636Y0TaZOxafHx6y1YXF0O38c5cE_ImmtZZEYpfUrWjLEi08qIc3KR0vscNWd6RVZcCmFKsSb7PYw-Buhoi8m_BQqhpX3s0E4dDBSdQzsmGh0FGvCTjvEYfYo9DpCQVhX14eAbP8aBwg-M8cuHS3LmoEt4tdwNeX24f9k-Zbvnx2p7t8sOIi_HTDZopNHauBzRyjIvctdKyTjj82quhERWgi6FbrjNlUOYWaGVUrNsGys35Pav9zjEjwnTWPc-Wew6CBinVBvJCqYMn8XrRZyaHtv6OPgehu96ecLMbxYOyULnBgjWp39Nq1xzIeQvmWVlxg</recordid><startdate>19920815</startdate><enddate>19920815</enddate><creator>LETEURTRE, F</creator><creator>MADALENGOITIA, J</creator><creator>ORR, A</creator><creator>CUZI, T. J</creator><creator>LEHNERT, E</creator><creator>MACDONALD, T</creator><creator>POMMIER, Y</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>19920815</creationdate><title>Rational design and molecular effects of a new topoisomerase II inhibitor azatoxin</title><author>LETEURTRE, F ; MADALENGOITIA, J ; ORR, A ; CUZI, T. J ; LEHNERT, E ; MACDONALD, T ; POMMIER, Y</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h269t-3be737557f6eec39686fd330101eff6423e09a5925b1c64fea30185444c39cbc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1992</creationdate><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>DNA - drug effects</topic><topic>DNA Damage</topic><topic>DNA Topoisomerases, Type I - pharmacology</topic><topic>DNA, Superhelical - drug effects</topic><topic>DNA, Viral - drug effects</topic><topic>Drug Design</topic><topic>General aspects</topic><topic>Humans</topic><topic>Indoles - chemistry</topic><topic>Indoles - pharmacology</topic><topic>Medical sciences</topic><topic>Pharmacology. Drug treatments</topic><topic>Podophyllotoxin - analogs & derivatives</topic><topic>Podophyllotoxin - pharmacology</topic><topic>Simian virus 40 - genetics</topic><topic>Topoisomerase II Inhibitors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>LETEURTRE, F</creatorcontrib><creatorcontrib>MADALENGOITIA, J</creatorcontrib><creatorcontrib>ORR, A</creatorcontrib><creatorcontrib>CUZI, T. J</creatorcontrib><creatorcontrib>LEHNERT, E</creatorcontrib><creatorcontrib>MACDONALD, T</creatorcontrib><creatorcontrib>POMMIER, Y</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>LETEURTRE, F</au><au>MADALENGOITIA, J</au><au>ORR, A</au><au>CUZI, T. J</au><au>LEHNERT, E</au><au>MACDONALD, T</au><au>POMMIER, Y</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Rational design and molecular effects of a new topoisomerase II inhibitor azatoxin</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>1992-08-15</date><risdate>1992</risdate><volume>52</volume><issue>16</issue><spage>4478</spage><epage>4483</epage><pages>4478-4483</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><abstract>Azatoxin [NSC 640737-M; 5.R,11aS-1H,6H,3-one-5,4,11,11a-tetrahydro-5-(3,5-dimethoxy-4-hydr oxyphenyl) oxazolo (3',4':1,6)pyrido-(3,4-b)indole] was rationally designed from a model for the pharmacophore of drugs with topoisomerase II inhibition activity. This pharmacophore has at least 2 domains: a quasiplanar polycyclic ring system proposed to bind between the DNA base pairs and a pendant substituent proposed to interact with the enzyme and/or to the DNA grooves. The present study shows that, in cell free systems, azatoxin induces a large number of double strand-breaks in linear Simian virus 40 and human c-myc DNA. These breaks yield cleavage patterns that are different from those of well established topoisomerase II inhibitors (epipodophyllotoxins, amsacrine, mitoxantrone). Azatoxin also inhibits the catalytic activity of purified topoisomerase II, and is a nonintercalator. The structure-activity relationship of 3 isomers and 6 derivatives of azatoxin shows a stringent stereochemical requirement for activity. The effects of azatoxin pendant ring substitution on topoisomerase II mediated DNA cleavage activity were similar to the relationship observed for etoposide.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>1322792</pmid><tpages>6</tpages></addata></record> |
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| ispartof | Cancer research (Chicago, Ill.), 1992-08, Vol.52 (16), p.4478-4483 |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; American Association for Cancer Research |
| subjects | Antineoplastic agents Biological and medical sciences DNA - drug effects DNA Damage DNA Topoisomerases, Type I - pharmacology DNA, Superhelical - drug effects DNA, Viral - drug effects Drug Design General aspects Humans Indoles - chemistry Indoles - pharmacology Medical sciences Pharmacology. Drug treatments Podophyllotoxin - analogs & derivatives Podophyllotoxin - pharmacology Simian virus 40 - genetics Topoisomerase II Inhibitors |
| title | Rational design and molecular effects of a new topoisomerase II inhibitor azatoxin |
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