Synthesis and Evaluation of Novel Fluorinated Methotrexate Derivatives for Application to Rheumatoid Arthritis Treatment
An ongoing search for new antifolate drugs useful against rheumatoid arthritis (RA) led us to prepare new methotrexate (MTX) derivatives containing enantiomerically pure l-erythro- or l-threo-γ-fluoroglutamic acid. The derivatives in which the phenyl ring was replaced by a 3‘-substituted phenyl or m...
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| Veröffentlicht in: | Journal of medicinal chemistry 1997-09, Vol.40 (20), p.3280-3291 |
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| creator | Kokuryo, Yoshitsugu Kawata, Kyozo Nakatani, Takuji Kugimiya, Akira Tamura, Yoshinori Kawada, Kenji Matsumoto, Mitsunobu Suzuki, Ryuji Kuwabara, Kenji Hori, Yozo Ohtani, Mitsuaki |
| description | An ongoing search for new antifolate drugs useful against rheumatoid arthritis (RA) led us to prepare new methotrexate (MTX) derivatives containing enantiomerically pure l-erythro- or l-threo-γ-fluoroglutamic acid. The derivatives in which the phenyl ring was replaced by a 3‘-substituted phenyl or methylthiophene ring showed potent immunosuppressive activities, including in vitro inhibition of mitogen responses of both T and B cells and in vivo inhibition of antibody production in mice. These compounds also exhibited inhibitory activity in adjuvant arthritis in rats. Their toxicity was lower than that of MTX, which was probably due to the strong electronegativity of fluorine, which increases the acidity of the γ-carboxyl group and thereby decreases polyglutamylation in normal cells. These results revealed the potential of the fluorinated MTX derivatives as candidate drugs for the treatment of RA. |
| doi_str_mv | 10.1021/jm970085n |
| format | Article |
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The derivatives in which the phenyl ring was replaced by a 3‘-substituted phenyl or methylthiophene ring showed potent immunosuppressive activities, including in vitro inhibition of mitogen responses of both T and B cells and in vivo inhibition of antibody production in mice. These compounds also exhibited inhibitory activity in adjuvant arthritis in rats. Their toxicity was lower than that of MTX, which was probably due to the strong electronegativity of fluorine, which increases the acidity of the γ-carboxyl group and thereby decreases polyglutamylation in normal cells. These results revealed the potential of the fluorinated MTX derivatives as candidate drugs for the treatment of RA.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm970085n</identifier><identifier>PMID: 9379448</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Antibody Formation - drug effects ; Arthritis, Experimental - drug therapy ; Arthritis, Experimental - immunology ; Arthritis, Rheumatoid - drug therapy ; Arthritis, Rheumatoid - immunology ; B-Lymphocytes - drug effects ; Biological and medical sciences ; Bones, joints and connective tissue. Antiinflammatory agents ; Female ; Fluorine - metabolism ; Folic Acid Antagonists - chemical synthesis ; Medical sciences ; Methotrexate - analogs & derivatives ; Methotrexate - therapeutic use ; Mice ; Models, Chemical ; Pharmacology. Drug treatments ; Rats ; Rats, Inbred Lew ; Stereoisomerism ; T-Lymphocytes - drug effects</subject><ispartof>Journal of medicinal chemistry, 1997-09, Vol.40 (20), p.3280-3291</ispartof><rights>Copyright © 1997 American Chemical Society</rights><rights>1997 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a408t-d9a43599b39fc6a4f1885a5876935ca8787214eb89e6d389c91056694f179b913</citedby><cites>FETCH-LOGICAL-a408t-d9a43599b39fc6a4f1885a5876935ca8787214eb89e6d389c91056694f179b913</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/jm970085n$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm970085n$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2751,27055,27903,27904,56717,56767</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=2833981$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9379448$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kokuryo, Yoshitsugu</creatorcontrib><creatorcontrib>Kawata, Kyozo</creatorcontrib><creatorcontrib>Nakatani, Takuji</creatorcontrib><creatorcontrib>Kugimiya, Akira</creatorcontrib><creatorcontrib>Tamura, Yoshinori</creatorcontrib><creatorcontrib>Kawada, Kenji</creatorcontrib><creatorcontrib>Matsumoto, Mitsunobu</creatorcontrib><creatorcontrib>Suzuki, Ryuji</creatorcontrib><creatorcontrib>Kuwabara, Kenji</creatorcontrib><creatorcontrib>Hori, Yozo</creatorcontrib><creatorcontrib>Ohtani, Mitsuaki</creatorcontrib><title>Synthesis and Evaluation of Novel Fluorinated Methotrexate Derivatives for Application to Rheumatoid Arthritis Treatment</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>An ongoing search for new antifolate drugs useful against rheumatoid arthritis (RA) led us to prepare new methotrexate (MTX) derivatives containing enantiomerically pure l-erythro- or l-threo-γ-fluoroglutamic acid. The derivatives in which the phenyl ring was replaced by a 3‘-substituted phenyl or methylthiophene ring showed potent immunosuppressive activities, including in vitro inhibition of mitogen responses of both T and B cells and in vivo inhibition of antibody production in mice. These compounds also exhibited inhibitory activity in adjuvant arthritis in rats. Their toxicity was lower than that of MTX, which was probably due to the strong electronegativity of fluorine, which increases the acidity of the γ-carboxyl group and thereby decreases polyglutamylation in normal cells. These results revealed the potential of the fluorinated MTX derivatives as candidate drugs for the treatment of RA.</description><subject>Animals</subject><subject>Antibody Formation - drug effects</subject><subject>Arthritis, Experimental - drug therapy</subject><subject>Arthritis, Experimental - immunology</subject><subject>Arthritis, Rheumatoid - drug therapy</subject><subject>Arthritis, Rheumatoid - immunology</subject><subject>B-Lymphocytes - drug effects</subject><subject>Biological and medical sciences</subject><subject>Bones, joints and connective tissue. Antiinflammatory agents</subject><subject>Female</subject><subject>Fluorine - metabolism</subject><subject>Folic Acid Antagonists - chemical synthesis</subject><subject>Medical sciences</subject><subject>Methotrexate - analogs & derivatives</subject><subject>Methotrexate - therapeutic use</subject><subject>Mice</subject><subject>Models, Chemical</subject><subject>Pharmacology. Drug treatments</subject><subject>Rats</subject><subject>Rats, Inbred Lew</subject><subject>Stereoisomerism</subject><subject>T-Lymphocytes - drug effects</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1997</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0MuO0zAUBmALgYbOwIIHQPICkGYRsOPEsZdlLoAYLpoGsbROkxPVJYmL7VSdt8ejVF2xsqz_8znWT8grzt5zlvMP20FXjKlyfEIWvMxZVihWPCULxvI8y2UunpPzELaMMcFzcUbOtKh0UagFOawexrjBYAOFsaU3e-gniNaN1HX0u9tjT2_7yXk7QsSWfsO4cdHjId3oNXq7T3iPgXbO0-Vu19tmfh0dvd_gNEB0tqVLHzfexrSk9ghxwDG-IM866AO-PJ4X5NftTX31Obv78enL1fIug4KpmLUaClFqvRa6ayQUHVeqhFJVUouyAVWpKucFrpVG2QqlG81ZKaVOsNJrzcUFeTfP3Xn3d8IQzWBDg30PI7opGC6F1GlGgpczbLwLwWNndt4O4B8MZ-axZXNqOdnXx6HTesD2JI-1pvzNMYfQQN95GBsbTixXQmj1uDKbmQ0RD6cY_B8jK1GVpv65Mtf1Pfv9cfXV1Mm_nT00wWzd5MfU3H--9w_qQ6Dp</recordid><startdate>19970926</startdate><enddate>19970926</enddate><creator>Kokuryo, Yoshitsugu</creator><creator>Kawata, Kyozo</creator><creator>Nakatani, Takuji</creator><creator>Kugimiya, Akira</creator><creator>Tamura, Yoshinori</creator><creator>Kawada, Kenji</creator><creator>Matsumoto, Mitsunobu</creator><creator>Suzuki, Ryuji</creator><creator>Kuwabara, Kenji</creator><creator>Hori, Yozo</creator><creator>Ohtani, Mitsuaki</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>7T5</scope><scope>H94</scope></search><sort><creationdate>19970926</creationdate><title>Synthesis and Evaluation of Novel Fluorinated Methotrexate Derivatives for Application to Rheumatoid Arthritis Treatment</title><author>Kokuryo, Yoshitsugu ; Kawata, Kyozo ; Nakatani, Takuji ; Kugimiya, Akira ; Tamura, Yoshinori ; Kawada, Kenji ; Matsumoto, Mitsunobu ; Suzuki, Ryuji ; Kuwabara, Kenji ; Hori, Yozo ; Ohtani, Mitsuaki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a408t-d9a43599b39fc6a4f1885a5876935ca8787214eb89e6d389c91056694f179b913</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1997</creationdate><topic>Animals</topic><topic>Antibody Formation - drug effects</topic><topic>Arthritis, Experimental - drug therapy</topic><topic>Arthritis, Experimental - immunology</topic><topic>Arthritis, Rheumatoid - drug therapy</topic><topic>Arthritis, Rheumatoid - immunology</topic><topic>B-Lymphocytes - drug effects</topic><topic>Biological and medical sciences</topic><topic>Bones, joints and connective tissue. Antiinflammatory agents</topic><topic>Female</topic><topic>Fluorine - metabolism</topic><topic>Folic Acid Antagonists - chemical synthesis</topic><topic>Medical sciences</topic><topic>Methotrexate - analogs & derivatives</topic><topic>Methotrexate - therapeutic use</topic><topic>Mice</topic><topic>Models, Chemical</topic><topic>Pharmacology. 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Med. Chem</addtitle><date>1997-09-26</date><risdate>1997</risdate><volume>40</volume><issue>20</issue><spage>3280</spage><epage>3291</epage><pages>3280-3291</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>An ongoing search for new antifolate drugs useful against rheumatoid arthritis (RA) led us to prepare new methotrexate (MTX) derivatives containing enantiomerically pure l-erythro- or l-threo-γ-fluoroglutamic acid. The derivatives in which the phenyl ring was replaced by a 3‘-substituted phenyl or methylthiophene ring showed potent immunosuppressive activities, including in vitro inhibition of mitogen responses of both T and B cells and in vivo inhibition of antibody production in mice. These compounds also exhibited inhibitory activity in adjuvant arthritis in rats. Their toxicity was lower than that of MTX, which was probably due to the strong electronegativity of fluorine, which increases the acidity of the γ-carboxyl group and thereby decreases polyglutamylation in normal cells. These results revealed the potential of the fluorinated MTX derivatives as candidate drugs for the treatment of RA.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>9379448</pmid><doi>10.1021/jm970085n</doi><tpages>12</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 1997-09, Vol.40 (20), p.3280-3291 |
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| subjects | Animals Antibody Formation - drug effects Arthritis, Experimental - drug therapy Arthritis, Experimental - immunology Arthritis, Rheumatoid - drug therapy Arthritis, Rheumatoid - immunology B-Lymphocytes - drug effects Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Female Fluorine - metabolism Folic Acid Antagonists - chemical synthesis Medical sciences Methotrexate - analogs & derivatives Methotrexate - therapeutic use Mice Models, Chemical Pharmacology. Drug treatments Rats Rats, Inbred Lew Stereoisomerism T-Lymphocytes - drug effects |
| title | Synthesis and Evaluation of Novel Fluorinated Methotrexate Derivatives for Application to Rheumatoid Arthritis Treatment |
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