Design, synthesis, and biological activities of classical N-[4-[2-(2-amino-4-ethylpyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid and its 6-methyl derivative as potential dual inhibitors of thymidylate synthase and dihydrofolate reductase and as potential antitumor agents
Two novel analogues, N-[2-amino-4-ethyl[(pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid (2) and N-[2-amino-4-ethyl-6-methyl[(pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid (4), were designed and synthesized as potent dual inhibitors of thymidylate synthase (TS) and dihydrof...
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| Veröffentlicht in: | Journal of medicinal chemistry 2003-02, Vol.46 (4), p.591-600 |
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| creator | Gangjee, Aleem Yu, Jianming Kisliuk, Roy L Haile, William H Sobrero, Giulia McGuire, John J |
| description | Two novel analogues, N-[2-amino-4-ethyl[(pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid (2) and N-[2-amino-4-ethyl-6-methyl[(pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid (4), were designed and synthesized as potent dual inhibitors of thymidylate synthase (TS) and dihydrofolate reductase (DHFR) and as antitumor agents. Compound 2 had inhibitory potency against human DHFR similar to N-[4-[2-(amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid (LY231514) and 1, whereas 4 was inactive against human DHFR. Both 2 and 4 were more potent than LY231514 against E. coliTS. Against human TS, 2 was 7-fold less potent than LY231514 and 4 showed similar inhibitory activity as LY231514. In contrast to 2, which was an efficient substrate of human folypolyglutamate synthetase (FPGS), 4 was a poor substrate of FPGS. Compound 2 showed GI50 values in the nanomolar range against more than 18 human tumor cell lines in the standard NCI preclinical in vitro screen. |
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Compound 2 had inhibitory potency against human DHFR similar to N-[4-[2-(amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid (LY231514) and 1, whereas 4 was inactive against human DHFR. Both 2 and 4 were more potent than LY231514 against E. coliTS. Against human TS, 2 was 7-fold less potent than LY231514 and 4 showed similar inhibitory activity as LY231514. In contrast to 2, which was an efficient substrate of human folypolyglutamate synthetase (FPGS), 4 was a poor substrate of FPGS. Compound 2 showed GI50 values in the nanomolar range against more than 18 human tumor cell lines in the standard NCI preclinical in vitro screen.</description><identifier>ISSN: 0022-2623</identifier><identifier>PMID: 12570380</identifier><language>eng</language><publisher>United States</publisher><subject>Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Cell Division - drug effects ; Drug Resistance, Neoplasm ; Drug Screening Assays, Antitumor ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Escherichia coli - chemistry ; Folic Acid Antagonists - chemical synthesis ; Folic Acid Antagonists - chemistry ; Folic Acid Antagonists - pharmacology ; Glutamic Acid - analogs & derivatives ; Glutamic Acid - chemical synthesis ; Glutamic Acid - chemistry ; Glutamic Acid - pharmacology ; Humans ; Lactobacillus casei - chemistry ; Peptide Synthases - metabolism ; Pyrimidines - chemical synthesis ; Pyrimidines - chemistry ; Pyrimidines - pharmacology ; Structure-Activity Relationship ; Tetrahydrofolate Dehydrogenase - metabolism ; Thymidylate Synthase - antagonists & inhibitors ; Tumor Cells, Cultured</subject><ispartof>Journal of medicinal chemistry, 2003-02, Vol.46 (4), p.591-600</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12570380$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gangjee, Aleem</creatorcontrib><creatorcontrib>Yu, Jianming</creatorcontrib><creatorcontrib>Kisliuk, Roy L</creatorcontrib><creatorcontrib>Haile, William H</creatorcontrib><creatorcontrib>Sobrero, Giulia</creatorcontrib><creatorcontrib>McGuire, John J</creatorcontrib><title>Design, synthesis, and biological activities of classical N-[4-[2-(2-amino-4-ethylpyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid and its 6-methyl derivative as potential dual inhibitors of thymidylate synthase and dihydrofolate reductase and as potential antitumor agents</title><title>Journal of medicinal chemistry</title><addtitle>J Med Chem</addtitle><description>Two novel analogues, N-[2-amino-4-ethyl[(pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid (2) and N-[2-amino-4-ethyl-6-methyl[(pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid (4), were designed and synthesized as potent dual inhibitors of thymidylate synthase (TS) and dihydrofolate reductase (DHFR) and as antitumor agents. Compound 2 had inhibitory potency against human DHFR similar to N-[4-[2-(amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid (LY231514) and 1, whereas 4 was inactive against human DHFR. Both 2 and 4 were more potent than LY231514 against E. coliTS. Against human TS, 2 was 7-fold less potent than LY231514 and 4 showed similar inhibitory activity as LY231514. In contrast to 2, which was an efficient substrate of human folypolyglutamate synthetase (FPGS), 4 was a poor substrate of FPGS. Compound 2 showed GI50 values in the nanomolar range against more than 18 human tumor cell lines in the standard NCI preclinical in vitro screen.</description><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Cell Division - drug effects</subject><subject>Drug Resistance, Neoplasm</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Escherichia coli - chemistry</subject><subject>Folic Acid Antagonists - chemical synthesis</subject><subject>Folic Acid Antagonists - chemistry</subject><subject>Folic Acid Antagonists - pharmacology</subject><subject>Glutamic Acid - analogs & derivatives</subject><subject>Glutamic Acid - chemical synthesis</subject><subject>Glutamic Acid - chemistry</subject><subject>Glutamic Acid - pharmacology</subject><subject>Humans</subject><subject>Lactobacillus casei - chemistry</subject><subject>Peptide Synthases - metabolism</subject><subject>Pyrimidines - chemical synthesis</subject><subject>Pyrimidines - chemistry</subject><subject>Pyrimidines - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>Tetrahydrofolate Dehydrogenase - metabolism</subject><subject>Thymidylate Synthase - antagonists & inhibitors</subject><subject>Tumor Cells, Cultured</subject><issn>0022-2623</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUU1r3DAQdaGhSdP-g1J0Ki2sQJYs7_pY0k8I6SW3JSySNd6dIkuuJAecX5_BSQ696Glm3rw30ryuLoSQkstWqvPqbc5_hRCqlupNdV5LvRVqJy5effgGGY9hw_ISyonuecNMcMxi9PGIvfHM9AXvsSBkFgfWe5Pzmr_h-4bvJf8suRkxRN5wKKfFT0tK1LyXG8XdHUU4osPANV_8l5VxZyE8RELu-dHPhdp7skG3WmPJrOXjymQOEt4bGgCYyWyKBUJBMnczHRhOaLHEtE5GfDJavCnw9BqTYRV0eFpcikNcSwnc3JeX2n-ihqDMY0zMHCmV31Vng_EZ3j_jZXX74_vt1S9-_efn76uv13zSjeBSNroG2fW9EnWvKexa2w1gO7mttVVSg5Cq1baG2u52zm6JJKxt6qGlhbTqsvr0JDul-G-GXA4j5h68NwHinA9b0m217Ij48Zk42xHcYaKvNWk5vKxTPQIqcqCc</recordid><startdate>20030213</startdate><enddate>20030213</enddate><creator>Gangjee, Aleem</creator><creator>Yu, Jianming</creator><creator>Kisliuk, Roy L</creator><creator>Haile, William H</creator><creator>Sobrero, Giulia</creator><creator>McGuire, John J</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20030213</creationdate><title>Design, synthesis, and biological activities of classical N-[4-[2-(2-amino-4-ethylpyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid and its 6-methyl derivative as potential dual inhibitors of thymidylate synthase and dihydrofolate reductase and as potential antitumor agents</title><author>Gangjee, Aleem ; Yu, Jianming ; Kisliuk, Roy L ; Haile, William H ; Sobrero, Giulia ; McGuire, John J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p540-22451e29cc301c522496b9feb92715b325e02365b1e1b88db7c520bb41f603163</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Cell Division - drug effects</topic><topic>Drug Resistance, Neoplasm</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Escherichia coli - chemistry</topic><topic>Folic Acid Antagonists - chemical synthesis</topic><topic>Folic Acid Antagonists - chemistry</topic><topic>Folic Acid Antagonists - pharmacology</topic><topic>Glutamic Acid - analogs & derivatives</topic><topic>Glutamic Acid - chemical synthesis</topic><topic>Glutamic Acid - chemistry</topic><topic>Glutamic Acid - pharmacology</topic><topic>Humans</topic><topic>Lactobacillus casei - chemistry</topic><topic>Peptide Synthases - metabolism</topic><topic>Pyrimidines - chemical synthesis</topic><topic>Pyrimidines - chemistry</topic><topic>Pyrimidines - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>Tetrahydrofolate Dehydrogenase - metabolism</topic><topic>Thymidylate Synthase - antagonists & inhibitors</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gangjee, Aleem</creatorcontrib><creatorcontrib>Yu, Jianming</creatorcontrib><creatorcontrib>Kisliuk, Roy L</creatorcontrib><creatorcontrib>Haile, William H</creatorcontrib><creatorcontrib>Sobrero, Giulia</creatorcontrib><creatorcontrib>McGuire, John J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gangjee, Aleem</au><au>Yu, Jianming</au><au>Kisliuk, Roy L</au><au>Haile, William H</au><au>Sobrero, Giulia</au><au>McGuire, John J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design, synthesis, and biological activities of classical N-[4-[2-(2-amino-4-ethylpyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid and its 6-methyl derivative as potential dual inhibitors of thymidylate synthase and dihydrofolate reductase and as potential antitumor agents</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J Med Chem</addtitle><date>2003-02-13</date><risdate>2003</risdate><volume>46</volume><issue>4</issue><spage>591</spage><epage>600</epage><pages>591-600</pages><issn>0022-2623</issn><abstract>Two novel analogues, N-[2-amino-4-ethyl[(pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid (2) and N-[2-amino-4-ethyl-6-methyl[(pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid (4), were designed and synthesized as potent dual inhibitors of thymidylate synthase (TS) and dihydrofolate reductase (DHFR) and as antitumor agents. Compound 2 had inhibitory potency against human DHFR similar to N-[4-[2-(amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid (LY231514) and 1, whereas 4 was inactive against human DHFR. Both 2 and 4 were more potent than LY231514 against E. coliTS. Against human TS, 2 was 7-fold less potent than LY231514 and 4 showed similar inhibitory activity as LY231514. In contrast to 2, which was an efficient substrate of human folypolyglutamate synthetase (FPGS), 4 was a poor substrate of FPGS. Compound 2 showed GI50 values in the nanomolar range against more than 18 human tumor cell lines in the standard NCI preclinical in vitro screen.</abstract><cop>United States</cop><pmid>12570380</pmid><tpages>10</tpages></addata></record> |
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| subjects | Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Cell Division - drug effects Drug Resistance, Neoplasm Drug Screening Assays, Antitumor Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Escherichia coli - chemistry Folic Acid Antagonists - chemical synthesis Folic Acid Antagonists - chemistry Folic Acid Antagonists - pharmacology Glutamic Acid - analogs & derivatives Glutamic Acid - chemical synthesis Glutamic Acid - chemistry Glutamic Acid - pharmacology Humans Lactobacillus casei - chemistry Peptide Synthases - metabolism Pyrimidines - chemical synthesis Pyrimidines - chemistry Pyrimidines - pharmacology Structure-Activity Relationship Tetrahydrofolate Dehydrogenase - metabolism Thymidylate Synthase - antagonists & inhibitors Tumor Cells, Cultured |
| title | Design, synthesis, and biological activities of classical N-[4-[2-(2-amino-4-ethylpyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-l-glutamic acid and its 6-methyl derivative as potential dual inhibitors of thymidylate synthase and dihydrofolate reductase and as potential antitumor agents |
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