Inhibitory Effects of Pyrimidine, Barbituric Acid and Pyridine Derivatives on 5-Fluorouracil Degradation in Rat Liver Extracts
The inhibitory effects of about 30 compounds, mainly pyrimidine and pyridine derivatives, on 5-fluorouracil degradation catalyzed by dihydrouracil dehydrogenase (DHU dehydrogenase) were investigated. The inhibitory activities of 5-substituted uracil derivatives decreased time-dependently during prei...
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| Veröffentlicht in: | Japanese Journal of Cancer Research GANN 1987, Vol.78(7), pp.748-755 |
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| container_title | Japanese Journal of Cancer Research GANN |
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| creator | TATSUMI, Kunihiko FUKUSHIMA, Masakazu SHIRASAKA, Tetsuhiko FUJII, Setsuro |
| description | The inhibitory effects of about 30 compounds, mainly pyrimidine and pyridine derivatives, on 5-fluorouracil degradation catalyzed by dihydrouracil dehydrogenase (DHU dehydrogenase) were investigated. The inhibitory activities of 5-substituted uracil derivatives decreased time-dependently during preincubation with liver extracts, indicating that these compounds are substrates of DHU dehydrogenase. During preincubation, 4, 6-dihydroxypyrimidine derivatives were found to be converted to barbituric acid derivatives, which have stronger activities. The inhibitory activity of 2, 4-dihydroxypyridine (3-deazauracil), which was stronger than that of uracil, did not change during preincubation, indicating that this compound is not a substrate but is an inhibitor of DHU dehydrogenase, and suggesting that 2, 6-dihydroxypyridine (1-deazauracil) could be a potent inhibitor. In the light of these findings, we examined various derivatives of barbituric acid, 2, 4-dihydroxypyridine and 2, 6-dihydroxypyridine. Among these compounds, 3-cyano-2, 6-dihydroxypyridine and 5-chloro-2, 4-dihydroxypyridine were the strongest inhibitors with Ki values for DHU dehydrogenase of 2.3×10-7M and 3.6×10-7M, respectively. |
| doi_str_mv | 10.20772/cancersci1985.78.7_748 |
| format | Article |
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The inhibitory activities of 5-substituted uracil derivatives decreased time-dependently during preincubation with liver extracts, indicating that these compounds are substrates of DHU dehydrogenase. During preincubation, 4, 6-dihydroxypyrimidine derivatives were found to be converted to barbituric acid derivatives, which have stronger activities. The inhibitory activity of 2, 4-dihydroxypyridine (3-deazauracil), which was stronger than that of uracil, did not change during preincubation, indicating that this compound is not a substrate but is an inhibitor of DHU dehydrogenase, and suggesting that 2, 6-dihydroxypyridine (1-deazauracil) could be a potent inhibitor. In the light of these findings, we examined various derivatives of barbituric acid, 2, 4-dihydroxypyridine and 2, 6-dihydroxypyridine. Among these compounds, 3-cyano-2, 6-dihydroxypyridine and 5-chloro-2, 4-dihydroxypyridine were the strongest inhibitors with Ki values for DHU dehydrogenase of 2.3×10-7M and 3.6×10-7M, respectively.</description><identifier>ISSN: 0910-5050</identifier><identifier>EISSN: 1876-4673</identifier><identifier>DOI: 10.20772/cancersci1985.78.7_748</identifier><identifier>PMID: 3114201</identifier><identifier>CODEN: GANNA2</identifier><language>eng</language><publisher>Tokyo: The Japanese Cancer Association</publisher><subject>5-Fluorouracil ; 5-Fluorouracil degradation ; Animals ; Antineoplastic agents ; Barbiturates - pharmacology ; Barbituric acid ; Biological and medical sciences ; Chromatography, High Pressure Liquid ; Dihydrouracil dehydrogenase ; Dihydrouracil Dehydrogenase (NAD+) ; Fluorouracil - metabolism ; General aspects ; Kinetics ; Liver - drug effects ; Liver - metabolism ; Medical sciences ; Oxidoreductases - metabolism ; Oxidoreductases Acting on CH-CH Group Donors ; Pharmacology. Drug treatments ; Phosphorylation ; Pyridines - pharmacology ; Pyrimidine ; Pyrimidines - pharmacology ; Rats ; Sarcoma 180 - metabolism ; Thymine - pharmacology ; Uracil - pharmacology</subject><ispartof>Japanese Journal of Cancer Research GANN, 1987, Vol.78(7), pp.748-755</ispartof><rights>The Japanese Cancer Association</rights><rights>1988 INIST-CNRS</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,1883,4024,27923,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=7573460$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/3114201$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>TATSUMI, Kunihiko</creatorcontrib><creatorcontrib>FUKUSHIMA, Masakazu</creatorcontrib><creatorcontrib>SHIRASAKA, Tetsuhiko</creatorcontrib><creatorcontrib>FUJII, Setsuro</creatorcontrib><title>Inhibitory Effects of Pyrimidine, Barbituric Acid and Pyridine Derivatives on 5-Fluorouracil Degradation in Rat Liver Extracts</title><title>Japanese Journal of Cancer Research GANN</title><addtitle>Japanese Journal of Cancer Research GANN</addtitle><description>The inhibitory effects of about 30 compounds, mainly pyrimidine and pyridine derivatives, on 5-fluorouracil degradation catalyzed by dihydrouracil dehydrogenase (DHU dehydrogenase) were investigated. The inhibitory activities of 5-substituted uracil derivatives decreased time-dependently during preincubation with liver extracts, indicating that these compounds are substrates of DHU dehydrogenase. During preincubation, 4, 6-dihydroxypyrimidine derivatives were found to be converted to barbituric acid derivatives, which have stronger activities. The inhibitory activity of 2, 4-dihydroxypyridine (3-deazauracil), which was stronger than that of uracil, did not change during preincubation, indicating that this compound is not a substrate but is an inhibitor of DHU dehydrogenase, and suggesting that 2, 6-dihydroxypyridine (1-deazauracil) could be a potent inhibitor. In the light of these findings, we examined various derivatives of barbituric acid, 2, 4-dihydroxypyridine and 2, 6-dihydroxypyridine. Among these compounds, 3-cyano-2, 6-dihydroxypyridine and 5-chloro-2, 4-dihydroxypyridine were the strongest inhibitors with Ki values for DHU dehydrogenase of 2.3×10-7M and 3.6×10-7M, respectively.</description><subject>5-Fluorouracil</subject><subject>5-Fluorouracil degradation</subject><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Barbiturates - pharmacology</subject><subject>Barbituric acid</subject><subject>Biological and medical sciences</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Dihydrouracil dehydrogenase</subject><subject>Dihydrouracil Dehydrogenase (NAD+)</subject><subject>Fluorouracil - metabolism</subject><subject>General aspects</subject><subject>Kinetics</subject><subject>Liver - drug effects</subject><subject>Liver - metabolism</subject><subject>Medical sciences</subject><subject>Oxidoreductases - metabolism</subject><subject>Oxidoreductases Acting on CH-CH Group Donors</subject><subject>Pharmacology. Drug treatments</subject><subject>Phosphorylation</subject><subject>Pyridines - pharmacology</subject><subject>Pyrimidine</subject><subject>Pyrimidines - pharmacology</subject><subject>Rats</subject><subject>Sarcoma 180 - metabolism</subject><subject>Thymine - pharmacology</subject><subject>Uracil - pharmacology</subject><issn>0910-5050</issn><issn>1876-4673</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1987</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkcFu1DAQhi0EKkvhERA-IE5ksRMn4xxL2cJKK4EQnK1Ze9x6lU2K7VTshWfH0KiIy8zh-2akmZ-xV1KsawFQv7M4WorJBtnrdg16DQaUfsRWUkNXqQ6ax2wleimqVrTiKXuW0kEICaKrz9hZI6WqhVyxX9vxJuxDnuKJb7wnmxOfPP9yiuEYXBjpLX-PsQhzDJZf2OA4ju4v_0P5B4rhDnO4ozI38ra6GuYpTnNEG4ZCryO6ggsKI_-Kme-KGvnmZy5GTs_ZE49DohdLP2ffrzbfLj9Vu88ft5cXu-rQKpkrKRtUPfVQW2rIw9731HlCtPvGOVEudlILp62rlXJOC1ELsn0tu8ZrWWbO2Zv7vbdx-jFTyuYYkqVhwJGmORmADvpWt0V8uYjz_kjO3JY_YDyZ5WGFv144JouDjyWGkB40aKFRnSja9l47pIzX9MAx5mAHMv-lZ0AbWIrS_5wbjIbG5jdzYplM</recordid><startdate>1987</startdate><enddate>1987</enddate><creator>TATSUMI, Kunihiko</creator><creator>FUKUSHIMA, Masakazu</creator><creator>SHIRASAKA, Tetsuhiko</creator><creator>FUJII, Setsuro</creator><general>The Japanese Cancer Association</general><general>Japanese Cancer Association</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>1987</creationdate><title>Inhibitory Effects of Pyrimidine, Barbituric Acid and Pyridine Derivatives on 5-Fluorouracil Degradation in Rat Liver Extracts</title><author>TATSUMI, Kunihiko ; FUKUSHIMA, Masakazu ; SHIRASAKA, Tetsuhiko ; FUJII, Setsuro</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-j541t-113a49e972ce3ef7bf9e6feaacb3dd0876d180d8cd244dd80020ec92163f81ce3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1987</creationdate><topic>5-Fluorouracil</topic><topic>5-Fluorouracil degradation</topic><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Barbiturates - pharmacology</topic><topic>Barbituric acid</topic><topic>Biological and medical sciences</topic><topic>Chromatography, High Pressure Liquid</topic><topic>Dihydrouracil dehydrogenase</topic><topic>Dihydrouracil Dehydrogenase (NAD+)</topic><topic>Fluorouracil - metabolism</topic><topic>General aspects</topic><topic>Kinetics</topic><topic>Liver - drug effects</topic><topic>Liver - metabolism</topic><topic>Medical sciences</topic><topic>Oxidoreductases - metabolism</topic><topic>Oxidoreductases Acting on CH-CH Group Donors</topic><topic>Pharmacology. Drug treatments</topic><topic>Phosphorylation</topic><topic>Pyridines - pharmacology</topic><topic>Pyrimidine</topic><topic>Pyrimidines - pharmacology</topic><topic>Rats</topic><topic>Sarcoma 180 - metabolism</topic><topic>Thymine - pharmacology</topic><topic>Uracil - pharmacology</topic><toplevel>online_resources</toplevel><creatorcontrib>TATSUMI, Kunihiko</creatorcontrib><creatorcontrib>FUKUSHIMA, Masakazu</creatorcontrib><creatorcontrib>SHIRASAKA, Tetsuhiko</creatorcontrib><creatorcontrib>FUJII, Setsuro</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>Japanese Journal of Cancer Research GANN</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>TATSUMI, Kunihiko</au><au>FUKUSHIMA, Masakazu</au><au>SHIRASAKA, Tetsuhiko</au><au>FUJII, Setsuro</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibitory Effects of Pyrimidine, Barbituric Acid and Pyridine Derivatives on 5-Fluorouracil Degradation in Rat Liver Extracts</atitle><jtitle>Japanese Journal of Cancer Research GANN</jtitle><addtitle>Japanese Journal of Cancer Research GANN</addtitle><date>1987</date><risdate>1987</risdate><volume>78</volume><issue>7</issue><spage>748</spage><epage>755</epage><pages>748-755</pages><issn>0910-5050</issn><eissn>1876-4673</eissn><coden>GANNA2</coden><abstract>The inhibitory effects of about 30 compounds, mainly pyrimidine and pyridine derivatives, on 5-fluorouracil degradation catalyzed by dihydrouracil dehydrogenase (DHU dehydrogenase) were investigated. The inhibitory activities of 5-substituted uracil derivatives decreased time-dependently during preincubation with liver extracts, indicating that these compounds are substrates of DHU dehydrogenase. During preincubation, 4, 6-dihydroxypyrimidine derivatives were found to be converted to barbituric acid derivatives, which have stronger activities. The inhibitory activity of 2, 4-dihydroxypyridine (3-deazauracil), which was stronger than that of uracil, did not change during preincubation, indicating that this compound is not a substrate but is an inhibitor of DHU dehydrogenase, and suggesting that 2, 6-dihydroxypyridine (1-deazauracil) could be a potent inhibitor. In the light of these findings, we examined various derivatives of barbituric acid, 2, 4-dihydroxypyridine and 2, 6-dihydroxypyridine. Among these compounds, 3-cyano-2, 6-dihydroxypyridine and 5-chloro-2, 4-dihydroxypyridine were the strongest inhibitors with Ki values for DHU dehydrogenase of 2.3×10-7M and 3.6×10-7M, respectively.</abstract><cop>Tokyo</cop><pub>The Japanese Cancer Association</pub><pmid>3114201</pmid><doi>10.20772/cancersci1985.78.7_748</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; J-STAGE (Japan Science & Technology Information Aggregator, Electronic) Freely Available Titles - Japanese; EZB-FREE-00999 freely available EZB journals |
| subjects | 5-Fluorouracil 5-Fluorouracil degradation Animals Antineoplastic agents Barbiturates - pharmacology Barbituric acid Biological and medical sciences Chromatography, High Pressure Liquid Dihydrouracil dehydrogenase Dihydrouracil Dehydrogenase (NAD+) Fluorouracil - metabolism General aspects Kinetics Liver - drug effects Liver - metabolism Medical sciences Oxidoreductases - metabolism Oxidoreductases Acting on CH-CH Group Donors Pharmacology. Drug treatments Phosphorylation Pyridines - pharmacology Pyrimidine Pyrimidines - pharmacology Rats Sarcoma 180 - metabolism Thymine - pharmacology Uracil - pharmacology |
| title | Inhibitory Effects of Pyrimidine, Barbituric Acid and Pyridine Derivatives on 5-Fluorouracil Degradation in Rat Liver Extracts |
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