Synthesis of and a Comparative Study on the Inhibition of Muscle and Liver Glycogen Phosphorylases by Epimeric Pairs of d-Gluco- and d-Xylopyranosylidene-spiro-(thio)hydantoins and N-(d-Glucopyranosyl) Amides
d-Gluco- and d-xylopyranosylidene-spiro-hydantoins and -thiohydantoins were prepared from the parent sugars in a six-step, highly chemo-, regio-, and stereoselective procedure. In the key step of the syntheses C-(1-bromo-1-deoxy-β-d-glycopyranosyl)formamides were reacted with cyanate ion to give spi...
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| Veröffentlicht in: | Journal of medicinal chemistry 2001-08, Vol.44 (17), p.2843-2848 |
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| creator | Somsák, László Kovács, László Tóth, Marietta Ősz, Erzsébet Szilágyi, László Györgydeák, Zoltán Dinya, Zoltán Docsa, Tibor Tóth, Béla Gergely, Pál |
| description | d-Gluco- and d-xylopyranosylidene-spiro-hydantoins and -thiohydantoins were prepared from the parent sugars in a six-step, highly chemo-, regio-, and stereoselective procedure. In the key step of the syntheses C-(1-bromo-1-deoxy-β-d-glycopyranosyl)formamides were reacted with cyanate ion to give spiro-hydantoins with a retained configuration at the anomeric center as the major products. On the other hand, thiocyanate ions gave spiro-thiohydantoins with an inverted anomeric carbon as the only products. On the basis of radical inhibition studies, a mechanistic rationale was proposed to explain this unique stereoselectivity and the formation of C-(1-hydroxy-β-d-glycopyranosyl)formamides as byproducts. Enzyme assays with a and b forms of muscle and liver glycogen phosphorylases showed spiro-hydantoin 12 and spiro-thiohydantoin 14 to be the best and equipotent inhibitors with K i values in the low micromolar range. The study of epimeric pairs of d-gluco and d-xylo configurated spiro-hydantoins and N-(d-glucopyranosyl)amides corroborated the role of specific hydrogen bridges in binding the inhibitors to the enzyme. |
| doi_str_mv | 10.1021/jm010892t |
| format | Article |
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In the key step of the syntheses C-(1-bromo-1-deoxy-β-d-glycopyranosyl)formamides were reacted with cyanate ion to give spiro-hydantoins with a retained configuration at the anomeric center as the major products. On the other hand, thiocyanate ions gave spiro-thiohydantoins with an inverted anomeric carbon as the only products. On the basis of radical inhibition studies, a mechanistic rationale was proposed to explain this unique stereoselectivity and the formation of C-(1-hydroxy-β-d-glycopyranosyl)formamides as byproducts. Enzyme assays with a and b forms of muscle and liver glycogen phosphorylases showed spiro-hydantoin 12 and spiro-thiohydantoin 14 to be the best and equipotent inhibitors with K i values in the low micromolar range. The study of epimeric pairs of d-gluco and d-xylo configurated spiro-hydantoins and N-(d-glucopyranosyl)amides corroborated the role of specific hydrogen bridges in binding the inhibitors to the enzyme.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm010892t</identifier><identifier>PMID: 11495595</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Amides - chemical synthesis ; Amides - chemistry ; Biological and medical sciences ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; General and cellular metabolism. Vitamins ; Hydantoins - chemical synthesis ; Hydantoins - chemistry ; Hydrogen Bonding ; Hypoglycemic Agents - chemical synthesis ; Hypoglycemic Agents - chemistry ; Liver - enzymology ; Medical sciences ; Molecular Conformation ; Monosaccharides - chemical synthesis ; Monosaccharides - chemistry ; Muscles - enzymology ; Pharmacology. Drug treatments ; Phosphorylase a - antagonists & inhibitors ; Phosphorylase b - antagonists & inhibitors ; Phosphorylases - antagonists & inhibitors ; Spiro Compounds - chemical synthesis ; Spiro Compounds - chemistry ; Stereoisomerism ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2001-08, Vol.44 (17), p.2843-2848</ispartof><rights>Copyright © 2001 American Chemical Society</rights><rights>2001 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a444t-e4155109a0ecac0d3dcf8093947db85acf6061518e32f5c206d2ef7a66059523</citedby><cites>FETCH-LOGICAL-a444t-e4155109a0ecac0d3dcf8093947db85acf6061518e32f5c206d2ef7a66059523</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/jm010892t$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm010892t$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1107709$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11495595$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Somsák, László</creatorcontrib><creatorcontrib>Kovács, László</creatorcontrib><creatorcontrib>Tóth, Marietta</creatorcontrib><creatorcontrib>Ősz, Erzsébet</creatorcontrib><creatorcontrib>Szilágyi, László</creatorcontrib><creatorcontrib>Györgydeák, Zoltán</creatorcontrib><creatorcontrib>Dinya, Zoltán</creatorcontrib><creatorcontrib>Docsa, Tibor</creatorcontrib><creatorcontrib>Tóth, Béla</creatorcontrib><creatorcontrib>Gergely, Pál</creatorcontrib><title>Synthesis of and a Comparative Study on the Inhibition of Muscle and Liver Glycogen Phosphorylases by Epimeric Pairs of d-Gluco- and d-Xylopyranosylidene-spiro-(thio)hydantoins and N-(d-Glucopyranosyl) Amides</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>d-Gluco- and d-xylopyranosylidene-spiro-hydantoins and -thiohydantoins were prepared from the parent sugars in a six-step, highly chemo-, regio-, and stereoselective procedure. In the key step of the syntheses C-(1-bromo-1-deoxy-β-d-glycopyranosyl)formamides were reacted with cyanate ion to give spiro-hydantoins with a retained configuration at the anomeric center as the major products. On the other hand, thiocyanate ions gave spiro-thiohydantoins with an inverted anomeric carbon as the only products. On the basis of radical inhibition studies, a mechanistic rationale was proposed to explain this unique stereoselectivity and the formation of C-(1-hydroxy-β-d-glycopyranosyl)formamides as byproducts. Enzyme assays with a and b forms of muscle and liver glycogen phosphorylases showed spiro-hydantoin 12 and spiro-thiohydantoin 14 to be the best and equipotent inhibitors with K i values in the low micromolar range. The study of epimeric pairs of d-gluco and d-xylo configurated spiro-hydantoins and N-(d-glucopyranosyl)amides corroborated the role of specific hydrogen bridges in binding the inhibitors to the enzyme.</description><subject>Amides - chemical synthesis</subject><subject>Amides - chemistry</subject><subject>Biological and medical sciences</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>General and cellular metabolism. Vitamins</subject><subject>Hydantoins - chemical synthesis</subject><subject>Hydantoins - chemistry</subject><subject>Hydrogen Bonding</subject><subject>Hypoglycemic Agents - chemical synthesis</subject><subject>Hypoglycemic Agents - chemistry</subject><subject>Liver - enzymology</subject><subject>Medical sciences</subject><subject>Molecular Conformation</subject><subject>Monosaccharides - chemical synthesis</subject><subject>Monosaccharides - chemistry</subject><subject>Muscles - enzymology</subject><subject>Pharmacology. Drug treatments</subject><subject>Phosphorylase a - antagonists & inhibitors</subject><subject>Phosphorylase b - antagonists & inhibitors</subject><subject>Phosphorylases - antagonists & inhibitors</subject><subject>Spiro Compounds - chemical synthesis</subject><subject>Spiro Compounds - chemistry</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0c-PEyEUB3BiNO5aPfgPGA5qtgcUmF-d46au3Y1VJ7aJ3ggFxqHOwMibMc5_6Z8ktk314IkQPt_3gIfQU0ZfMcrZ631HGV2UfLiHLlnGKUkXNL2PLinlnPCcJxfoEcCeUpownjxEF4ylZZaV2SX6tZnc0BiwgH2NpdNY4qXvehnkYH8YvBlGPWHvcET4zjV2ZwcbtxG_H0G15pBZRxrwqp2U_2ocrhoPfePD1EowgHcTvultZ4JVuJI2HFppsmpH5ckhr8mXqfX9FKTzMLVWG2cI9DZ4cjU01s-bSUs3eOvg4D-Qq1P-nJnj6y7m4DF6UMsWzJPTOkPbtzfb5S1Zf1zdLa_XRKZpOhCTsixjtJTUKKmoTrSqF7RMyrTQu0UmVZ3TnGVsYRJeZ4rTXHNTFzLPafw3nszQy2PZPvjvo4FBdBaUaVvpjB9BFIwWRZbmEc6PUAUPEEwt-mA7GSbBqPgzPXGeXrTPTkXHXWf0X3kaVwTPT0CCkm0d364s_ONi0_iIGSJHZmEwP8_HMnwTeZEUmdhWG1G9efe5-pTciir6F0cvFYi9H4OLP_ef-_0Gtp3AZQ</recordid><startdate>20010816</startdate><enddate>20010816</enddate><creator>Somsák, László</creator><creator>Kovács, László</creator><creator>Tóth, Marietta</creator><creator>Ősz, Erzsébet</creator><creator>Szilágyi, László</creator><creator>Györgydeák, Zoltán</creator><creator>Dinya, Zoltán</creator><creator>Docsa, Tibor</creator><creator>Tóth, Béla</creator><creator>Gergely, Pál</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>7X8</scope></search><sort><creationdate>20010816</creationdate><title>Synthesis of and a Comparative Study on the Inhibition of Muscle and Liver Glycogen Phosphorylases by Epimeric Pairs of d-Gluco- and d-Xylopyranosylidene-spiro-(thio)hydantoins and N-(d-Glucopyranosyl) Amides</title><author>Somsák, László ; Kovács, László ; Tóth, Marietta ; Ősz, Erzsébet ; Szilágyi, László ; Györgydeák, Zoltán ; Dinya, Zoltán ; Docsa, Tibor ; Tóth, Béla ; Gergely, Pál</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a444t-e4155109a0ecac0d3dcf8093947db85acf6061518e32f5c206d2ef7a66059523</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Amides - chemical synthesis</topic><topic>Amides - chemistry</topic><topic>Biological and medical sciences</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>General and cellular metabolism. Vitamins</topic><topic>Hydantoins - chemical synthesis</topic><topic>Hydantoins - chemistry</topic><topic>Hydrogen Bonding</topic><topic>Hypoglycemic Agents - chemical synthesis</topic><topic>Hypoglycemic Agents - chemistry</topic><topic>Liver - enzymology</topic><topic>Medical sciences</topic><topic>Molecular Conformation</topic><topic>Monosaccharides - chemical synthesis</topic><topic>Monosaccharides - chemistry</topic><topic>Muscles - enzymology</topic><topic>Pharmacology. Drug treatments</topic><topic>Phosphorylase a - antagonists & inhibitors</topic><topic>Phosphorylase b - antagonists & inhibitors</topic><topic>Phosphorylases - antagonists & inhibitors</topic><topic>Spiro Compounds - chemical synthesis</topic><topic>Spiro Compounds - chemistry</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Somsák, László</creatorcontrib><creatorcontrib>Kovács, László</creatorcontrib><creatorcontrib>Tóth, Marietta</creatorcontrib><creatorcontrib>Ősz, Erzsébet</creatorcontrib><creatorcontrib>Szilágyi, László</creatorcontrib><creatorcontrib>Györgydeák, Zoltán</creatorcontrib><creatorcontrib>Dinya, Zoltán</creatorcontrib><creatorcontrib>Docsa, Tibor</creatorcontrib><creatorcontrib>Tóth, Béla</creatorcontrib><creatorcontrib>Gergely, Pál</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Somsák, László</au><au>Kovács, László</au><au>Tóth, Marietta</au><au>Ősz, Erzsébet</au><au>Szilágyi, László</au><au>Györgydeák, Zoltán</au><au>Dinya, Zoltán</au><au>Docsa, Tibor</au><au>Tóth, Béla</au><au>Gergely, Pál</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis of and a Comparative Study on the Inhibition of Muscle and Liver Glycogen Phosphorylases by Epimeric Pairs of d-Gluco- and d-Xylopyranosylidene-spiro-(thio)hydantoins and N-(d-Glucopyranosyl) Amides</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2001-08-16</date><risdate>2001</risdate><volume>44</volume><issue>17</issue><spage>2843</spage><epage>2848</epage><pages>2843-2848</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>d-Gluco- and d-xylopyranosylidene-spiro-hydantoins and -thiohydantoins were prepared from the parent sugars in a six-step, highly chemo-, regio-, and stereoselective procedure. In the key step of the syntheses C-(1-bromo-1-deoxy-β-d-glycopyranosyl)formamides were reacted with cyanate ion to give spiro-hydantoins with a retained configuration at the anomeric center as the major products. On the other hand, thiocyanate ions gave spiro-thiohydantoins with an inverted anomeric carbon as the only products. On the basis of radical inhibition studies, a mechanistic rationale was proposed to explain this unique stereoselectivity and the formation of C-(1-hydroxy-β-d-glycopyranosyl)formamides as byproducts. Enzyme assays with a and b forms of muscle and liver glycogen phosphorylases showed spiro-hydantoin 12 and spiro-thiohydantoin 14 to be the best and equipotent inhibitors with K i values in the low micromolar range. The study of epimeric pairs of d-gluco and d-xylo configurated spiro-hydantoins and N-(d-glucopyranosyl)amides corroborated the role of specific hydrogen bridges in binding the inhibitors to the enzyme.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>11495595</pmid><doi>10.1021/jm010892t</doi><tpages>6</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Journal of medicinal chemistry, 2001-08, Vol.44 (17), p.2843-2848 |
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| source | MEDLINE; American Chemical Society Journals |
| subjects | Amides - chemical synthesis Amides - chemistry Biological and medical sciences Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry General and cellular metabolism. Vitamins Hydantoins - chemical synthesis Hydantoins - chemistry Hydrogen Bonding Hypoglycemic Agents - chemical synthesis Hypoglycemic Agents - chemistry Liver - enzymology Medical sciences Molecular Conformation Monosaccharides - chemical synthesis Monosaccharides - chemistry Muscles - enzymology Pharmacology. Drug treatments Phosphorylase a - antagonists & inhibitors Phosphorylase b - antagonists & inhibitors Phosphorylases - antagonists & inhibitors Spiro Compounds - chemical synthesis Spiro Compounds - chemistry Stereoisomerism Structure-Activity Relationship |
| title | Synthesis of and a Comparative Study on the Inhibition of Muscle and Liver Glycogen Phosphorylases by Epimeric Pairs of d-Gluco- and d-Xylopyranosylidene-spiro-(thio)hydantoins and N-(d-Glucopyranosyl) Amides |
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