Synthesis of a Methylenebis(phosphonate) Analogue of Mycophenolic Adenine Dinucleotide: A Glucuronidation-Resistant MAD Analogue of NAD
Mycophenolic alcohol (MPAlc), obtained by reduction of the carboxylic group of mycophenolic acid (MPA), was coupled with 2‘,3‘-O-isopropylideneadenosine 5‘-methylenebis(phosphonate) (4) in the presence of diisopropylcarbodiimide (DIC) to give P -(2‘,3‘-O-isopropylideneadenosin-5‘-yl)-P -(mycophenoli...
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| Veröffentlicht in: | Journal of medicinal chemistry 1998-02, Vol.41 (4), p.618-622 |
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| container_title | Journal of medicinal chemistry |
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| creator | Lesiak, Krystyna Watanabe, Kyoichi A Majumdar, Alokes Powell, James Seidman, Michael Vanderveen, Kristen Goldstein, Barry M Pankiewicz, Krzysztof W |
| description | Mycophenolic alcohol (MPAlc), obtained by reduction of the carboxylic group of mycophenolic acid (MPA), was coupled with 2‘,3‘-O-isopropylideneadenosine 5‘-methylenebis(phosphonate) (4) in the presence of diisopropylcarbodiimide (DIC) to give P -(2‘,3‘-O-isopropylideneadenosin-5‘-yl)-P -(mycophenolic alcohol-6‘-yl)methylenebis(phosphonate) (8) in 32% yield. Deisopropylidenation of 8 with CF3COOH/H2O afforded the methylenebis(phosphonate) analogue 3 of mycophenolic adenine dinucleotide (MAD). Compound 3, β-methylene-MAD, was found to be a potent inhibitor of inosine monophosphate dehydrogenase (IMPDH) type II (K i = 0.3 μM) as well as an inhibitor of growth of K562 cells (IC50 = 1.5 μM). In contrast to MPA and mycophenolic alcohol, β-methylene-MAD was not converted into the glucuronide when incubated with uridine 5‘-diphosphoglucuronyltransferase. |
| doi_str_mv | 10.1021/jm970705k |
| format | Article |
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Deisopropylidenation of 8 with CF3COOH/H2O afforded the methylenebis(phosphonate) analogue 3 of mycophenolic adenine dinucleotide (MAD). Compound 3, β-methylene-MAD, was found to be a potent inhibitor of inosine monophosphate dehydrogenase (IMPDH) type II (K i = 0.3 μM) as well as an inhibitor of growth of K562 cells (IC50 = 1.5 μM). In contrast to MPA and mycophenolic alcohol, β-methylene-MAD was not converted into the glucuronide when incubated with uridine 5‘-diphosphoglucuronyltransferase.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm970705k</identifier><identifier>PMID: 9484510</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Adenine Nucleotides ; Antineoplastic agents ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - toxicity ; Biological and medical sciences ; Biotransformation ; Cell Division - drug effects ; General aspects ; Glucuronates ; Glucuronosyltransferase - metabolism ; Humans ; IMP Dehydrogenase - antagonists & inhibitors ; Indicators and Reagents ; Medical sciences ; Molecular Structure ; Mycophenolic Acid - analogs & derivatives ; Mycophenolic Acid - chemical synthesis ; Mycophenolic Acid - chemistry ; Mycophenolic Acid - pharmacology ; Mycophenolic Acid - toxicity ; NAD - analogs & derivatives ; Pharmacology. Drug treatments ; Structure-Activity Relationship ; Tumor Cells, Cultured</subject><ispartof>Journal of medicinal chemistry, 1998-02, Vol.41 (4), p.618-622</ispartof><rights>Copyright © 1998 American Chemical Society</rights><rights>1998 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a377t-aa73a9f17777dc08b045916ca032825524e7c29d4d03acc3c7b15b64f52804463</citedby><cites>FETCH-LOGICAL-a377t-aa73a9f17777dc08b045916ca032825524e7c29d4d03acc3c7b15b64f52804463</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/jm970705k$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm970705k$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>315,782,786,2767,27083,27931,27932,56745,56795</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=2158588$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9484510$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lesiak, Krystyna</creatorcontrib><creatorcontrib>Watanabe, Kyoichi A</creatorcontrib><creatorcontrib>Majumdar, Alokes</creatorcontrib><creatorcontrib>Powell, James</creatorcontrib><creatorcontrib>Seidman, Michael</creatorcontrib><creatorcontrib>Vanderveen, Kristen</creatorcontrib><creatorcontrib>Goldstein, Barry M</creatorcontrib><creatorcontrib>Pankiewicz, Krzysztof W</creatorcontrib><title>Synthesis of a Methylenebis(phosphonate) Analogue of Mycophenolic Adenine Dinucleotide: A Glucuronidation-Resistant MAD Analogue of NAD</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Mycophenolic alcohol (MPAlc), obtained by reduction of the carboxylic group of mycophenolic acid (MPA), was coupled with 2‘,3‘-O-isopropylideneadenosine 5‘-methylenebis(phosphonate) (4) in the presence of diisopropylcarbodiimide (DIC) to give P -(2‘,3‘-O-isopropylideneadenosin-5‘-yl)-P -(mycophenolic alcohol-6‘-yl)methylenebis(phosphonate) (8) in 32% yield. Deisopropylidenation of 8 with CF3COOH/H2O afforded the methylenebis(phosphonate) analogue 3 of mycophenolic adenine dinucleotide (MAD). Compound 3, β-methylene-MAD, was found to be a potent inhibitor of inosine monophosphate dehydrogenase (IMPDH) type II (K i = 0.3 μM) as well as an inhibitor of growth of K562 cells (IC50 = 1.5 μM). In contrast to MPA and mycophenolic alcohol, β-methylene-MAD was not converted into the glucuronide when incubated with uridine 5‘-diphosphoglucuronyltransferase.</description><subject>Adenine Nucleotides</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - toxicity</subject><subject>Biological and medical sciences</subject><subject>Biotransformation</subject><subject>Cell Division - drug effects</subject><subject>General aspects</subject><subject>Glucuronates</subject><subject>Glucuronosyltransferase - metabolism</subject><subject>Humans</subject><subject>IMP Dehydrogenase - antagonists & inhibitors</subject><subject>Indicators and Reagents</subject><subject>Medical sciences</subject><subject>Molecular Structure</subject><subject>Mycophenolic Acid - analogs & derivatives</subject><subject>Mycophenolic Acid - chemical synthesis</subject><subject>Mycophenolic Acid - chemistry</subject><subject>Mycophenolic Acid - pharmacology</subject><subject>Mycophenolic Acid - toxicity</subject><subject>NAD - analogs & derivatives</subject><subject>Pharmacology. Drug treatments</subject><subject>Structure-Activity Relationship</subject><subject>Tumor Cells, Cultured</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1998</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkM9uEzEQhy1EVULhwAMg-QASPWzx3_UutyWBttAU1JSzNev1EqcbO1rvSuTGFR6TJ8FRokhIjDSaw-_TjP0h9IKSC0oYfbtal4ooIh8eoQmVjGSiIOIxmhDCWMZyxp-gpzGuCCGcMn6KTktRCEnJBP1ebP2wtNFFHFoMeG6H5baz3tYuvtksQ0ztYbDnuPLQhe-j3XHzrQmbpfWhcwZXjfXOWzxzfjSdDYNr7Ls_P3_hCl92oxn74F0Dgws-u9sdGsAPeF7N_tl4W82eoZMWumifH-YZ-vbxw_30Krv5cnk9rW4y4EoNGYDiULZUpWoMKWoiZElzA4SzgknJhFWGlY1oCAdjuFE1lXUuWsmSFJHzM3S-32v6EGNvW73p3Rr6raZE73Tqo87Evtyzm7Fe2-ZIHvyl_NUhh2iga3vwxsUjxqgsZFEkLNtj6ff2xzGG_kHniiup778udLl4fzf9dKv058S_3vNgol6FsU-m4n-e9xfhB5lD</recordid><startdate>19980212</startdate><enddate>19980212</enddate><creator>Lesiak, Krystyna</creator><creator>Watanabe, Kyoichi A</creator><creator>Majumdar, Alokes</creator><creator>Powell, James</creator><creator>Seidman, Michael</creator><creator>Vanderveen, Kristen</creator><creator>Goldstein, Barry M</creator><creator>Pankiewicz, Krzysztof W</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></search><sort><creationdate>19980212</creationdate><title>Synthesis of a Methylenebis(phosphonate) Analogue of Mycophenolic Adenine Dinucleotide: A Glucuronidation-Resistant MAD Analogue of NAD</title><author>Lesiak, Krystyna ; Watanabe, Kyoichi A ; Majumdar, Alokes ; Powell, James ; Seidman, Michael ; Vanderveen, Kristen ; Goldstein, Barry M ; Pankiewicz, Krzysztof W</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a377t-aa73a9f17777dc08b045916ca032825524e7c29d4d03acc3c7b15b64f52804463</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1998</creationdate><topic>Adenine Nucleotides</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - toxicity</topic><topic>Biological and medical sciences</topic><topic>Biotransformation</topic><topic>Cell Division - drug effects</topic><topic>General aspects</topic><topic>Glucuronates</topic><topic>Glucuronosyltransferase - metabolism</topic><topic>Humans</topic><topic>IMP Dehydrogenase - antagonists & inhibitors</topic><topic>Indicators and Reagents</topic><topic>Medical sciences</topic><topic>Molecular Structure</topic><topic>Mycophenolic Acid - analogs & derivatives</topic><topic>Mycophenolic Acid - chemical synthesis</topic><topic>Mycophenolic Acid - chemistry</topic><topic>Mycophenolic Acid - pharmacology</topic><topic>Mycophenolic Acid - toxicity</topic><topic>NAD - analogs & derivatives</topic><topic>Pharmacology. Drug treatments</topic><topic>Structure-Activity Relationship</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lesiak, Krystyna</creatorcontrib><creatorcontrib>Watanabe, Kyoichi A</creatorcontrib><creatorcontrib>Majumdar, Alokes</creatorcontrib><creatorcontrib>Powell, James</creatorcontrib><creatorcontrib>Seidman, Michael</creatorcontrib><creatorcontrib>Vanderveen, Kristen</creatorcontrib><creatorcontrib>Goldstein, Barry M</creatorcontrib><creatorcontrib>Pankiewicz, Krzysztof W</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><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lesiak, Krystyna</au><au>Watanabe, Kyoichi A</au><au>Majumdar, Alokes</au><au>Powell, James</au><au>Seidman, Michael</au><au>Vanderveen, Kristen</au><au>Goldstein, Barry M</au><au>Pankiewicz, Krzysztof W</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis of a Methylenebis(phosphonate) Analogue of Mycophenolic Adenine Dinucleotide: A Glucuronidation-Resistant MAD Analogue of NAD</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1998-02-12</date><risdate>1998</risdate><volume>41</volume><issue>4</issue><spage>618</spage><epage>622</epage><pages>618-622</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Mycophenolic alcohol (MPAlc), obtained by reduction of the carboxylic group of mycophenolic acid (MPA), was coupled with 2‘,3‘-O-isopropylideneadenosine 5‘-methylenebis(phosphonate) (4) in the presence of diisopropylcarbodiimide (DIC) to give P -(2‘,3‘-O-isopropylideneadenosin-5‘-yl)-P -(mycophenolic alcohol-6‘-yl)methylenebis(phosphonate) (8) in 32% yield. Deisopropylidenation of 8 with CF3COOH/H2O afforded the methylenebis(phosphonate) analogue 3 of mycophenolic adenine dinucleotide (MAD). Compound 3, β-methylene-MAD, was found to be a potent inhibitor of inosine monophosphate dehydrogenase (IMPDH) type II (K i = 0.3 μM) as well as an inhibitor of growth of K562 cells (IC50 = 1.5 μM). In contrast to MPA and mycophenolic alcohol, β-methylene-MAD was not converted into the glucuronide when incubated with uridine 5‘-diphosphoglucuronyltransferase.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>9484510</pmid><doi>10.1021/jm970705k</doi><tpages>5</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 1998-02, Vol.41 (4), p.618-622 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_crossref_primary_10_1021_jm970705k |
| source | MEDLINE; ACS Publications |
| subjects | Adenine Nucleotides Antineoplastic agents Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - toxicity Biological and medical sciences Biotransformation Cell Division - drug effects General aspects Glucuronates Glucuronosyltransferase - metabolism Humans IMP Dehydrogenase - antagonists & inhibitors Indicators and Reagents Medical sciences Molecular Structure Mycophenolic Acid - analogs & derivatives Mycophenolic Acid - chemical synthesis Mycophenolic Acid - chemistry Mycophenolic Acid - pharmacology Mycophenolic Acid - toxicity NAD - analogs & derivatives Pharmacology. Drug treatments Structure-Activity Relationship Tumor Cells, Cultured |
| title | Synthesis of a Methylenebis(phosphonate) Analogue of Mycophenolic Adenine Dinucleotide: A Glucuronidation-Resistant MAD Analogue of NAD |
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