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
Hauptverfasser: Lesiak, Krystyna, Watanabe, Kyoichi A, Majumdar, Alokes, Powell, James, Seidman, Michael, Vanderveen, Kristen, Goldstein, Barry M, Pankiewicz, Krzysztof W
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container_end_page 622
container_issue 4
container_start_page 618
container_title Journal of medicinal chemistry
container_volume 41
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
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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). 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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$$H</linktohtml><link.rule.ids>315,781,785,2766,27081,27929,27930,56743,56793</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;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 &amp; inhibitors</subject><subject>Indicators and Reagents</subject><subject>Medical sciences</subject><subject>Molecular Structure</subject><subject>Mycophenolic Acid - analogs &amp; 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 &amp; 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 &amp; inhibitors</topic><topic>Indicators and Reagents</topic><topic>Medical sciences</topic><topic>Molecular Structure</topic><topic>Mycophenolic Acid - analogs &amp; 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 &amp; 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>
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ispartof Journal of medicinal chemistry, 1998-02, Vol.41 (4), p.618-622
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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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