Synthesis and biological evaluation of indomethacin analogs possessing a N-difluoromethyl-1,2-dihydropyrid-2-one ring system: A search for novel cyclooxygenase and lipoxygenase inhibitors
A novel class of indomethacin analogs were synthesized wherein a N-difluoromethyl-1,2-dihydropyrid-2-one moiety (5-LOX pharmacophore) was attached at its C-4 or C-5 position via either a C O ( 14a– b) or CH 2 ( 19a– b) linker to the indole N 1-position. In this regard, replacement of the 4-chloroben...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2010-10, Vol.20 (19), p.5776-5780 |
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| creator | Chowdhury, Morshed A. Huang, Zhangjian Abdellatif, Khaled R.A. Dong, Ying Yu, Gang Velázquez, Carlos A. Knaus, Edward E. |
| description | A novel class of indomethacin analogs were synthesized wherein a
N-difluoromethyl-1,2-dihydropyrid-2-one moiety (5-LOX pharmacophore) was attached at its C-4 or C-5 position via either a C
O (
14a–
b) or CH
2 (
19a–
b) linker to the indole N
1-position. In this regard, replacement of the 4-chlorobenzoyl group present in indomethacin by
N-difluoromethyl-1,2-dihydropyrid-2-one-4-(or 5-)carbonyl and
N-difluoromethyl-1,2-dihydropyrid-2-one-4-yl(or 5-yl)methylene moieties furnished compounds showing no inhibitory activities against the COX-2/5-LOX enzymes (except for the weak but selective COX-2 inhibitor
19a, COX-2 IC
50
=
31
μM), and moderate in vivo anti-inflammatory activities (except for the methylene compound
19a that was inactive). These structure–activity data indicate replacement of the 4-chlorobenzoyl group present in indomethacin by a
N-difluoromethyl-1,2-dihydropyrid-2-one ring system connected by a C
O or CH
2 linker is not a suitable approach for the design of dual COX-2/5-LOX inhibitory analogs of indomethacin. |
| doi_str_mv | 10.1016/j.bmcl.2010.07.132 |
| format | Article |
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N-difluoromethyl-1,2-dihydropyrid-2-one moiety (5-LOX pharmacophore) was attached at its C-4 or C-5 position via either a C
O (
14a–
b) or CH
2 (
19a–
b) linker to the indole N
1-position. In this regard, replacement of the 4-chlorobenzoyl group present in indomethacin by
N-difluoromethyl-1,2-dihydropyrid-2-one-4-(or 5-)carbonyl and
N-difluoromethyl-1,2-dihydropyrid-2-one-4-yl(or 5-yl)methylene moieties furnished compounds showing no inhibitory activities against the COX-2/5-LOX enzymes (except for the weak but selective COX-2 inhibitor
19a, COX-2 IC
50
=
31
μM), and moderate in vivo anti-inflammatory activities (except for the methylene compound
19a that was inactive). These structure–activity data indicate replacement of the 4-chlorobenzoyl group present in indomethacin by a
N-difluoromethyl-1,2-dihydropyrid-2-one ring system connected by a C
O or CH
2 linker is not a suitable approach for the design of dual COX-2/5-LOX inhibitory analogs of indomethacin.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2010.07.132</identifier><identifier>PMID: 20727750</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>Animals ; Anti-inflammatory activity ; Anti-Inflammatory Agents - chemical synthesis ; Anti-Inflammatory Agents - chemistry ; Anti-Inflammatory Agents - therapeutic use ; Arachidonate 5-Lipoxygenase - chemistry ; Arachidonate 5-Lipoxygenase - metabolism ; Biological and medical sciences ; Bones, joints and connective tissue. Antiinflammatory agents ; Cyclooxygenase 2 - chemistry ; Cyclooxygenase 2 - metabolism ; Cyclooxygenase 2 Inhibitors - chemical synthesis ; Cyclooxygenase 2 Inhibitors - therapeutic use ; Cyclooxygenase and 5-lipoxygenase inhibition ; Edema - chemically induced ; Edema - drug therapy ; Indoles - chemical synthesis ; Indoles - chemistry ; Indoles - therapeutic use ; Indomethacin - chemical synthesis ; Indomethacin - chemistry ; Indomethacin - pharmacology ; Indomethacin analogs ; Lipoxygenase Inhibitors - chemical synthesis ; Lipoxygenase Inhibitors - chemistry ; Lipoxygenase Inhibitors - therapeutic use ; Medical sciences ; N-Difluoromethyl-1,2-dihydropyrid-2-one 5-Lipoxygenase pharmacophore ; Pharmacology. Drug treatments ; Pyridones - chemical synthesis ; Pyridones - chemistry ; Pyridones - therapeutic use ; Rats ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry letters, 2010-10, Vol.20 (19), p.5776-5780</ispartof><rights>2010 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2010 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c385t-c1c228fc2329268c4d9313a6378c467619fd5a33b4a0e06a7c95e7234eaa19263</citedby><cites>FETCH-LOGICAL-c385t-c1c228fc2329268c4d9313a6378c467619fd5a33b4a0e06a7c95e7234eaa19263</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X10011017$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=23270224$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20727750$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chowdhury, Morshed A.</creatorcontrib><creatorcontrib>Huang, Zhangjian</creatorcontrib><creatorcontrib>Abdellatif, Khaled R.A.</creatorcontrib><creatorcontrib>Dong, Ying</creatorcontrib><creatorcontrib>Yu, Gang</creatorcontrib><creatorcontrib>Velázquez, Carlos A.</creatorcontrib><creatorcontrib>Knaus, Edward E.</creatorcontrib><title>Synthesis and biological evaluation of indomethacin analogs possessing a N-difluoromethyl-1,2-dihydropyrid-2-one ring system: A search for novel cyclooxygenase and lipoxygenase inhibitors</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>A novel class of indomethacin analogs were synthesized wherein a
N-difluoromethyl-1,2-dihydropyrid-2-one moiety (5-LOX pharmacophore) was attached at its C-4 or C-5 position via either a C
O (
14a–
b) or CH
2 (
19a–
b) linker to the indole N
1-position. In this regard, replacement of the 4-chlorobenzoyl group present in indomethacin by
N-difluoromethyl-1,2-dihydropyrid-2-one-4-(or 5-)carbonyl and
N-difluoromethyl-1,2-dihydropyrid-2-one-4-yl(or 5-yl)methylene moieties furnished compounds showing no inhibitory activities against the COX-2/5-LOX enzymes (except for the weak but selective COX-2 inhibitor
19a, COX-2 IC
50
=
31
μM), and moderate in vivo anti-inflammatory activities (except for the methylene compound
19a that was inactive). These structure–activity data indicate replacement of the 4-chlorobenzoyl group present in indomethacin by a
N-difluoromethyl-1,2-dihydropyrid-2-one ring system connected by a C
O or CH
2 linker is not a suitable approach for the design of dual COX-2/5-LOX inhibitory analogs of indomethacin.</description><subject>Animals</subject><subject>Anti-inflammatory activity</subject><subject>Anti-Inflammatory Agents - chemical synthesis</subject><subject>Anti-Inflammatory Agents - chemistry</subject><subject>Anti-Inflammatory Agents - therapeutic use</subject><subject>Arachidonate 5-Lipoxygenase - chemistry</subject><subject>Arachidonate 5-Lipoxygenase - metabolism</subject><subject>Biological and medical sciences</subject><subject>Bones, joints and connective tissue. Antiinflammatory agents</subject><subject>Cyclooxygenase 2 - chemistry</subject><subject>Cyclooxygenase 2 - metabolism</subject><subject>Cyclooxygenase 2 Inhibitors - chemical synthesis</subject><subject>Cyclooxygenase 2 Inhibitors - therapeutic use</subject><subject>Cyclooxygenase and 5-lipoxygenase inhibition</subject><subject>Edema - chemically induced</subject><subject>Edema - drug therapy</subject><subject>Indoles - chemical synthesis</subject><subject>Indoles - chemistry</subject><subject>Indoles - therapeutic use</subject><subject>Indomethacin - chemical synthesis</subject><subject>Indomethacin - chemistry</subject><subject>Indomethacin - pharmacology</subject><subject>Indomethacin analogs</subject><subject>Lipoxygenase Inhibitors - chemical synthesis</subject><subject>Lipoxygenase Inhibitors - chemistry</subject><subject>Lipoxygenase Inhibitors - therapeutic use</subject><subject>Medical sciences</subject><subject>N-Difluoromethyl-1,2-dihydropyrid-2-one 5-Lipoxygenase pharmacophore</subject><subject>Pharmacology. Drug treatments</subject><subject>Pyridones - chemical synthesis</subject><subject>Pyridones - chemistry</subject><subject>Pyridones - therapeutic use</subject><subject>Rats</subject><subject>Structure-Activity Relationship</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kcuO0zAUhiMEYsrAC7BA3iA2pPiWuEGzGY24SSNYABI7y3FOGleOXXySijwbL4c7LcyOla1f3390dL6ieM7omlFWv9mt29H6Nac5oGrNBH9QrJisZSkkrR4WK9rUtNw08sdF8QRxRymTVMrHxQWniitV0VXx--sSpgHQITGhI62LPm6dNZ7AwfjZTC4GEnviQhdHmAZjXcikyRSSfUQERBe2xJDPZed6P8d0xy2-ZK95joalS3G_JNeVvIwBSDriuOAE41tyTRBMsgPpYyIhHsATu1gf469lC8Eg3G3l3f4-cGFwrZtiwqfFo954hGfn97L4_v7dt5uP5e2XD59urm9LKzbVVFpmOd_0lgve8HpjZdcIJkwtVP7XqmZN31VGiFYaCrQ2yjYVKC4kGMNyQ1wWr05z9yn-nAEnPTq04L0JEGfUqpKUyqqimeQn0qZ8mgS93ic3mrRoRvXRmd7pozN9dKap0tlZLr04j5_bEbp_lb-SMvDyDBjMZvpkgnV4zwmuKOcyc1cnDvIxDg6SRusgWOhcAjvpLrr_7fEHASC5KQ</recordid><startdate>20101001</startdate><enddate>20101001</enddate><creator>Chowdhury, Morshed A.</creator><creator>Huang, Zhangjian</creator><creator>Abdellatif, Khaled R.A.</creator><creator>Dong, Ying</creator><creator>Yu, Gang</creator><creator>Velázquez, Carlos A.</creator><creator>Knaus, Edward E.</creator><general>Elsevier Ltd</general><general>Elsevier</general><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>20101001</creationdate><title>Synthesis and biological evaluation of indomethacin analogs possessing a N-difluoromethyl-1,2-dihydropyrid-2-one ring system: A search for novel cyclooxygenase and lipoxygenase inhibitors</title><author>Chowdhury, Morshed A. ; Huang, Zhangjian ; Abdellatif, Khaled R.A. ; Dong, Ying ; Yu, Gang ; Velázquez, Carlos A. ; Knaus, Edward E.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c385t-c1c228fc2329268c4d9313a6378c467619fd5a33b4a0e06a7c95e7234eaa19263</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Anti-inflammatory activity</topic><topic>Anti-Inflammatory Agents - chemical synthesis</topic><topic>Anti-Inflammatory Agents - chemistry</topic><topic>Anti-Inflammatory Agents - therapeutic use</topic><topic>Arachidonate 5-Lipoxygenase - chemistry</topic><topic>Arachidonate 5-Lipoxygenase - metabolism</topic><topic>Biological and medical sciences</topic><topic>Bones, joints and connective tissue. Antiinflammatory agents</topic><topic>Cyclooxygenase 2 - chemistry</topic><topic>Cyclooxygenase 2 - metabolism</topic><topic>Cyclooxygenase 2 Inhibitors - chemical synthesis</topic><topic>Cyclooxygenase 2 Inhibitors - therapeutic use</topic><topic>Cyclooxygenase and 5-lipoxygenase inhibition</topic><topic>Edema - chemically induced</topic><topic>Edema - drug therapy</topic><topic>Indoles - chemical synthesis</topic><topic>Indoles - chemistry</topic><topic>Indoles - therapeutic use</topic><topic>Indomethacin - chemical synthesis</topic><topic>Indomethacin - chemistry</topic><topic>Indomethacin - pharmacology</topic><topic>Indomethacin analogs</topic><topic>Lipoxygenase Inhibitors - chemical synthesis</topic><topic>Lipoxygenase Inhibitors - chemistry</topic><topic>Lipoxygenase Inhibitors - therapeutic use</topic><topic>Medical sciences</topic><topic>N-Difluoromethyl-1,2-dihydropyrid-2-one 5-Lipoxygenase pharmacophore</topic><topic>Pharmacology. Drug treatments</topic><topic>Pyridones - chemical synthesis</topic><topic>Pyridones - chemistry</topic><topic>Pyridones - therapeutic use</topic><topic>Rats</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chowdhury, Morshed A.</creatorcontrib><creatorcontrib>Huang, Zhangjian</creatorcontrib><creatorcontrib>Abdellatif, Khaled R.A.</creatorcontrib><creatorcontrib>Dong, Ying</creatorcontrib><creatorcontrib>Yu, Gang</creatorcontrib><creatorcontrib>Velázquez, Carlos A.</creatorcontrib><creatorcontrib>Knaus, Edward E.</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>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chowdhury, Morshed A.</au><au>Huang, Zhangjian</au><au>Abdellatif, Khaled R.A.</au><au>Dong, Ying</au><au>Yu, Gang</au><au>Velázquez, Carlos A.</au><au>Knaus, Edward E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and biological evaluation of indomethacin analogs possessing a N-difluoromethyl-1,2-dihydropyrid-2-one ring system: A search for novel cyclooxygenase and lipoxygenase inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2010-10-01</date><risdate>2010</risdate><volume>20</volume><issue>19</issue><spage>5776</spage><epage>5780</epage><pages>5776-5780</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>A novel class of indomethacin analogs were synthesized wherein a
N-difluoromethyl-1,2-dihydropyrid-2-one moiety (5-LOX pharmacophore) was attached at its C-4 or C-5 position via either a C
O (
14a–
b) or CH
2 (
19a–
b) linker to the indole N
1-position. In this regard, replacement of the 4-chlorobenzoyl group present in indomethacin by
N-difluoromethyl-1,2-dihydropyrid-2-one-4-(or 5-)carbonyl and
N-difluoromethyl-1,2-dihydropyrid-2-one-4-yl(or 5-yl)methylene moieties furnished compounds showing no inhibitory activities against the COX-2/5-LOX enzymes (except for the weak but selective COX-2 inhibitor
19a, COX-2 IC
50
=
31
μM), and moderate in vivo anti-inflammatory activities (except for the methylene compound
19a that was inactive). These structure–activity data indicate replacement of the 4-chlorobenzoyl group present in indomethacin by a
N-difluoromethyl-1,2-dihydropyrid-2-one ring system connected by a C
O or CH
2 linker is not a suitable approach for the design of dual COX-2/5-LOX inhibitory analogs of indomethacin.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>20727750</pmid><doi>10.1016/j.bmcl.2010.07.132</doi><tpages>5</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2010-10, Vol.20 (19), p.5776-5780 |
| issn | 0960-894X 1464-3405 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_754004550 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Animals Anti-inflammatory activity Anti-Inflammatory Agents - chemical synthesis Anti-Inflammatory Agents - chemistry Anti-Inflammatory Agents - therapeutic use Arachidonate 5-Lipoxygenase - chemistry Arachidonate 5-Lipoxygenase - metabolism Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Cyclooxygenase 2 - chemistry Cyclooxygenase 2 - metabolism Cyclooxygenase 2 Inhibitors - chemical synthesis Cyclooxygenase 2 Inhibitors - therapeutic use Cyclooxygenase and 5-lipoxygenase inhibition Edema - chemically induced Edema - drug therapy Indoles - chemical synthesis Indoles - chemistry Indoles - therapeutic use Indomethacin - chemical synthesis Indomethacin - chemistry Indomethacin - pharmacology Indomethacin analogs Lipoxygenase Inhibitors - chemical synthesis Lipoxygenase Inhibitors - chemistry Lipoxygenase Inhibitors - therapeutic use Medical sciences N-Difluoromethyl-1,2-dihydropyrid-2-one 5-Lipoxygenase pharmacophore Pharmacology. Drug treatments Pyridones - chemical synthesis Pyridones - chemistry Pyridones - therapeutic use Rats Structure-Activity Relationship |
| title | Synthesis and biological evaluation of indomethacin analogs possessing a N-difluoromethyl-1,2-dihydropyrid-2-one ring system: A search for novel cyclooxygenase and lipoxygenase inhibitors |
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