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Design, Synthesis, and Biological Evaluation of New-Generation Taxoids
Novel second-generation taxoids with systematic modifications at the C2, C10, and C3′N positions were synthesized and their structure−activity relationships studied. A number of these taxoids exhibited exceptionally high potency against multidrug-resistant cell lines, and several taxoids exhibited v...
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| Published in: | Journal of medicinal chemistry 2008-06, Vol.51 (11), p.3203-3221 |
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| cites | cdi_FETCH-LOGICAL-a471t-5605249c9da9e640723502fdb1449cb2f481d1a4ad5f8a3fdfcb8d23a06d5a7e3 |
| container_end_page | 3221 |
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| container_title | Journal of medicinal chemistry |
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| creator | Ojima, Iwao Chen, Jin Sun, Liang Borella, Christopher P Wang, Tao Miller, Michael L Lin, Songnian Geng, Xudong Kuznetsova, Larisa Qu, Chuanxing Gallager, David Zhao, Xianrui Zanardi, Ilaria Xia, Shujun Horwitz, Susan B Mallen-St. Clair, Jon Guerriero, Jennifer L Bar-Sagi, Dafna Veith, Jean M Pera, Paula Bernacki, Ralph J |
| description | Novel second-generation taxoids with systematic modifications at the C2, C10, and C3′N positions were synthesized and their structure−activity relationships studied. A number of these taxoids exhibited exceptionally high potency against multidrug-resistant cell lines, and several taxoids exhibited virtually no difference in potency against the drug-sensitive and drug-resistant cell lines. These exceptionally potent taxoids were termed “third-generation taxoids”. 19 (SB-T-1214), 14g (SB-T-121303), and 14i (SB-T-1213031) exhibited excellent activity against paclitaxel-resistant ovarian cancer cell lines with mutations in β-tubulin as well, wherein the drug resistance is mediated by the β-tubulin mutation. These taxoids were found to possess exceptional activity in promoting tubulin assembly, forming numerous very short microtubules similar to those formed by discodermolide. Taxoids 19 and 14g also showed excellent cytotoxicity against four pancreatic cancer cell lines, expressing three to four multidrug-resistant genes. Moreover, taxoid 19 exhibited excellent in vivo efficacy against highly drug-resistant CFPAC-1 pancreatic as well as DLD-1 human colon tumor xenografts in mice. |
| doi_str_mv | 10.1021/jm800086e |
| format | article |
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A number of these taxoids exhibited exceptionally high potency against multidrug-resistant cell lines, and several taxoids exhibited virtually no difference in potency against the drug-sensitive and drug-resistant cell lines. These exceptionally potent taxoids were termed “third-generation taxoids”. 19 (SB-T-1214), 14g (SB-T-121303), and 14i (SB-T-1213031) exhibited excellent activity against paclitaxel-resistant ovarian cancer cell lines with mutations in β-tubulin as well, wherein the drug resistance is mediated by the β-tubulin mutation. These taxoids were found to possess exceptional activity in promoting tubulin assembly, forming numerous very short microtubules similar to those formed by discodermolide. Taxoids 19 and 14g also showed excellent cytotoxicity against four pancreatic cancer cell lines, expressing three to four multidrug-resistant genes. Moreover, taxoid 19 exhibited excellent in vivo efficacy against highly drug-resistant CFPAC-1 pancreatic as well as DLD-1 human colon tumor xenografts in mice.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm800086e</identifier><identifier>PMID: 18465846</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Antineoplastic agents ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Biological and medical sciences ; Biopolymers ; Cell Line, Tumor ; Drug Design ; Drug Resistance, Neoplasm ; Drug Screening Assays, Antitumor ; Female ; General aspects ; Humans ; Male ; Medical sciences ; Mice ; Mice, Nude ; Neoplasm Transplantation ; Paclitaxel - pharmacology ; Pharmacology. Drug treatments ; Point Mutation ; Structure-Activity Relationship ; Taxoids - chemical synthesis ; Taxoids - chemistry ; Taxoids - pharmacology ; Transplantation, Heterologous ; Tubulin - chemistry ; Tubulin - genetics</subject><ispartof>Journal of medicinal chemistry, 2008-06, Vol.51 (11), p.3203-3221</ispartof><rights>Copyright © 2008 American Chemical Society</rights><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a471t-5605249c9da9e640723502fdb1449cb2f481d1a4ad5f8a3fdfcb8d23a06d5a7e3</citedby><cites>FETCH-LOGICAL-a471t-5605249c9da9e640723502fdb1449cb2f481d1a4ad5f8a3fdfcb8d23a06d5a7e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20405971$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18465846$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ojima, Iwao</creatorcontrib><creatorcontrib>Chen, Jin</creatorcontrib><creatorcontrib>Sun, Liang</creatorcontrib><creatorcontrib>Borella, Christopher P</creatorcontrib><creatorcontrib>Wang, Tao</creatorcontrib><creatorcontrib>Miller, Michael L</creatorcontrib><creatorcontrib>Lin, Songnian</creatorcontrib><creatorcontrib>Geng, Xudong</creatorcontrib><creatorcontrib>Kuznetsova, Larisa</creatorcontrib><creatorcontrib>Qu, Chuanxing</creatorcontrib><creatorcontrib>Gallager, David</creatorcontrib><creatorcontrib>Zhao, Xianrui</creatorcontrib><creatorcontrib>Zanardi, Ilaria</creatorcontrib><creatorcontrib>Xia, Shujun</creatorcontrib><creatorcontrib>Horwitz, Susan B</creatorcontrib><creatorcontrib>Mallen-St. Clair, Jon</creatorcontrib><creatorcontrib>Guerriero, Jennifer L</creatorcontrib><creatorcontrib>Bar-Sagi, Dafna</creatorcontrib><creatorcontrib>Veith, Jean M</creatorcontrib><creatorcontrib>Pera, Paula</creatorcontrib><creatorcontrib>Bernacki, Ralph J</creatorcontrib><title>Design, Synthesis, and Biological Evaluation of New-Generation Taxoids</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Novel second-generation taxoids with systematic modifications at the C2, C10, and C3′N positions were synthesized and their structure−activity relationships studied. A number of these taxoids exhibited exceptionally high potency against multidrug-resistant cell lines, and several taxoids exhibited virtually no difference in potency against the drug-sensitive and drug-resistant cell lines. These exceptionally potent taxoids were termed “third-generation taxoids”. 19 (SB-T-1214), 14g (SB-T-121303), and 14i (SB-T-1213031) exhibited excellent activity against paclitaxel-resistant ovarian cancer cell lines with mutations in β-tubulin as well, wherein the drug resistance is mediated by the β-tubulin mutation. These taxoids were found to possess exceptional activity in promoting tubulin assembly, forming numerous very short microtubules similar to those formed by discodermolide. Taxoids 19 and 14g also showed excellent cytotoxicity against four pancreatic cancer cell lines, expressing three to four multidrug-resistant genes. Moreover, taxoid 19 exhibited excellent in vivo efficacy against highly drug-resistant CFPAC-1 pancreatic as well as DLD-1 human colon tumor xenografts in mice.</description><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Biopolymers</subject><subject>Cell Line, Tumor</subject><subject>Drug Design</subject><subject>Drug Resistance, Neoplasm</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Female</subject><subject>General aspects</subject><subject>Humans</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Neoplasm Transplantation</subject><subject>Paclitaxel - pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Point Mutation</subject><subject>Structure-Activity Relationship</subject><subject>Taxoids - chemical synthesis</subject><subject>Taxoids - chemistry</subject><subject>Taxoids - pharmacology</subject><subject>Transplantation, Heterologous</subject><subject>Tubulin - chemistry</subject><subject>Tubulin - genetics</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><recordid>eNptkF1rFDEUhoModvtx4R-QuVEQOjafk8xNwdZ2K6xa6Hodzk6SbdbZpCYz_fj3RnbZKngRTjjn4T2HB6E3BH8kmJKT1VphjFVjX6AJERTXXGH-Ek0wprSmDWV7aD_nVWEYoew12iOKN6K8Cbr8bLNfhuPq5ikMt-WfjysIpjrzsY9L30FfXdxDP8LgY6iiq77Zh3pqg02bzhweozf5EL1y0Gd7tK0H6Mflxfz8qp59n345_zSrgUsy1KLBgvK2aw20tuFYUiYwdWZBeOkuqOOKGAIcjHAKmDOuWyhDGeDGCJCWHaDTTe7duFhb09kwJOj1XfJrSE86gtf_ToK_1ct4r6lkvMWyBLzfBqT4a7R50GufO9v3EGwcs5ak4YrLtoAfNmCXYs7Jut0SgvUf63pnvbBv_77qmdxqLsC7LQC5KHUJQufzjqOYY9FKUrh6w_k82MfdHNJP3UgmhZ5f3-jZ1dczLhXV0-dc6LJexTGFIv8_B_4Gek2lcQ</recordid><startdate>20080612</startdate><enddate>20080612</enddate><creator>Ojima, Iwao</creator><creator>Chen, Jin</creator><creator>Sun, Liang</creator><creator>Borella, Christopher P</creator><creator>Wang, Tao</creator><creator>Miller, Michael L</creator><creator>Lin, Songnian</creator><creator>Geng, Xudong</creator><creator>Kuznetsova, Larisa</creator><creator>Qu, Chuanxing</creator><creator>Gallager, David</creator><creator>Zhao, Xianrui</creator><creator>Zanardi, Ilaria</creator><creator>Xia, Shujun</creator><creator>Horwitz, Susan B</creator><creator>Mallen-St. Clair, Jon</creator><creator>Guerriero, Jennifer L</creator><creator>Bar-Sagi, Dafna</creator><creator>Veith, Jean M</creator><creator>Pera, Paula</creator><creator>Bernacki, Ralph J</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><scope>5PM</scope></search><sort><creationdate>20080612</creationdate><title>Design, Synthesis, and Biological Evaluation of New-Generation Taxoids</title><author>Ojima, Iwao ; Chen, Jin ; Sun, Liang ; Borella, Christopher P ; Wang, Tao ; Miller, Michael L ; Lin, Songnian ; Geng, Xudong ; Kuznetsova, Larisa ; Qu, Chuanxing ; Gallager, David ; Zhao, Xianrui ; Zanardi, Ilaria ; Xia, Shujun ; Horwitz, Susan B ; Mallen-St. Clair, Jon ; Guerriero, Jennifer L ; Bar-Sagi, Dafna ; Veith, Jean M ; Pera, Paula ; Bernacki, Ralph J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a471t-5605249c9da9e640723502fdb1449cb2f481d1a4ad5f8a3fdfcb8d23a06d5a7e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Biopolymers</topic><topic>Cell Line, Tumor</topic><topic>Drug Design</topic><topic>Drug Resistance, Neoplasm</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Female</topic><topic>General aspects</topic><topic>Humans</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Neoplasm Transplantation</topic><topic>Paclitaxel - pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Point Mutation</topic><topic>Structure-Activity Relationship</topic><topic>Taxoids - chemical synthesis</topic><topic>Taxoids - chemistry</topic><topic>Taxoids - pharmacology</topic><topic>Transplantation, Heterologous</topic><topic>Tubulin - chemistry</topic><topic>Tubulin - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ojima, Iwao</creatorcontrib><creatorcontrib>Chen, Jin</creatorcontrib><creatorcontrib>Sun, Liang</creatorcontrib><creatorcontrib>Borella, Christopher P</creatorcontrib><creatorcontrib>Wang, Tao</creatorcontrib><creatorcontrib>Miller, Michael L</creatorcontrib><creatorcontrib>Lin, Songnian</creatorcontrib><creatorcontrib>Geng, Xudong</creatorcontrib><creatorcontrib>Kuznetsova, Larisa</creatorcontrib><creatorcontrib>Qu, Chuanxing</creatorcontrib><creatorcontrib>Gallager, David</creatorcontrib><creatorcontrib>Zhao, Xianrui</creatorcontrib><creatorcontrib>Zanardi, Ilaria</creatorcontrib><creatorcontrib>Xia, Shujun</creatorcontrib><creatorcontrib>Horwitz, Susan B</creatorcontrib><creatorcontrib>Mallen-St. Clair, Jon</creatorcontrib><creatorcontrib>Guerriero, Jennifer L</creatorcontrib><creatorcontrib>Bar-Sagi, Dafna</creatorcontrib><creatorcontrib>Veith, Jean M</creatorcontrib><creatorcontrib>Pera, Paula</creatorcontrib><creatorcontrib>Bernacki, Ralph J</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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ojima, Iwao</au><au>Chen, Jin</au><au>Sun, Liang</au><au>Borella, Christopher P</au><au>Wang, Tao</au><au>Miller, Michael L</au><au>Lin, Songnian</au><au>Geng, Xudong</au><au>Kuznetsova, Larisa</au><au>Qu, Chuanxing</au><au>Gallager, David</au><au>Zhao, Xianrui</au><au>Zanardi, Ilaria</au><au>Xia, Shujun</au><au>Horwitz, Susan B</au><au>Mallen-St. Clair, Jon</au><au>Guerriero, Jennifer L</au><au>Bar-Sagi, Dafna</au><au>Veith, Jean M</au><au>Pera, Paula</au><au>Bernacki, Ralph J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design, Synthesis, and Biological Evaluation of New-Generation Taxoids</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2008-06-12</date><risdate>2008</risdate><volume>51</volume><issue>11</issue><spage>3203</spage><epage>3221</epage><pages>3203-3221</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Novel second-generation taxoids with systematic modifications at the C2, C10, and C3′N positions were synthesized and their structure−activity relationships studied. A number of these taxoids exhibited exceptionally high potency against multidrug-resistant cell lines, and several taxoids exhibited virtually no difference in potency against the drug-sensitive and drug-resistant cell lines. These exceptionally potent taxoids were termed “third-generation taxoids”. 19 (SB-T-1214), 14g (SB-T-121303), and 14i (SB-T-1213031) exhibited excellent activity against paclitaxel-resistant ovarian cancer cell lines with mutations in β-tubulin as well, wherein the drug resistance is mediated by the β-tubulin mutation. These taxoids were found to possess exceptional activity in promoting tubulin assembly, forming numerous very short microtubules similar to those formed by discodermolide. Taxoids 19 and 14g also showed excellent cytotoxicity against four pancreatic cancer cell lines, expressing three to four multidrug-resistant genes. Moreover, taxoid 19 exhibited excellent in vivo efficacy against highly drug-resistant CFPAC-1 pancreatic as well as DLD-1 human colon tumor xenografts in mice.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>18465846</pmid><doi>10.1021/jm800086e</doi><tpages>19</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2008-06, Vol.51 (11), p.3203-3221 |
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| language | eng |
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| source | American Chemical Society:Jisc Collections:American Chemical Society Read & Publish Agreement 2022-2024 (Reading list) |
| subjects | Animals Antineoplastic agents Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Biological and medical sciences Biopolymers Cell Line, Tumor Drug Design Drug Resistance, Neoplasm Drug Screening Assays, Antitumor Female General aspects Humans Male Medical sciences Mice Mice, Nude Neoplasm Transplantation Paclitaxel - pharmacology Pharmacology. Drug treatments Point Mutation Structure-Activity Relationship Taxoids - chemical synthesis Taxoids - chemistry Taxoids - pharmacology Transplantation, Heterologous Tubulin - chemistry Tubulin - genetics |
| title | Design, Synthesis, and Biological Evaluation of New-Generation Taxoids |
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