Discovery of platelet-type 12-human lipoxygenase selective inhibitors by high-throughput screening of structurally diverse libraries
15-hLO-1/12-hLO Inhibition ratios of selective inhibitors against platelet 12-hLO. Human lipoxygenases (hLO) have been implicated in a variety of diseases and cancers and each hLO isozyme appears to have distinct roles in cellular biology. This fact emphasizes the need for discovering selective hLO...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2007-11, Vol.15 (22), p.6900-6908 |
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| creator | Deschamps, Joshua D. Gautschi, Jeffrey T. Whitman, Stephanie Johnson, Tyler A. Gassner, Nadine C. Crews, Phillip Holman, Theodore R. |
| description | 15-hLO-1/12-hLO Inhibition ratios of selective inhibitors against platelet 12-hLO.
Human lipoxygenases (hLO) have been implicated in a variety of diseases and cancers and each hLO isozyme appears to have distinct roles in cellular biology. This fact emphasizes the need for discovering selective hLO inhibitors for both understanding the role of specific lipoxygenases in the cell and developing pharmaceutical therapeutics. To this end, we have modified a known lipoxygenase assay for high-throughput (HTP) screening of both the National Cancer Institute (NCI) and the UC Santa Cruz marine extract library (UCSC-MEL) in search of platelet-type 12-hLO (12-hLO) selective inhibitors. The HTP screen led to the characterization of five novel 12-hLO inhibitors from the NCI repository. One is the potent but non-selective michellamine B, a natural product, anti-viral agent. The other four compounds were selective inhibitors against 12-hLO, with three being synthetic compounds and one being α-mangostin, a natural product, caspase-3 pathway inhibitor. In addition, a selective inhibitor was isolated from the UCSC-MEL (neodysidenin), which has a unique chemical scaffold for a hLO inhibitor. Due to the unique structure of neodysidenin, steady-state inhibition kinetics were performed and its mode of inhibition against 12-hLO was determined to be competitive (
K
i
=
17
μM) and selective over reticulocyte 15-hLO-1 (
K
i 15-hLO-1/12-hLO
>
30). |
| doi_str_mv | 10.1016/j.bmc.2007.08.015 |
| format | Article |
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Human lipoxygenases (hLO) have been implicated in a variety of diseases and cancers and each hLO isozyme appears to have distinct roles in cellular biology. This fact emphasizes the need for discovering selective hLO inhibitors for both understanding the role of specific lipoxygenases in the cell and developing pharmaceutical therapeutics. To this end, we have modified a known lipoxygenase assay for high-throughput (HTP) screening of both the National Cancer Institute (NCI) and the UC Santa Cruz marine extract library (UCSC-MEL) in search of platelet-type 12-hLO (12-hLO) selective inhibitors. The HTP screen led to the characterization of five novel 12-hLO inhibitors from the NCI repository. One is the potent but non-selective michellamine B, a natural product, anti-viral agent. The other four compounds were selective inhibitors against 12-hLO, with three being synthetic compounds and one being α-mangostin, a natural product, caspase-3 pathway inhibitor. In addition, a selective inhibitor was isolated from the UCSC-MEL (neodysidenin), which has a unique chemical scaffold for a hLO inhibitor. Due to the unique structure of neodysidenin, steady-state inhibition kinetics were performed and its mode of inhibition against 12-hLO was determined to be competitive (
K
i
=
17
μM) and selective over reticulocyte 15-hLO-1 (
K
i 15-hLO-1/12-hLO
>
30).</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2007.08.015</identifier><identifier>PMID: 17826100</identifier><language>eng</language><publisher>Oxford: Elsevier Ltd</publisher><subject>Analytical, structural and metabolic biochemistry ; Biological and medical sciences ; Blood Platelets - enzymology ; Combinatorial Chemistry Techniques ; Databases, Factual ; Drug Evaluation, Preclinical - methods ; Drug Evaluation, Preclinical - statistics & numerical data ; Dysidenin ; Enzymes and enzyme inhibitors ; Fundamental and applied biological sciences. Psychology ; High-throughput ; Humans ; IC 50 ; Isoenzymes - antagonists & inhibitors ; Kinetics ; Lipoxygenase ; Lipoxygenase Inhibitors - chemical synthesis ; Lipoxygenase Inhibitors - chemistry ; Lipoxygenase Inhibitors - pharmacology ; Medical sciences ; Michellamine B ; Miscellaneous ; Molecular Structure ; NCI ; Neodysidenin ; Oxidoreductases ; Pharmacology. Drug treatments ; Reproducibility of Results ; Structure-Activity Relationship ; α-mangostin</subject><ispartof>Bioorganic & medicinal chemistry, 2007-11, Vol.15 (22), p.6900-6908</ispartof><rights>2007 Elsevier Ltd</rights><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c545t-b7c73f8cbcf5b4fdf1c59d6fd7cb474a0ab5d78d96fad19ddae3a41fe5ee338d3</citedby><cites>FETCH-LOGICAL-c545t-b7c73f8cbcf5b4fdf1c59d6fd7cb474a0ab5d78d96fad19ddae3a41fe5ee338d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0968089607007079$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=19133333$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17826100$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Deschamps, Joshua D.</creatorcontrib><creatorcontrib>Gautschi, Jeffrey T.</creatorcontrib><creatorcontrib>Whitman, Stephanie</creatorcontrib><creatorcontrib>Johnson, Tyler A.</creatorcontrib><creatorcontrib>Gassner, Nadine C.</creatorcontrib><creatorcontrib>Crews, Phillip</creatorcontrib><creatorcontrib>Holman, Theodore R.</creatorcontrib><title>Discovery of platelet-type 12-human lipoxygenase selective inhibitors by high-throughput screening of structurally diverse libraries</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>15-hLO-1/12-hLO Inhibition ratios of selective inhibitors against platelet 12-hLO.
Human lipoxygenases (hLO) have been implicated in a variety of diseases and cancers and each hLO isozyme appears to have distinct roles in cellular biology. This fact emphasizes the need for discovering selective hLO inhibitors for both understanding the role of specific lipoxygenases in the cell and developing pharmaceutical therapeutics. To this end, we have modified a known lipoxygenase assay for high-throughput (HTP) screening of both the National Cancer Institute (NCI) and the UC Santa Cruz marine extract library (UCSC-MEL) in search of platelet-type 12-hLO (12-hLO) selective inhibitors. The HTP screen led to the characterization of five novel 12-hLO inhibitors from the NCI repository. One is the potent but non-selective michellamine B, a natural product, anti-viral agent. The other four compounds were selective inhibitors against 12-hLO, with three being synthetic compounds and one being α-mangostin, a natural product, caspase-3 pathway inhibitor. In addition, a selective inhibitor was isolated from the UCSC-MEL (neodysidenin), which has a unique chemical scaffold for a hLO inhibitor. Due to the unique structure of neodysidenin, steady-state inhibition kinetics were performed and its mode of inhibition against 12-hLO was determined to be competitive (
K
i
=
17
μM) and selective over reticulocyte 15-hLO-1 (
K
i 15-hLO-1/12-hLO
>
30).</description><subject>Analytical, structural and metabolic biochemistry</subject><subject>Biological and medical sciences</subject><subject>Blood Platelets - enzymology</subject><subject>Combinatorial Chemistry Techniques</subject><subject>Databases, Factual</subject><subject>Drug Evaluation, Preclinical - methods</subject><subject>Drug Evaluation, Preclinical - statistics & numerical data</subject><subject>Dysidenin</subject><subject>Enzymes and enzyme inhibitors</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>High-throughput</subject><subject>Humans</subject><subject>IC 50</subject><subject>Isoenzymes - antagonists & inhibitors</subject><subject>Kinetics</subject><subject>Lipoxygenase</subject><subject>Lipoxygenase Inhibitors - chemical synthesis</subject><subject>Lipoxygenase Inhibitors - chemistry</subject><subject>Lipoxygenase Inhibitors - pharmacology</subject><subject>Medical sciences</subject><subject>Michellamine B</subject><subject>Miscellaneous</subject><subject>Molecular Structure</subject><subject>NCI</subject><subject>Neodysidenin</subject><subject>Oxidoreductases</subject><subject>Pharmacology. Drug treatments</subject><subject>Reproducibility of Results</subject><subject>Structure-Activity Relationship</subject><subject>α-mangostin</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kb2O1DAUhS0EYmcHHoAGpYEuwY7zZyEhrRYWkFaigdryz3XiURIH2xmRngfHw4xYaHDjwt89ProfQi8ILggmzZtDISdVlBi3Be4KTOpHaEeqpsopZeQx2mHWdDnuWHOFrkM4YIzLipGn6Iq0XdkQjHfo53sblDuC3zJnsmUUEUaIedwWyEiZD-sk5my0i_ux9TCLAFlIgIr2CJmdByttdD5kcssG2w95HLxb-2FZYxaUB5jt3J-CQ_SriqsX47hlOg37lDRa6YW3EJ6hJ0aMAZ5f7j36dvfh6-2n_P7Lx8-3N_e5qqs65rJVLTWdksrUsjLaEFUz3RjdKlm1lcBC1rrtNGuM0IRpLYCKihioASjtNN2jd-fcZZUTaAVzTI344u0k_MadsPzfl9kOvHdHXpaYsoamgNeXAO--rxAin9L6YBzFDG4NvOkorQjrEkjOoPIuBA_mzycE85M7fuDJHT-547jjyV2aefl3u4eJi6wEvLoAIigxGi9mZcMDxwj9ffbo7ZmDtMujBc-DsjAr0NYndVw7-58avwCr3L3z</recordid><startdate>20071115</startdate><enddate>20071115</enddate><creator>Deschamps, Joshua D.</creator><creator>Gautschi, Jeffrey T.</creator><creator>Whitman, Stephanie</creator><creator>Johnson, Tyler A.</creator><creator>Gassner, Nadine C.</creator><creator>Crews, Phillip</creator><creator>Holman, Theodore R.</creator><general>Elsevier Ltd</general><general>Elsevier Science</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><scope>5PM</scope></search><sort><creationdate>20071115</creationdate><title>Discovery of platelet-type 12-human lipoxygenase selective inhibitors by high-throughput screening of structurally diverse libraries</title><author>Deschamps, Joshua D. ; Gautschi, Jeffrey T. ; Whitman, Stephanie ; Johnson, Tyler A. ; Gassner, Nadine C. ; Crews, Phillip ; Holman, Theodore R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c545t-b7c73f8cbcf5b4fdf1c59d6fd7cb474a0ab5d78d96fad19ddae3a41fe5ee338d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Analytical, structural and metabolic biochemistry</topic><topic>Biological and medical sciences</topic><topic>Blood Platelets - enzymology</topic><topic>Combinatorial Chemistry Techniques</topic><topic>Databases, Factual</topic><topic>Drug Evaluation, Preclinical - methods</topic><topic>Drug Evaluation, Preclinical - statistics & numerical data</topic><topic>Dysidenin</topic><topic>Enzymes and enzyme inhibitors</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>High-throughput</topic><topic>Humans</topic><topic>IC 50</topic><topic>Isoenzymes - antagonists & inhibitors</topic><topic>Kinetics</topic><topic>Lipoxygenase</topic><topic>Lipoxygenase Inhibitors - chemical synthesis</topic><topic>Lipoxygenase Inhibitors - chemistry</topic><topic>Lipoxygenase Inhibitors - pharmacology</topic><topic>Medical sciences</topic><topic>Michellamine B</topic><topic>Miscellaneous</topic><topic>Molecular Structure</topic><topic>NCI</topic><topic>Neodysidenin</topic><topic>Oxidoreductases</topic><topic>Pharmacology. Drug treatments</topic><topic>Reproducibility of Results</topic><topic>Structure-Activity Relationship</topic><topic>α-mangostin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Deschamps, Joshua D.</creatorcontrib><creatorcontrib>Gautschi, Jeffrey T.</creatorcontrib><creatorcontrib>Whitman, Stephanie</creatorcontrib><creatorcontrib>Johnson, Tyler A.</creatorcontrib><creatorcontrib>Gassner, Nadine C.</creatorcontrib><creatorcontrib>Crews, Phillip</creatorcontrib><creatorcontrib>Holman, Theodore R.</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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Deschamps, Joshua D.</au><au>Gautschi, Jeffrey T.</au><au>Whitman, Stephanie</au><au>Johnson, Tyler A.</au><au>Gassner, Nadine C.</au><au>Crews, Phillip</au><au>Holman, Theodore R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of platelet-type 12-human lipoxygenase selective inhibitors by high-throughput screening of structurally diverse libraries</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2007-11-15</date><risdate>2007</risdate><volume>15</volume><issue>22</issue><spage>6900</spage><epage>6908</epage><pages>6900-6908</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>15-hLO-1/12-hLO Inhibition ratios of selective inhibitors against platelet 12-hLO.
Human lipoxygenases (hLO) have been implicated in a variety of diseases and cancers and each hLO isozyme appears to have distinct roles in cellular biology. This fact emphasizes the need for discovering selective hLO inhibitors for both understanding the role of specific lipoxygenases in the cell and developing pharmaceutical therapeutics. To this end, we have modified a known lipoxygenase assay for high-throughput (HTP) screening of both the National Cancer Institute (NCI) and the UC Santa Cruz marine extract library (UCSC-MEL) in search of platelet-type 12-hLO (12-hLO) selective inhibitors. The HTP screen led to the characterization of five novel 12-hLO inhibitors from the NCI repository. One is the potent but non-selective michellamine B, a natural product, anti-viral agent. The other four compounds were selective inhibitors against 12-hLO, with three being synthetic compounds and one being α-mangostin, a natural product, caspase-3 pathway inhibitor. In addition, a selective inhibitor was isolated from the UCSC-MEL (neodysidenin), which has a unique chemical scaffold for a hLO inhibitor. Due to the unique structure of neodysidenin, steady-state inhibition kinetics were performed and its mode of inhibition against 12-hLO was determined to be competitive (
K
i
=
17
μM) and selective over reticulocyte 15-hLO-1 (
K
i 15-hLO-1/12-hLO
>
30).</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><pmid>17826100</pmid><doi>10.1016/j.bmc.2007.08.015</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry, 2007-11, Vol.15 (22), p.6900-6908 |
| issn | 0968-0896 1464-3391 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Analytical, structural and metabolic biochemistry Biological and medical sciences Blood Platelets - enzymology Combinatorial Chemistry Techniques Databases, Factual Drug Evaluation, Preclinical - methods Drug Evaluation, Preclinical - statistics & numerical data Dysidenin Enzymes and enzyme inhibitors Fundamental and applied biological sciences. Psychology High-throughput Humans IC 50 Isoenzymes - antagonists & inhibitors Kinetics Lipoxygenase Lipoxygenase Inhibitors - chemical synthesis Lipoxygenase Inhibitors - chemistry Lipoxygenase Inhibitors - pharmacology Medical sciences Michellamine B Miscellaneous Molecular Structure NCI Neodysidenin Oxidoreductases Pharmacology. Drug treatments Reproducibility of Results Structure-Activity Relationship α-mangostin |
| title | Discovery of platelet-type 12-human lipoxygenase selective inhibitors by high-throughput screening of structurally diverse libraries |
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