Synthesis and biological evaluation of solubilized sulfonamide analogues of the phosphatidylinositol 3-kinase inhibitor ZSTK474
[Display omitted] Replacing one of the morpholine groups of the phosphatidylinositol 3-kinase (PI3K) inhibitor ZSTK474 with a variety of sulfonamide-linked solubilizing substituents produced a new class of active and potent PI3Kα inhibitors, with several derivatives demonstrating high PI3Kα enzyme p...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2019-04, Vol.27 (8), p.1529-1545 |
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| container_title | Bioorganic & medicinal chemistry |
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| creator | Giddens, Anna C. Gamage, Swarna A. Kendall, Jackie D. Lee, Woo-Jeong Baguley, Bruce C. Buchanan, Christina M. Jamieson, Stephen M.F. Dickson, James M.J. Shepherd, Peter R. Denny, William A. Rewcastle, Gordon W. |
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Replacing one of the morpholine groups of the phosphatidylinositol 3-kinase (PI3K) inhibitor ZSTK474 with a variety of sulfonamide-linked solubilizing substituents produced a new class of active and potent PI3Kα inhibitors, with several derivatives demonstrating high PI3Kα enzyme potency and good cellular potency in two human derived cell lines. The overall results suggest a preference for linear and somewhat flexible solubilizing functions. From this series, compound 16, also known as SN32976, was selected for advanced preclinical evaluation. |
| doi_str_mv | 10.1016/j.bmc.2019.02.050 |
| format | Article |
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Replacing one of the morpholine groups of the phosphatidylinositol 3-kinase (PI3K) inhibitor ZSTK474 with a variety of sulfonamide-linked solubilizing substituents produced a new class of active and potent PI3Kα inhibitors, with several derivatives demonstrating high PI3Kα enzyme potency and good cellular potency in two human derived cell lines. The overall results suggest a preference for linear and somewhat flexible solubilizing functions. From this series, compound 16, also known as SN32976, was selected for advanced preclinical evaluation.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2019.02.050</identifier><identifier>PMID: 30850264</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Animals ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Drug Evaluation, Preclinical ; Female ; Humans ; Inhibitory Concentration 50 ; Mice ; Neoplasms - drug therapy ; p110α ; Phosphatidylinositol 3-kinase ; Phosphatidylinositol 3-Kinases - chemistry ; Phosphatidylinositol 3-Kinases - metabolism ; Phosphoinositide-3 Kinase Inhibitors - chemical synthesis ; Phosphoinositide-3 Kinase Inhibitors - pharmacology ; Phosphoinositide-3 Kinase Inhibitors - therapeutic use ; PI3K ; Protein Subunits - antagonists & inhibitors ; Protein Subunits - metabolism ; SN32976 ; Structure-Activity Relationship ; Sulfonamides - chemistry ; Sulfonamides - pharmacology ; Sulfonamides - therapeutic use ; Transplantation, Heterologous ; Triazines - chemistry ; ZSTK474</subject><ispartof>Bioorganic & medicinal chemistry, 2019-04, Vol.27 (8), p.1529-1545</ispartof><rights>2019 Elsevier Ltd</rights><rights>Copyright © 2019 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c353t-8d025eae0598aca647885e5f7ab446db378b5190dae80ff161940122b75ccedb3</citedby><cites>FETCH-LOGICAL-c353t-8d025eae0598aca647885e5f7ab446db378b5190dae80ff161940122b75ccedb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0968089618320455$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30850264$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Giddens, Anna C.</creatorcontrib><creatorcontrib>Gamage, Swarna A.</creatorcontrib><creatorcontrib>Kendall, Jackie D.</creatorcontrib><creatorcontrib>Lee, Woo-Jeong</creatorcontrib><creatorcontrib>Baguley, Bruce C.</creatorcontrib><creatorcontrib>Buchanan, Christina M.</creatorcontrib><creatorcontrib>Jamieson, Stephen M.F.</creatorcontrib><creatorcontrib>Dickson, James M.J.</creatorcontrib><creatorcontrib>Shepherd, Peter R.</creatorcontrib><creatorcontrib>Denny, William A.</creatorcontrib><creatorcontrib>Rewcastle, Gordon W.</creatorcontrib><title>Synthesis and biological evaluation of solubilized sulfonamide analogues of the phosphatidylinositol 3-kinase inhibitor ZSTK474</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>[Display omitted]
Replacing one of the morpholine groups of the phosphatidylinositol 3-kinase (PI3K) inhibitor ZSTK474 with a variety of sulfonamide-linked solubilizing substituents produced a new class of active and potent PI3Kα inhibitors, with several derivatives demonstrating high PI3Kα enzyme potency and good cellular potency in two human derived cell lines. The overall results suggest a preference for linear and somewhat flexible solubilizing functions. From this series, compound 16, also known as SN32976, was selected for advanced preclinical evaluation.</description><subject>Animals</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Drug Evaluation, Preclinical</subject><subject>Female</subject><subject>Humans</subject><subject>Inhibitory Concentration 50</subject><subject>Mice</subject><subject>Neoplasms - drug therapy</subject><subject>p110α</subject><subject>Phosphatidylinositol 3-kinase</subject><subject>Phosphatidylinositol 3-Kinases - chemistry</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Phosphoinositide-3 Kinase Inhibitors - chemical synthesis</subject><subject>Phosphoinositide-3 Kinase Inhibitors - pharmacology</subject><subject>Phosphoinositide-3 Kinase Inhibitors - therapeutic use</subject><subject>PI3K</subject><subject>Protein Subunits - antagonists & inhibitors</subject><subject>Protein Subunits - metabolism</subject><subject>SN32976</subject><subject>Structure-Activity Relationship</subject><subject>Sulfonamides - chemistry</subject><subject>Sulfonamides - pharmacology</subject><subject>Sulfonamides - therapeutic use</subject><subject>Transplantation, Heterologous</subject><subject>Triazines - chemistry</subject><subject>ZSTK474</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1v1DAQhi1ERZfCD-CCfOSSMHbsxBEnVJUPUYlD20svlj8mrBcnXuKk0nLpX8erLRw5jeR5nlfjl5A3DGoGrH2_q-3oag6sr4HXIOEZ2TDRiqppevacbKBvVQWqb8_Jy5x3AMBFz16Q8waUBN6KDXm8OUzLFnPI1Eye2pBi-hGciRQfTFzNEtJE00BziqsNMfxGT_MahzSZMXgskinCivkIlSC636a83xbPH2KYUg5LirSpfobJZKRh2gZbnmZ6f3P7TXTiFTkbTMz4-mlekLtPV7eXX6rr75-_Xn68rlwjm6VSHrhEgyB7ZZxpRaeURDl0xgrRett0ykrWgzeoYBhYy3oBjHPbSeew7C_Iu1Pufk6_yrmLHkN2GKOZMK1Zc6Z6KaXgbUHZCXVzynnGQe_nMJr5oBnoY-96p0vv-ti7Bq5L78V5-xS_2hH9P-Nv0QX4cAKwfPIh4KyzCziV28KMbtE-hf_E_wHDQpWU</recordid><startdate>20190415</startdate><enddate>20190415</enddate><creator>Giddens, Anna C.</creator><creator>Gamage, Swarna A.</creator><creator>Kendall, Jackie D.</creator><creator>Lee, Woo-Jeong</creator><creator>Baguley, Bruce C.</creator><creator>Buchanan, Christina M.</creator><creator>Jamieson, Stephen M.F.</creator><creator>Dickson, James M.J.</creator><creator>Shepherd, Peter R.</creator><creator>Denny, William A.</creator><creator>Rewcastle, Gordon W.</creator><general>Elsevier Ltd</general><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>20190415</creationdate><title>Synthesis and biological evaluation of solubilized sulfonamide analogues of the phosphatidylinositol 3-kinase inhibitor ZSTK474</title><author>Giddens, Anna C. ; Gamage, Swarna A. ; Kendall, Jackie D. ; Lee, Woo-Jeong ; Baguley, Bruce C. ; Buchanan, Christina M. ; Jamieson, Stephen M.F. ; Dickson, James M.J. ; Shepherd, Peter R. ; Denny, William A. ; Rewcastle, Gordon W.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c353t-8d025eae0598aca647885e5f7ab446db378b5190dae80ff161940122b75ccedb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Drug Evaluation, Preclinical</topic><topic>Female</topic><topic>Humans</topic><topic>Inhibitory Concentration 50</topic><topic>Mice</topic><topic>Neoplasms - drug therapy</topic><topic>p110α</topic><topic>Phosphatidylinositol 3-kinase</topic><topic>Phosphatidylinositol 3-Kinases - chemistry</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Phosphoinositide-3 Kinase Inhibitors - chemical synthesis</topic><topic>Phosphoinositide-3 Kinase Inhibitors - pharmacology</topic><topic>Phosphoinositide-3 Kinase Inhibitors - therapeutic use</topic><topic>PI3K</topic><topic>Protein Subunits - antagonists & inhibitors</topic><topic>Protein Subunits - metabolism</topic><topic>SN32976</topic><topic>Structure-Activity Relationship</topic><topic>Sulfonamides - chemistry</topic><topic>Sulfonamides - pharmacology</topic><topic>Sulfonamides - therapeutic use</topic><topic>Transplantation, Heterologous</topic><topic>Triazines - chemistry</topic><topic>ZSTK474</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Giddens, Anna C.</creatorcontrib><creatorcontrib>Gamage, Swarna A.</creatorcontrib><creatorcontrib>Kendall, Jackie D.</creatorcontrib><creatorcontrib>Lee, Woo-Jeong</creatorcontrib><creatorcontrib>Baguley, Bruce C.</creatorcontrib><creatorcontrib>Buchanan, Christina M.</creatorcontrib><creatorcontrib>Jamieson, Stephen M.F.</creatorcontrib><creatorcontrib>Dickson, James M.J.</creatorcontrib><creatorcontrib>Shepherd, Peter R.</creatorcontrib><creatorcontrib>Denny, William A.</creatorcontrib><creatorcontrib>Rewcastle, Gordon W.</creatorcontrib><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</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Giddens, Anna C.</au><au>Gamage, Swarna A.</au><au>Kendall, Jackie D.</au><au>Lee, Woo-Jeong</au><au>Baguley, Bruce C.</au><au>Buchanan, Christina M.</au><au>Jamieson, Stephen M.F.</au><au>Dickson, James M.J.</au><au>Shepherd, Peter R.</au><au>Denny, William A.</au><au>Rewcastle, Gordon W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and biological evaluation of solubilized sulfonamide analogues of the phosphatidylinositol 3-kinase inhibitor ZSTK474</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2019-04-15</date><risdate>2019</risdate><volume>27</volume><issue>8</issue><spage>1529</spage><epage>1545</epage><pages>1529-1545</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>[Display omitted]
Replacing one of the morpholine groups of the phosphatidylinositol 3-kinase (PI3K) inhibitor ZSTK474 with a variety of sulfonamide-linked solubilizing substituents produced a new class of active and potent PI3Kα inhibitors, with several derivatives demonstrating high PI3Kα enzyme potency and good cellular potency in two human derived cell lines. The overall results suggest a preference for linear and somewhat flexible solubilizing functions. From this series, compound 16, also known as SN32976, was selected for advanced preclinical evaluation.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>30850264</pmid><doi>10.1016/j.bmc.2019.02.050</doi><tpages>17</tpages></addata></record> |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Animals Antineoplastic Agents - chemical synthesis Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Cell Line, Tumor Cell Proliferation - drug effects Drug Evaluation, Preclinical Female Humans Inhibitory Concentration 50 Mice Neoplasms - drug therapy p110α Phosphatidylinositol 3-kinase Phosphatidylinositol 3-Kinases - chemistry Phosphatidylinositol 3-Kinases - metabolism Phosphoinositide-3 Kinase Inhibitors - chemical synthesis Phosphoinositide-3 Kinase Inhibitors - pharmacology Phosphoinositide-3 Kinase Inhibitors - therapeutic use PI3K Protein Subunits - antagonists & inhibitors Protein Subunits - metabolism SN32976 Structure-Activity Relationship Sulfonamides - chemistry Sulfonamides - pharmacology Sulfonamides - therapeutic use Transplantation, Heterologous Triazines - chemistry ZSTK474 |
| title | Synthesis and biological evaluation of solubilized sulfonamide analogues of the phosphatidylinositol 3-kinase inhibitor ZSTK474 |
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