Synthesis and biological evaluation of a water-soluble phosphate prodrug salt and structural analogues of KGP94, a lead inhibitor of cathepsin L
[Display omitted] The magnitude of expression of cathepsin L, often upregulated in the tumor microenvironment, correlates with the invasive and metastatic nature of certain tumors. Inhibition of cathepsin L represents an emerging strategy for the treatment of metastatic cancer. A potent, small-molec...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2017-03, Vol.27 (5), p.1304-1310 |
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| creator | Parker, Erica N. Odutola, Samuel O. Wang, Yifan Strecker, Tracy E. Mukherjee, Rajeswari Shi, Zhe Chaplin, David J. Trawick, Mary Lynn Pinney, Kevin G. |
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The magnitude of expression of cathepsin L, often upregulated in the tumor microenvironment, correlates with the invasive and metastatic nature of certain tumors. Inhibition of cathepsin L represents an emerging strategy for the treatment of metastatic cancer. A potent, small-molecule inhibitor (referred to as KGP94) of cathepsin L, and new KGP94 analogues were synthesized. (3,5-Dibromophenyl)-(3-hydroxyphenyl) ketone thiosemicarbazone (22), with an IC50 value of 202nM, exhibited similar inhibitory activity against cathepsin L compared to KGP94 (IC50=189nM). Due to limited aqueous solubility of KGP94, a water-soluble phosphate salt (KGP420) was prepared in order to facilitate future in vivo studies. Enzymatic hydrolysis with alkaline phosphatase (ALP) demonstrated that the phosphate prodrug, KGP420, was readily converted to the parent compound, KGP94. |
| doi_str_mv | 10.1016/j.bmcl.2016.12.039 |
| format | Article |
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The magnitude of expression of cathepsin L, often upregulated in the tumor microenvironment, correlates with the invasive and metastatic nature of certain tumors. Inhibition of cathepsin L represents an emerging strategy for the treatment of metastatic cancer. A potent, small-molecule inhibitor (referred to as KGP94) of cathepsin L, and new KGP94 analogues were synthesized. (3,5-Dibromophenyl)-(3-hydroxyphenyl) ketone thiosemicarbazone (22), with an IC50 value of 202nM, exhibited similar inhibitory activity against cathepsin L compared to KGP94 (IC50=189nM). Due to limited aqueous solubility of KGP94, a water-soluble phosphate salt (KGP420) was prepared in order to facilitate future in vivo studies. Enzymatic hydrolysis with alkaline phosphatase (ALP) demonstrated that the phosphate prodrug, KGP420, was readily converted to the parent compound, KGP94.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2016.12.039</identifier><identifier>PMID: 28117205</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Anti-metastatic agent ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Benzophenone ; Cathepsin L - antagonists & inhibitors ; Cell Line, Tumor ; Cysteine protease inhibitor ; Enzyme Activation - drug effects ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Humans ; Molecular Structure ; Organophosphates - chemistry ; Phosphate prodrug ; Prodrugs - chemical synthesis ; Prodrugs - chemistry ; Prodrugs - pharmacology ; Salts - chemical synthesis ; Salts - pharmacology ; Solubility ; Thiosemicarbazone ; Thiosemicarbazones - chemical synthesis ; Thiosemicarbazones - chemistry ; Thiosemicarbazones - pharmacology ; Thiourea - analogs & derivatives ; Thiourea - chemical synthesis ; Thiourea - chemistry ; Thiourea - pharmacology ; Water - chemistry</subject><ispartof>Bioorganic & medicinal chemistry letters, 2017-03, Vol.27 (5), p.1304-1310</ispartof><rights>2016 Elsevier Ltd</rights><rights>Copyright © 2016 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-cd4ab9fcc3d933d1ee66f9fad17c19dba4c8c89008de9637dcc6bd34d51373723</citedby><cites>FETCH-LOGICAL-c356t-cd4ab9fcc3d933d1ee66f9fad17c19dba4c8c89008de9637dcc6bd34d51373723</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2016.12.039$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3536,27903,27904,45974</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28117205$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Parker, Erica N.</creatorcontrib><creatorcontrib>Odutola, Samuel O.</creatorcontrib><creatorcontrib>Wang, Yifan</creatorcontrib><creatorcontrib>Strecker, Tracy E.</creatorcontrib><creatorcontrib>Mukherjee, Rajeswari</creatorcontrib><creatorcontrib>Shi, Zhe</creatorcontrib><creatorcontrib>Chaplin, David J.</creatorcontrib><creatorcontrib>Trawick, Mary Lynn</creatorcontrib><creatorcontrib>Pinney, Kevin G.</creatorcontrib><title>Synthesis and biological evaluation of a water-soluble phosphate prodrug salt and structural analogues of KGP94, a lead inhibitor of cathepsin L</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
The magnitude of expression of cathepsin L, often upregulated in the tumor microenvironment, correlates with the invasive and metastatic nature of certain tumors. Inhibition of cathepsin L represents an emerging strategy for the treatment of metastatic cancer. A potent, small-molecule inhibitor (referred to as KGP94) of cathepsin L, and new KGP94 analogues were synthesized. (3,5-Dibromophenyl)-(3-hydroxyphenyl) ketone thiosemicarbazone (22), with an IC50 value of 202nM, exhibited similar inhibitory activity against cathepsin L compared to KGP94 (IC50=189nM). Due to limited aqueous solubility of KGP94, a water-soluble phosphate salt (KGP420) was prepared in order to facilitate future in vivo studies. Enzymatic hydrolysis with alkaline phosphatase (ALP) demonstrated that the phosphate prodrug, KGP420, was readily converted to the parent compound, KGP94.</description><subject>Anti-metastatic agent</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Benzophenone</subject><subject>Cathepsin L - antagonists & inhibitors</subject><subject>Cell Line, Tumor</subject><subject>Cysteine protease inhibitor</subject><subject>Enzyme Activation - drug effects</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Humans</subject><subject>Molecular Structure</subject><subject>Organophosphates - chemistry</subject><subject>Phosphate prodrug</subject><subject>Prodrugs - chemical synthesis</subject><subject>Prodrugs - chemistry</subject><subject>Prodrugs - pharmacology</subject><subject>Salts - chemical synthesis</subject><subject>Salts - pharmacology</subject><subject>Solubility</subject><subject>Thiosemicarbazone</subject><subject>Thiosemicarbazones - chemical synthesis</subject><subject>Thiosemicarbazones - chemistry</subject><subject>Thiosemicarbazones - pharmacology</subject><subject>Thiourea - analogs & derivatives</subject><subject>Thiourea - chemical synthesis</subject><subject>Thiourea - chemistry</subject><subject>Thiourea - pharmacology</subject><subject>Water - chemistry</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kcFu1DAQhq0K1G4LL8AB-ciBBDv2OrHUS1WVFrESSC0SN8uxJ12vvHFqO0V9Cx4Zh205chpr_M-nf-ZH6B0lNSVUfNrV_d74uinvmjY1YfIIrSgXvGKcrF-hFZGCVJ3kP0_QaUo7QignnB-jk6ajtG3IeoV-3z6NeQvJJaxHi3sXfLh3RnsMj9rPOrsw4jBgjX_pDLFKwc-9BzxtQ5q2pYWnGGyc73HSPv9lpBxnk-dYGHrUBTdDWhBfr79L_rGQPGiL3bh1vcshLl9GFw9TciPevEGvB-0TvH2uZ-jH56u7y5tq8-36y-XFpjJsLXJlLNe9HIxhVjJmKYAQgxy0pa2h0vaam850kpDOghSstcaI3jJu15S1rG3YGfpw4Bb_D8VhVnuXDHivRwhzUrQTVJC2XKpIm4PUxJBShEFN0e11fFKUqCUJtVNLEmpJQtFGlSTK0Ptn_tzvwf4beTl9EZwfBFC2fHQQVTIORgPWRTBZ2eD-x_8D89Kc8Q</recordid><startdate>20170301</startdate><enddate>20170301</enddate><creator>Parker, Erica N.</creator><creator>Odutola, Samuel O.</creator><creator>Wang, Yifan</creator><creator>Strecker, Tracy E.</creator><creator>Mukherjee, Rajeswari</creator><creator>Shi, Zhe</creator><creator>Chaplin, David J.</creator><creator>Trawick, Mary Lynn</creator><creator>Pinney, Kevin G.</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>20170301</creationdate><title>Synthesis and biological evaluation of a water-soluble phosphate prodrug salt and structural analogues of KGP94, a lead inhibitor of cathepsin L</title><author>Parker, Erica N. ; Odutola, Samuel O. ; Wang, Yifan ; Strecker, Tracy E. ; Mukherjee, Rajeswari ; Shi, Zhe ; Chaplin, David J. ; Trawick, Mary Lynn ; Pinney, Kevin G.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-cd4ab9fcc3d933d1ee66f9fad17c19dba4c8c89008de9637dcc6bd34d51373723</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Anti-metastatic agent</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Benzophenone</topic><topic>Cathepsin L - antagonists & inhibitors</topic><topic>Cell Line, Tumor</topic><topic>Cysteine protease inhibitor</topic><topic>Enzyme Activation - drug effects</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Humans</topic><topic>Molecular Structure</topic><topic>Organophosphates - chemistry</topic><topic>Phosphate prodrug</topic><topic>Prodrugs - chemical synthesis</topic><topic>Prodrugs - chemistry</topic><topic>Prodrugs - pharmacology</topic><topic>Salts - chemical synthesis</topic><topic>Salts - pharmacology</topic><topic>Solubility</topic><topic>Thiosemicarbazone</topic><topic>Thiosemicarbazones - chemical synthesis</topic><topic>Thiosemicarbazones - chemistry</topic><topic>Thiosemicarbazones - pharmacology</topic><topic>Thiourea - analogs & derivatives</topic><topic>Thiourea - chemical synthesis</topic><topic>Thiourea - chemistry</topic><topic>Thiourea - pharmacology</topic><topic>Water - chemistry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Parker, Erica N.</creatorcontrib><creatorcontrib>Odutola, Samuel O.</creatorcontrib><creatorcontrib>Wang, Yifan</creatorcontrib><creatorcontrib>Strecker, Tracy E.</creatorcontrib><creatorcontrib>Mukherjee, Rajeswari</creatorcontrib><creatorcontrib>Shi, Zhe</creatorcontrib><creatorcontrib>Chaplin, David J.</creatorcontrib><creatorcontrib>Trawick, Mary Lynn</creatorcontrib><creatorcontrib>Pinney, Kevin G.</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 letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Parker, Erica N.</au><au>Odutola, Samuel O.</au><au>Wang, Yifan</au><au>Strecker, Tracy E.</au><au>Mukherjee, Rajeswari</au><au>Shi, Zhe</au><au>Chaplin, David J.</au><au>Trawick, Mary Lynn</au><au>Pinney, Kevin G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and biological evaluation of a water-soluble phosphate prodrug salt and structural analogues of KGP94, a lead inhibitor of cathepsin L</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2017-03-01</date><risdate>2017</risdate><volume>27</volume><issue>5</issue><spage>1304</spage><epage>1310</epage><pages>1304-1310</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
The magnitude of expression of cathepsin L, often upregulated in the tumor microenvironment, correlates with the invasive and metastatic nature of certain tumors. Inhibition of cathepsin L represents an emerging strategy for the treatment of metastatic cancer. A potent, small-molecule inhibitor (referred to as KGP94) of cathepsin L, and new KGP94 analogues were synthesized. (3,5-Dibromophenyl)-(3-hydroxyphenyl) ketone thiosemicarbazone (22), with an IC50 value of 202nM, exhibited similar inhibitory activity against cathepsin L compared to KGP94 (IC50=189nM). Due to limited aqueous solubility of KGP94, a water-soluble phosphate salt (KGP420) was prepared in order to facilitate future in vivo studies. Enzymatic hydrolysis with alkaline phosphatase (ALP) demonstrated that the phosphate prodrug, KGP420, was readily converted to the parent compound, KGP94.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>28117205</pmid><doi>10.1016/j.bmcl.2016.12.039</doi><tpages>7</tpages></addata></record> |
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| subjects | Anti-metastatic agent Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Benzophenone Cathepsin L - antagonists & inhibitors Cell Line, Tumor Cysteine protease inhibitor Enzyme Activation - drug effects Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Humans Molecular Structure Organophosphates - chemistry Phosphate prodrug Prodrugs - chemical synthesis Prodrugs - chemistry Prodrugs - pharmacology Salts - chemical synthesis Salts - pharmacology Solubility Thiosemicarbazone Thiosemicarbazones - chemical synthesis Thiosemicarbazones - chemistry Thiosemicarbazones - pharmacology Thiourea - analogs & derivatives Thiourea - chemical synthesis Thiourea - chemistry Thiourea - pharmacology Water - chemistry |
| title | Synthesis and biological evaluation of a water-soluble phosphate prodrug salt and structural analogues of KGP94, a lead inhibitor of cathepsin L |
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