Structure-Based Drug Design and Identification of H 2 O-Soluble and Low Toxic Hexacyclic Camptothecin Derivatives with Improved Efficacy in Cancer and Lethal Inflammation Models in Vivo
Camptothecin (CPT) has been shown to block disassembly of the topoisomerase I (Topo I)/DNA cleavable complex. However, the poor aqueous solubility, intrinsic instability, and severe toxicity of CPTs have limited their clinical applications. Herein, we report the design and synthesis of H O-soluble a...
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| Veröffentlicht in: | Journal of medicinal chemistry 2018-10, Vol.61 (19), p.8613-8624 |
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| container_title | Journal of medicinal chemistry |
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| creator | Pan, Peichen Chen, Jiean Li, Xijian Li, Miyang Yu, Huidong Zhao, Jean J Ni, Jing Wang, Xuwen Sun, Huiyong Tian, Sheng Zhu, Feng Liu, Feng Huang, Yong Hou, Tingjun |
| description | Camptothecin (CPT) has been shown to block disassembly of the topoisomerase I (Topo I)/DNA cleavable complex. However, the poor aqueous solubility, intrinsic instability, and severe toxicity of CPTs have limited their clinical applications. Herein, we report the design and synthesis of H
O-soluble and orally bioavailable hexacyclic CPT derivatives. By analysis of a virtual chemical library and cytotoxicity screening in vitro, 9 and 11 were identified as potential prodrugs and chosen for further characterization in vivo. Both compounds exhibited remarkable anticancer and anti-inflammation efficacies in animals and improved drug-like profiles. |
| doi_str_mv | 10.1021/acs.jmedchem.8b00498 |
| format | Article |
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O-soluble and orally bioavailable hexacyclic CPT derivatives. By analysis of a virtual chemical library and cytotoxicity screening in vitro, 9 and 11 were identified as potential prodrugs and chosen for further characterization in vivo. Both compounds exhibited remarkable anticancer and anti-inflammation efficacies in animals and improved drug-like profiles.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.8b00498</identifier><identifier>PMID: 30227711</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Anti-Inflammatory Agents - pharmacology ; Antineoplastic Agents - pharmacology ; Apoptosis ; Camptothecin - chemistry ; Camptothecin - pharmacology ; Cell Proliferation ; Drug Design ; Humans ; Lipopolysaccharides - toxicity ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Nude ; Neoplasms - drug therapy ; Neoplasms - pathology ; Sepsis - chemically induced ; Sepsis - drug therapy ; Sepsis - pathology ; Solubility ; Structure-Activity Relationship ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays</subject><ispartof>Journal of medicinal chemistry, 2018-10, Vol.61 (19), p.8613-8624</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c1191-5a8027eee103ed1d8d3266557004e7c8cdfa568f19d16a7db63c7dac96c5d8173</citedby><cites>FETCH-LOGICAL-c1191-5a8027eee103ed1d8d3266557004e7c8cdfa568f19d16a7db63c7dac96c5d8173</cites><orcidid>0000-0001-8377-8923 ; 0000-0001-7227-2580 ; 0000-0002-7107-7481 ; 0000-0003-2669-5448 ; 0000-0001-8069-0053</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,2766,27929,27930</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30227711$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pan, Peichen</creatorcontrib><creatorcontrib>Chen, Jiean</creatorcontrib><creatorcontrib>Li, Xijian</creatorcontrib><creatorcontrib>Li, Miyang</creatorcontrib><creatorcontrib>Yu, Huidong</creatorcontrib><creatorcontrib>Zhao, Jean J</creatorcontrib><creatorcontrib>Ni, Jing</creatorcontrib><creatorcontrib>Wang, Xuwen</creatorcontrib><creatorcontrib>Sun, Huiyong</creatorcontrib><creatorcontrib>Tian, Sheng</creatorcontrib><creatorcontrib>Zhu, Feng</creatorcontrib><creatorcontrib>Liu, Feng</creatorcontrib><creatorcontrib>Huang, Yong</creatorcontrib><creatorcontrib>Hou, Tingjun</creatorcontrib><title>Structure-Based Drug Design and Identification of H 2 O-Soluble and Low Toxic Hexacyclic Camptothecin Derivatives with Improved Efficacy in Cancer and Lethal Inflammation Models in Vivo</title><title>Journal of medicinal chemistry</title><addtitle>J Med Chem</addtitle><description>Camptothecin (CPT) has been shown to block disassembly of the topoisomerase I (Topo I)/DNA cleavable complex. However, the poor aqueous solubility, intrinsic instability, and severe toxicity of CPTs have limited their clinical applications. Herein, we report the design and synthesis of H
O-soluble and orally bioavailable hexacyclic CPT derivatives. By analysis of a virtual chemical library and cytotoxicity screening in vitro, 9 and 11 were identified as potential prodrugs and chosen for further characterization in vivo. Both compounds exhibited remarkable anticancer and anti-inflammation efficacies in animals and improved drug-like profiles.</description><subject>Animals</subject><subject>Anti-Inflammatory Agents - pharmacology</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis</subject><subject>Camptothecin - chemistry</subject><subject>Camptothecin - pharmacology</subject><subject>Cell Proliferation</subject><subject>Drug Design</subject><subject>Humans</subject><subject>Lipopolysaccharides - toxicity</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Nude</subject><subject>Neoplasms - drug therapy</subject><subject>Neoplasms - pathology</subject><subject>Sepsis - chemically induced</subject><subject>Sepsis - drug therapy</subject><subject>Sepsis - pathology</subject><subject>Solubility</subject><subject>Structure-Activity Relationship</subject><subject>Tumor Cells, Cultured</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kctOwzAQRS0EglL4A4T8Ayl-5NUllEcrFXXRwjZyxhNqlMSVnRT6afwdLgVWM9Lce0a6l5ArzkacCX6jwI_eG9SwxmaUl4zF4_yIDHgiWBTnLD4mA8aEiEQq5Bk59_6dMSa5kKfkTIZDlnE-IF_LzvXQ9Q6jO-VR03vXv9F79OatparVdKax7UxlQHXGttRWdEoFXURLW_dljT-auf2gK_tpgE7xU8EO6rBOVLPpbLdGMG0AOrMNhC16-mG6NZ01G2e34d9DtWfDjgbVRLWA7oDEbq1qOmurWjXN4fez1Vj7vfDVbO0FOalU7fHydw7Jy-PDajKN5oun2eR2HgHnYx4lKmciQ0TOJGqucy1FmiZJFgLDDHLQlUrSvOJjzVOV6TKVkGkF4xQSnfNMDkl84IKz3jusio0zjXK7grNi30QRmij-mih-mwi264Nt05fh9m_6i15-A7i-iuI</recordid><startdate>20181011</startdate><enddate>20181011</enddate><creator>Pan, Peichen</creator><creator>Chen, Jiean</creator><creator>Li, Xijian</creator><creator>Li, Miyang</creator><creator>Yu, Huidong</creator><creator>Zhao, Jean J</creator><creator>Ni, Jing</creator><creator>Wang, Xuwen</creator><creator>Sun, Huiyong</creator><creator>Tian, Sheng</creator><creator>Zhu, Feng</creator><creator>Liu, Feng</creator><creator>Huang, Yong</creator><creator>Hou, Tingjun</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><orcidid>https://orcid.org/0000-0001-8377-8923</orcidid><orcidid>https://orcid.org/0000-0001-7227-2580</orcidid><orcidid>https://orcid.org/0000-0002-7107-7481</orcidid><orcidid>https://orcid.org/0000-0003-2669-5448</orcidid><orcidid>https://orcid.org/0000-0001-8069-0053</orcidid></search><sort><creationdate>20181011</creationdate><title>Structure-Based Drug Design and Identification of H 2 O-Soluble and Low Toxic Hexacyclic Camptothecin Derivatives with Improved Efficacy in Cancer and Lethal Inflammation Models in Vivo</title><author>Pan, Peichen ; Chen, Jiean ; Li, Xijian ; Li, Miyang ; Yu, Huidong ; Zhao, Jean J ; Ni, Jing ; Wang, Xuwen ; Sun, Huiyong ; Tian, Sheng ; Zhu, Feng ; Liu, Feng ; Huang, Yong ; Hou, Tingjun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c1191-5a8027eee103ed1d8d3266557004e7c8cdfa568f19d16a7db63c7dac96c5d8173</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Animals</topic><topic>Anti-Inflammatory Agents - pharmacology</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis</topic><topic>Camptothecin - chemistry</topic><topic>Camptothecin - pharmacology</topic><topic>Cell Proliferation</topic><topic>Drug Design</topic><topic>Humans</topic><topic>Lipopolysaccharides - toxicity</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Nude</topic><topic>Neoplasms - drug therapy</topic><topic>Neoplasms - pathology</topic><topic>Sepsis - chemically induced</topic><topic>Sepsis - drug therapy</topic><topic>Sepsis - pathology</topic><topic>Solubility</topic><topic>Structure-Activity Relationship</topic><topic>Tumor Cells, Cultured</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pan, Peichen</creatorcontrib><creatorcontrib>Chen, Jiean</creatorcontrib><creatorcontrib>Li, Xijian</creatorcontrib><creatorcontrib>Li, Miyang</creatorcontrib><creatorcontrib>Yu, Huidong</creatorcontrib><creatorcontrib>Zhao, Jean J</creatorcontrib><creatorcontrib>Ni, Jing</creatorcontrib><creatorcontrib>Wang, Xuwen</creatorcontrib><creatorcontrib>Sun, Huiyong</creatorcontrib><creatorcontrib>Tian, Sheng</creatorcontrib><creatorcontrib>Zhu, Feng</creatorcontrib><creatorcontrib>Liu, Feng</creatorcontrib><creatorcontrib>Huang, Yong</creatorcontrib><creatorcontrib>Hou, Tingjun</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pan, Peichen</au><au>Chen, Jiean</au><au>Li, Xijian</au><au>Li, Miyang</au><au>Yu, Huidong</au><au>Zhao, Jean J</au><au>Ni, Jing</au><au>Wang, Xuwen</au><au>Sun, Huiyong</au><au>Tian, Sheng</au><au>Zhu, Feng</au><au>Liu, Feng</au><au>Huang, Yong</au><au>Hou, Tingjun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure-Based Drug Design and Identification of H 2 O-Soluble and Low Toxic Hexacyclic Camptothecin Derivatives with Improved Efficacy in Cancer and Lethal Inflammation Models in Vivo</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J Med Chem</addtitle><date>2018-10-11</date><risdate>2018</risdate><volume>61</volume><issue>19</issue><spage>8613</spage><epage>8624</epage><pages>8613-8624</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Camptothecin (CPT) has been shown to block disassembly of the topoisomerase I (Topo I)/DNA cleavable complex. However, the poor aqueous solubility, intrinsic instability, and severe toxicity of CPTs have limited their clinical applications. Herein, we report the design and synthesis of H
O-soluble and orally bioavailable hexacyclic CPT derivatives. By analysis of a virtual chemical library and cytotoxicity screening in vitro, 9 and 11 were identified as potential prodrugs and chosen for further characterization in vivo. Both compounds exhibited remarkable anticancer and anti-inflammation efficacies in animals and improved drug-like profiles.</abstract><cop>United States</cop><pmid>30227711</pmid><doi>10.1021/acs.jmedchem.8b00498</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0001-8377-8923</orcidid><orcidid>https://orcid.org/0000-0001-7227-2580</orcidid><orcidid>https://orcid.org/0000-0002-7107-7481</orcidid><orcidid>https://orcid.org/0000-0003-2669-5448</orcidid><orcidid>https://orcid.org/0000-0001-8069-0053</orcidid></addata></record> |
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| subjects | Animals Anti-Inflammatory Agents - pharmacology Antineoplastic Agents - pharmacology Apoptosis Camptothecin - chemistry Camptothecin - pharmacology Cell Proliferation Drug Design Humans Lipopolysaccharides - toxicity Male Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Nude Neoplasms - drug therapy Neoplasms - pathology Sepsis - chemically induced Sepsis - drug therapy Sepsis - pathology Solubility Structure-Activity Relationship Tumor Cells, Cultured Xenograft Model Antitumor Assays |
| title | Structure-Based Drug Design and Identification of H 2 O-Soluble and Low Toxic Hexacyclic Camptothecin Derivatives with Improved Efficacy in Cancer and Lethal Inflammation Models in Vivo |
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