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Synthesis, human telomerase inhibition and anti-proliferative studies of a series of 2,7-bis-substituted amido-anthraquinone derivatives
Telomerase is important in tumor initiation and cellular immortalization. Given the striking correlations between telomerase activity and proliferation capacity in tumor cells, telomerase had been considered as a potentially important molecular target in cancer therapeutics. A series of 2,7-diamidoa...
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| Published in: | Bioorganic & medicinal chemistry 2008-07, Vol.16 (14), p.6976-6986 |
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| container_end_page | 6986 |
| container_issue | 14 |
| container_start_page | 6976 |
| container_title | Bioorganic & medicinal chemistry |
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| creator | Huang, Hsu-Shan Huang, Kuo-Feng Li, Cho-Lu Huang, Yi-Yuan Chiang, Yi-Hsuan Huang, Fong-Chun Lin, Jing-Jer |
| description | Telomerase is important in tumor initiation and cellular immortalization. Given the striking correlations between telomerase activity and proliferation capacity in tumor cells, telomerase had been considered as a potentially important molecular target in cancer therapeutics. A series of 2,7-diamidoanthraquinone were designed and synthesized. They were evaluated for their effects on telomerase activity, hTERT expression, cell proliferations, and cytotoxicity. In the series, compounds (
6,
10,
13,
16,
18,
19,
20–
22, and
24) showed potent telomerase inhibitory activity, while compounds
19,
21, and
22 activated hTERT expression in normal human fibroblasts. The results indicated that 2,7-diamidoanthraquinones represent an important class of compounds for telomerase-related drug developments. Compounds
8,
16,
18,
26, and
32 were also selected by the NCI for Screening Program and demonstrated high anti-proliferative activity against 60 human cancer cell lines. Structure–activity relationships (SAR) study revealed that the test compounds with side chains two carbon spacer between amido and amine are important structural moiety for telomerase inhibition. Although the exact mechanism of how this amine group contributes to its activity is still unclear, however, the amine group in the extended arm of the bis-substituted anthraquinone might contribute to proper binding to the residues within the grove of G-quadruplex structure. Our results indicated that the 2,7-disubstituted amido-anthraquinones are potent telomerase inhibitors that have the potential to be further developed into novel anticancer chemotherapeutic agents. |
| doi_str_mv | 10.1016/j.bmc.2008.05.072 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_69343491</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0968089608004860</els_id><sourcerecordid>69343491</sourcerecordid><originalsourceid>FETCH-LOGICAL-c447t-1bf901da93fe110d4cffc718ff7cc5bfe781a7731adfd99d383dee9e5a86b1643</originalsourceid><addsrcrecordid>eNp9kM1u1DAURi0EokPhAdigbGDVBDtO4lisqoo_qRILYG059rXmjhKn9XVG6hvw2LjMCHYsLFvy-T7dexh7LXgjuBjeH5ppcU3L-djwvuGqfcJ2ohu6WkotnrId18NY81EPF-wF0YFz3nZaPGcXYuyV0O24Y7--P8S8B0K6qvbbYmOVYV4XSJagwrjHCTOusbLRl5OxvkvrjKH8ZzxCRXnzCFStobIVQTq_2ytVT0g1bRNlzFuGkl7Qr3Xp2Cd7v2FcI1S-JI5_muglexbsTPDqfF-yn58-_rj5Ut9--_z15vq2dl2nci2moLnwVssAQnDfuRCcEmMIyrl-CqBGYZWSwvrgtfZylB5AQ2_HYRJDJy_Zu1NvWeR-A8pmQXIwzzbCupEZtOxksVRAcQJdWokSBHOXcLHpwQhuHvWbgyn6zaN-w3tT9JfMm3P5Ni3g_yXOvgvw9gxYcnYOyUaH9JdruSrz97JwH04cFBVHhGTIIUQHHhO4bPyK_xnjN-uApqM</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>69343491</pqid></control><display><type>article</type><title>Synthesis, human telomerase inhibition and anti-proliferative studies of a series of 2,7-bis-substituted amido-anthraquinone derivatives</title><source>Elsevier</source><creator>Huang, Hsu-Shan ; Huang, Kuo-Feng ; Li, Cho-Lu ; Huang, Yi-Yuan ; Chiang, Yi-Hsuan ; Huang, Fong-Chun ; Lin, Jing-Jer</creator><creatorcontrib>Huang, Hsu-Shan ; Huang, Kuo-Feng ; Li, Cho-Lu ; Huang, Yi-Yuan ; Chiang, Yi-Hsuan ; Huang, Fong-Chun ; Lin, Jing-Jer</creatorcontrib><description>Telomerase is important in tumor initiation and cellular immortalization. Given the striking correlations between telomerase activity and proliferation capacity in tumor cells, telomerase had been considered as a potentially important molecular target in cancer therapeutics. A series of 2,7-diamidoanthraquinone were designed and synthesized. They were evaluated for their effects on telomerase activity, hTERT expression, cell proliferations, and cytotoxicity. In the series, compounds (
6,
10,
13,
16,
18,
19,
20–
22, and
24) showed potent telomerase inhibitory activity, while compounds
19,
21, and
22 activated hTERT expression in normal human fibroblasts. The results indicated that 2,7-diamidoanthraquinones represent an important class of compounds for telomerase-related drug developments. Compounds
8,
16,
18,
26, and
32 were also selected by the NCI for Screening Program and demonstrated high anti-proliferative activity against 60 human cancer cell lines. Structure–activity relationships (SAR) study revealed that the test compounds with side chains two carbon spacer between amido and amine are important structural moiety for telomerase inhibition. Although the exact mechanism of how this amine group contributes to its activity is still unclear, however, the amine group in the extended arm of the bis-substituted anthraquinone might contribute to proper binding to the residues within the grove of G-quadruplex structure. Our results indicated that the 2,7-disubstituted amido-anthraquinones are potent telomerase inhibitors that have the potential to be further developed into novel anticancer chemotherapeutic agents.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2008.05.072</identifier><identifier>PMID: 18571928</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>Anthraquinones ; Anthraquinones - chemical synthesis ; Anthraquinones - chemistry ; Anthraquinones - pharmacology ; Antineoplastic agents ; Antineoplastic Agents - chemical synthesis ; Biological and medical sciences ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Cells, Cultured ; Cytotoxicity ; Drug Screening Assays, Antitumor ; Fibroblasts - drug effects ; G-quadruplex ; General aspects ; hTERT ; Humans ; Medical sciences ; Pharmacology. Drug treatments ; SEAP assay ; Structure-Activity Relationship ; Telomerase - antagonists & inhibitors ; Telomerase - drug effects ; Telomerase assay ; Telomerase inhibition ; TRAP assay</subject><ispartof>Bioorganic & medicinal chemistry, 2008-07, Vol.16 (14), p.6976-6986</ispartof><rights>2008 Elsevier Ltd</rights><rights>2009 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c447t-1bf901da93fe110d4cffc718ff7cc5bfe781a7731adfd99d383dee9e5a86b1643</citedby><cites>FETCH-LOGICAL-c447t-1bf901da93fe110d4cffc718ff7cc5bfe781a7731adfd99d383dee9e5a86b1643</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20778153$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18571928$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Huang, Hsu-Shan</creatorcontrib><creatorcontrib>Huang, Kuo-Feng</creatorcontrib><creatorcontrib>Li, Cho-Lu</creatorcontrib><creatorcontrib>Huang, Yi-Yuan</creatorcontrib><creatorcontrib>Chiang, Yi-Hsuan</creatorcontrib><creatorcontrib>Huang, Fong-Chun</creatorcontrib><creatorcontrib>Lin, Jing-Jer</creatorcontrib><title>Synthesis, human telomerase inhibition and anti-proliferative studies of a series of 2,7-bis-substituted amido-anthraquinone derivatives</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>Telomerase is important in tumor initiation and cellular immortalization. Given the striking correlations between telomerase activity and proliferation capacity in tumor cells, telomerase had been considered as a potentially important molecular target in cancer therapeutics. A series of 2,7-diamidoanthraquinone were designed and synthesized. They were evaluated for their effects on telomerase activity, hTERT expression, cell proliferations, and cytotoxicity. In the series, compounds (
6,
10,
13,
16,
18,
19,
20–
22, and
24) showed potent telomerase inhibitory activity, while compounds
19,
21, and
22 activated hTERT expression in normal human fibroblasts. The results indicated that 2,7-diamidoanthraquinones represent an important class of compounds for telomerase-related drug developments. Compounds
8,
16,
18,
26, and
32 were also selected by the NCI for Screening Program and demonstrated high anti-proliferative activity against 60 human cancer cell lines. Structure–activity relationships (SAR) study revealed that the test compounds with side chains two carbon spacer between amido and amine are important structural moiety for telomerase inhibition. Although the exact mechanism of how this amine group contributes to its activity is still unclear, however, the amine group in the extended arm of the bis-substituted anthraquinone might contribute to proper binding to the residues within the grove of G-quadruplex structure. Our results indicated that the 2,7-disubstituted amido-anthraquinones are potent telomerase inhibitors that have the potential to be further developed into novel anticancer chemotherapeutic agents.</description><subject>Anthraquinones</subject><subject>Anthraquinones - chemical synthesis</subject><subject>Anthraquinones - chemistry</subject><subject>Anthraquinones - pharmacology</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Biological and medical sciences</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Cells, Cultured</subject><subject>Cytotoxicity</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Fibroblasts - drug effects</subject><subject>G-quadruplex</subject><subject>General aspects</subject><subject>hTERT</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Pharmacology. Drug treatments</subject><subject>SEAP assay</subject><subject>Structure-Activity Relationship</subject><subject>Telomerase - antagonists & inhibitors</subject><subject>Telomerase - drug effects</subject><subject>Telomerase assay</subject><subject>Telomerase inhibition</subject><subject>TRAP assay</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><recordid>eNp9kM1u1DAURi0EokPhAdigbGDVBDtO4lisqoo_qRILYG059rXmjhKn9XVG6hvw2LjMCHYsLFvy-T7dexh7LXgjuBjeH5ppcU3L-djwvuGqfcJ2ohu6WkotnrId18NY81EPF-wF0YFz3nZaPGcXYuyV0O24Y7--P8S8B0K6qvbbYmOVYV4XSJagwrjHCTOusbLRl5OxvkvrjKH8ZzxCRXnzCFStobIVQTq_2ytVT0g1bRNlzFuGkl7Qr3Xp2Cd7v2FcI1S-JI5_muglexbsTPDqfF-yn58-_rj5Ut9--_z15vq2dl2nci2moLnwVssAQnDfuRCcEmMIyrl-CqBGYZWSwvrgtfZylB5AQ2_HYRJDJy_Zu1NvWeR-A8pmQXIwzzbCupEZtOxksVRAcQJdWokSBHOXcLHpwQhuHvWbgyn6zaN-w3tT9JfMm3P5Ni3g_yXOvgvw9gxYcnYOyUaH9JdruSrz97JwH04cFBVHhGTIIUQHHhO4bPyK_xnjN-uApqM</recordid><startdate>20080715</startdate><enddate>20080715</enddate><creator>Huang, Hsu-Shan</creator><creator>Huang, Kuo-Feng</creator><creator>Li, Cho-Lu</creator><creator>Huang, Yi-Yuan</creator><creator>Chiang, Yi-Hsuan</creator><creator>Huang, Fong-Chun</creator><creator>Lin, Jing-Jer</creator><general>Elsevier Ltd</general><general>Elsevier</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></search><sort><creationdate>20080715</creationdate><title>Synthesis, human telomerase inhibition and anti-proliferative studies of a series of 2,7-bis-substituted amido-anthraquinone derivatives</title><author>Huang, Hsu-Shan ; Huang, Kuo-Feng ; Li, Cho-Lu ; Huang, Yi-Yuan ; Chiang, Yi-Hsuan ; Huang, Fong-Chun ; Lin, Jing-Jer</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c447t-1bf901da93fe110d4cffc718ff7cc5bfe781a7731adfd99d383dee9e5a86b1643</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Anthraquinones</topic><topic>Anthraquinones - chemical synthesis</topic><topic>Anthraquinones - chemistry</topic><topic>Anthraquinones - pharmacology</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Biological and medical sciences</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Cells, Cultured</topic><topic>Cytotoxicity</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Fibroblasts - drug effects</topic><topic>G-quadruplex</topic><topic>General aspects</topic><topic>hTERT</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Pharmacology. Drug treatments</topic><topic>SEAP assay</topic><topic>Structure-Activity Relationship</topic><topic>Telomerase - antagonists & inhibitors</topic><topic>Telomerase - drug effects</topic><topic>Telomerase assay</topic><topic>Telomerase inhibition</topic><topic>TRAP assay</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Huang, Hsu-Shan</creatorcontrib><creatorcontrib>Huang, Kuo-Feng</creatorcontrib><creatorcontrib>Li, Cho-Lu</creatorcontrib><creatorcontrib>Huang, Yi-Yuan</creatorcontrib><creatorcontrib>Chiang, Yi-Hsuan</creatorcontrib><creatorcontrib>Huang, Fong-Chun</creatorcontrib><creatorcontrib>Lin, Jing-Jer</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><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Huang, Hsu-Shan</au><au>Huang, Kuo-Feng</au><au>Li, Cho-Lu</au><au>Huang, Yi-Yuan</au><au>Chiang, Yi-Hsuan</au><au>Huang, Fong-Chun</au><au>Lin, Jing-Jer</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis, human telomerase inhibition and anti-proliferative studies of a series of 2,7-bis-substituted amido-anthraquinone derivatives</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2008-07-15</date><risdate>2008</risdate><volume>16</volume><issue>14</issue><spage>6976</spage><epage>6986</epage><pages>6976-6986</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>Telomerase is important in tumor initiation and cellular immortalization. Given the striking correlations between telomerase activity and proliferation capacity in tumor cells, telomerase had been considered as a potentially important molecular target in cancer therapeutics. A series of 2,7-diamidoanthraquinone were designed and synthesized. They were evaluated for their effects on telomerase activity, hTERT expression, cell proliferations, and cytotoxicity. In the series, compounds (
6,
10,
13,
16,
18,
19,
20–
22, and
24) showed potent telomerase inhibitory activity, while compounds
19,
21, and
22 activated hTERT expression in normal human fibroblasts. The results indicated that 2,7-diamidoanthraquinones represent an important class of compounds for telomerase-related drug developments. Compounds
8,
16,
18,
26, and
32 were also selected by the NCI for Screening Program and demonstrated high anti-proliferative activity against 60 human cancer cell lines. Structure–activity relationships (SAR) study revealed that the test compounds with side chains two carbon spacer between amido and amine are important structural moiety for telomerase inhibition. Although the exact mechanism of how this amine group contributes to its activity is still unclear, however, the amine group in the extended arm of the bis-substituted anthraquinone might contribute to proper binding to the residues within the grove of G-quadruplex structure. Our results indicated that the 2,7-disubstituted amido-anthraquinones are potent telomerase inhibitors that have the potential to be further developed into novel anticancer chemotherapeutic agents.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>18571928</pmid><doi>10.1016/j.bmc.2008.05.072</doi><tpages>11</tpages></addata></record> |
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| identifier | ISSN: 0968-0896 |
| ispartof | Bioorganic & medicinal chemistry, 2008-07, Vol.16 (14), p.6976-6986 |
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| subjects | Anthraquinones Anthraquinones - chemical synthesis Anthraquinones - chemistry Anthraquinones - pharmacology Antineoplastic agents Antineoplastic Agents - chemical synthesis Biological and medical sciences Cell Line, Tumor Cell Proliferation - drug effects Cells, Cultured Cytotoxicity Drug Screening Assays, Antitumor Fibroblasts - drug effects G-quadruplex General aspects hTERT Humans Medical sciences Pharmacology. Drug treatments SEAP assay Structure-Activity Relationship Telomerase - antagonists & inhibitors Telomerase - drug effects Telomerase assay Telomerase inhibition TRAP assay |
| title | Synthesis, human telomerase inhibition and anti-proliferative studies of a series of 2,7-bis-substituted amido-anthraquinone derivatives |
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