Loading…
Design, Synthesis, and Biological Evaluation of Pyrrolo[2,1-c][1,4]benzodiazepine and Indole Conjugates as Anticancer Agents
A series of novel pyrrolo[2,1-c][1,4]benzodiazepine (PBD) hybrids linked with indole carboxylates is described. These compounds were prepared by linking C-8 of 3 (DC-81) with an indole 2-carbonyl moiety (9) through carbon chain linkers to afford PBD hybrid agents 17−21 in good yields. Preliminary in...
Saved in:
| Published in: | Journal of medicinal chemistry 2006-02, Vol.49 (4), p.1442-1449 |
|---|---|
| Main Authors: | , , , , , , |
| Format: | Article |
| Language: | English |
| Subjects: | |
| Citations: | Items that this one cites Items that cite this one |
| Online Access: | Get full text |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| cited_by | cdi_FETCH-LOGICAL-a412t-1e85ac870ec212508fb6a7688b0749dc2963b8b1ddae3f5f362fc7efd21be5893 |
|---|---|
| cites | cdi_FETCH-LOGICAL-a412t-1e85ac870ec212508fb6a7688b0749dc2963b8b1ddae3f5f362fc7efd21be5893 |
| container_end_page | 1449 |
| container_issue | 4 |
| container_start_page | 1442 |
| container_title | Journal of medicinal chemistry |
| container_volume | 49 |
| creator | Wang, Jeh-Jeng Shen, Yu-Kai Hu, Wan-Ping Hsieh, Ming-Chu Lin, Fu-Lung Hsu, Ming-Kuan Hsu, Mei-Hui |
| description | A series of novel pyrrolo[2,1-c][1,4]benzodiazepine (PBD) hybrids linked with indole carboxylates is described. These compounds were prepared by linking C-8 of 3 (DC-81) with an indole 2-carbonyl moiety (9) through carbon chain linkers to afford PBD hybrid agents 17−21 in good yields. Preliminary in vivo tests show that these hybrid agents have potent antitumor activity. The cytotoxic studies of the hybrid agents on human melanoma A2058 cells indicate most of the hybrids induced higher cytotoxicity, better DNA-binding ability, an increase in the apoptotic sub-G1 population, and a significant reduction in ΔΨmt relative to compound 3. In addition, DNA flow cytometric analysis shows that hybrids actively induce a marked loss of cells from the G2/M phase of the cell cycle, which progresses to early apoptosis as detected by flow cytometry after double-staining with annexin V and propidium iodide (PI). Thus, we suggest that the hybrid agents are potent inducers of cell apoptosis in A2058 cells. |
| doi_str_mv | 10.1021/jm050956q |
| format | article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_67662626</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>67662626</sourcerecordid><originalsourceid>FETCH-LOGICAL-a412t-1e85ac870ec212508fb6a7688b0749dc2963b8b1ddae3f5f362fc7efd21be5893</originalsourceid><addsrcrecordid>eNqFkU9vEzEQxS1ERdPAgS-AfAEJKQv-s-vdPaahhaoVFLVIiKqyvN5xcNjYqb2LSNUPX5dEzQWJ04w0v3maeQ-hl5S8o4TR94slKUhdiJsnaEQLRrK8IvlTNCKEsYwJxvfRQYwLQginjD9D-1QkglVkhO4-QLRzN8EXa9f_TH2cYOVafGh95-dWqw4f_VbdoHrrHfYGn69DSKMrNqGZvr6ik_y6AXfrW6tuYWUd_F0_ca3vAM-8Wwxz1UPEKuKp65Og0xDwdA6uj8_RnlFdhBfbOkbfjo8uZ5-ysy8fT2bTs0zllPUZhapQuioJaEZZQSrTCFWKqmpImdetZrXgTdXQtlXATWG4YEaXYFpGGyiqmo_Rm43uKvibAWIvlzZq6DrlwA9RilKIZJP4L0hrXnNGywS-3YA6-BgDGLkKdqnCWlIiHzKRj5kk9tVWdGiW0O7IbQgJeL0FVEyGm5A8snHHlQXPH4Ibo2zD2djDn8e5Cr_SB7ws5OX5haQ_vovP7OupPNzpKh3lwg_BJZP_ceA9mE2vIA</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>19393217</pqid></control><display><type>article</type><title>Design, Synthesis, and Biological Evaluation of Pyrrolo[2,1-c][1,4]benzodiazepine and Indole Conjugates as Anticancer Agents</title><source>American Chemical Society:Jisc Collections:American Chemical Society Read & Publish Agreement 2022-2024 (Reading list)</source><creator>Wang, Jeh-Jeng ; Shen, Yu-Kai ; Hu, Wan-Ping ; Hsieh, Ming-Chu ; Lin, Fu-Lung ; Hsu, Ming-Kuan ; Hsu, Mei-Hui</creator><creatorcontrib>Wang, Jeh-Jeng ; Shen, Yu-Kai ; Hu, Wan-Ping ; Hsieh, Ming-Chu ; Lin, Fu-Lung ; Hsu, Ming-Kuan ; Hsu, Mei-Hui</creatorcontrib><description>A series of novel pyrrolo[2,1-c][1,4]benzodiazepine (PBD) hybrids linked with indole carboxylates is described. These compounds were prepared by linking C-8 of 3 (DC-81) with an indole 2-carbonyl moiety (9) through carbon chain linkers to afford PBD hybrid agents 17−21 in good yields. Preliminary in vivo tests show that these hybrid agents have potent antitumor activity. The cytotoxic studies of the hybrid agents on human melanoma A2058 cells indicate most of the hybrids induced higher cytotoxicity, better DNA-binding ability, an increase in the apoptotic sub-G1 population, and a significant reduction in ΔΨmt relative to compound 3. In addition, DNA flow cytometric analysis shows that hybrids actively induce a marked loss of cells from the G2/M phase of the cell cycle, which progresses to early apoptosis as detected by flow cytometry after double-staining with annexin V and propidium iodide (PI). Thus, we suggest that the hybrid agents are potent inducers of cell apoptosis in A2058 cells.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm050956q</identifier><identifier>PMID: 16480280</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Antineoplastic agents ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Apoptosis ; Benzodiazepines - chemical synthesis ; Benzodiazepines - chemistry ; Benzodiazepines - pharmacology ; Biological and medical sciences ; Cell Cycle - drug effects ; Cell Line, Tumor ; DNA - chemistry ; Drug Design ; Drug Screening Assays, Antitumor ; General aspects ; Humans ; Indoles - chemical synthesis ; Indoles - chemistry ; Indoles - pharmacology ; Medical sciences ; Melanoma ; Membrane Potentials - drug effects ; Mitochondrial Membranes - drug effects ; Mitochondrial Membranes - physiology ; Models, Molecular ; Pharmacology. Drug treatments ; Pyrroles - chemical synthesis ; Pyrroles - chemistry ; Pyrroles - pharmacology ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2006-02, Vol.49 (4), p.1442-1449</ispartof><rights>Copyright © 2006 American Chemical Society</rights><rights>2006 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a412t-1e85ac870ec212508fb6a7688b0749dc2963b8b1ddae3f5f362fc7efd21be5893</citedby><cites>FETCH-LOGICAL-a412t-1e85ac870ec212508fb6a7688b0749dc2963b8b1ddae3f5f362fc7efd21be5893</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=17534312$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16480280$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Jeh-Jeng</creatorcontrib><creatorcontrib>Shen, Yu-Kai</creatorcontrib><creatorcontrib>Hu, Wan-Ping</creatorcontrib><creatorcontrib>Hsieh, Ming-Chu</creatorcontrib><creatorcontrib>Lin, Fu-Lung</creatorcontrib><creatorcontrib>Hsu, Ming-Kuan</creatorcontrib><creatorcontrib>Hsu, Mei-Hui</creatorcontrib><title>Design, Synthesis, and Biological Evaluation of Pyrrolo[2,1-c][1,4]benzodiazepine and Indole Conjugates as Anticancer Agents</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A series of novel pyrrolo[2,1-c][1,4]benzodiazepine (PBD) hybrids linked with indole carboxylates is described. These compounds were prepared by linking C-8 of 3 (DC-81) with an indole 2-carbonyl moiety (9) through carbon chain linkers to afford PBD hybrid agents 17−21 in good yields. Preliminary in vivo tests show that these hybrid agents have potent antitumor activity. The cytotoxic studies of the hybrid agents on human melanoma A2058 cells indicate most of the hybrids induced higher cytotoxicity, better DNA-binding ability, an increase in the apoptotic sub-G1 population, and a significant reduction in ΔΨmt relative to compound 3. In addition, DNA flow cytometric analysis shows that hybrids actively induce a marked loss of cells from the G2/M phase of the cell cycle, which progresses to early apoptosis as detected by flow cytometry after double-staining with annexin V and propidium iodide (PI). Thus, we suggest that the hybrid agents are potent inducers of cell apoptosis in A2058 cells.</description><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis</subject><subject>Benzodiazepines - chemical synthesis</subject><subject>Benzodiazepines - chemistry</subject><subject>Benzodiazepines - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Cell Cycle - drug effects</subject><subject>Cell Line, Tumor</subject><subject>DNA - chemistry</subject><subject>Drug Design</subject><subject>Drug Screening Assays, Antitumor</subject><subject>General aspects</subject><subject>Humans</subject><subject>Indoles - chemical synthesis</subject><subject>Indoles - chemistry</subject><subject>Indoles - pharmacology</subject><subject>Medical sciences</subject><subject>Melanoma</subject><subject>Membrane Potentials - drug effects</subject><subject>Mitochondrial Membranes - drug effects</subject><subject>Mitochondrial Membranes - physiology</subject><subject>Models, Molecular</subject><subject>Pharmacology. Drug treatments</subject><subject>Pyrroles - chemical synthesis</subject><subject>Pyrroles - chemistry</subject><subject>Pyrroles - pharmacology</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><recordid>eNqFkU9vEzEQxS1ERdPAgS-AfAEJKQv-s-vdPaahhaoVFLVIiKqyvN5xcNjYqb2LSNUPX5dEzQWJ04w0v3maeQ-hl5S8o4TR94slKUhdiJsnaEQLRrK8IvlTNCKEsYwJxvfRQYwLQginjD9D-1QkglVkhO4-QLRzN8EXa9f_TH2cYOVafGh95-dWqw4f_VbdoHrrHfYGn69DSKMrNqGZvr6ik_y6AXfrW6tuYWUd_F0_ca3vAM-8Wwxz1UPEKuKp65Og0xDwdA6uj8_RnlFdhBfbOkbfjo8uZ5-ysy8fT2bTs0zllPUZhapQuioJaEZZQSrTCFWKqmpImdetZrXgTdXQtlXATWG4YEaXYFpGGyiqmo_Rm43uKvibAWIvlzZq6DrlwA9RilKIZJP4L0hrXnNGywS-3YA6-BgDGLkKdqnCWlIiHzKRj5kk9tVWdGiW0O7IbQgJeL0FVEyGm5A8snHHlQXPH4Ibo2zD2djDn8e5Cr_SB7ws5OX5haQ_vovP7OupPNzpKh3lwg_BJZP_ceA9mE2vIA</recordid><startdate>20060223</startdate><enddate>20060223</enddate><creator>Wang, Jeh-Jeng</creator><creator>Shen, Yu-Kai</creator><creator>Hu, Wan-Ping</creator><creator>Hsieh, Ming-Chu</creator><creator>Lin, Fu-Lung</creator><creator>Hsu, Ming-Kuan</creator><creator>Hsu, Mei-Hui</creator><general>American Chemical Society</general><scope>BSCLL</scope><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>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20060223</creationdate><title>Design, Synthesis, and Biological Evaluation of Pyrrolo[2,1-c][1,4]benzodiazepine and Indole Conjugates as Anticancer Agents</title><author>Wang, Jeh-Jeng ; Shen, Yu-Kai ; Hu, Wan-Ping ; Hsieh, Ming-Chu ; Lin, Fu-Lung ; Hsu, Ming-Kuan ; Hsu, Mei-Hui</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a412t-1e85ac870ec212508fb6a7688b0749dc2963b8b1ddae3f5f362fc7efd21be5893</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis</topic><topic>Benzodiazepines - chemical synthesis</topic><topic>Benzodiazepines - chemistry</topic><topic>Benzodiazepines - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Cell Cycle - drug effects</topic><topic>Cell Line, Tumor</topic><topic>DNA - chemistry</topic><topic>Drug Design</topic><topic>Drug Screening Assays, Antitumor</topic><topic>General aspects</topic><topic>Humans</topic><topic>Indoles - chemical synthesis</topic><topic>Indoles - chemistry</topic><topic>Indoles - pharmacology</topic><topic>Medical sciences</topic><topic>Melanoma</topic><topic>Membrane Potentials - drug effects</topic><topic>Mitochondrial Membranes - drug effects</topic><topic>Mitochondrial Membranes - physiology</topic><topic>Models, Molecular</topic><topic>Pharmacology. Drug treatments</topic><topic>Pyrroles - chemical synthesis</topic><topic>Pyrroles - chemistry</topic><topic>Pyrroles - pharmacology</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Jeh-Jeng</creatorcontrib><creatorcontrib>Shen, Yu-Kai</creatorcontrib><creatorcontrib>Hu, Wan-Ping</creatorcontrib><creatorcontrib>Hsieh, Ming-Chu</creatorcontrib><creatorcontrib>Lin, Fu-Lung</creatorcontrib><creatorcontrib>Hsu, Ming-Kuan</creatorcontrib><creatorcontrib>Hsu, Mei-Hui</creatorcontrib><collection>Istex</collection><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>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Jeh-Jeng</au><au>Shen, Yu-Kai</au><au>Hu, Wan-Ping</au><au>Hsieh, Ming-Chu</au><au>Lin, Fu-Lung</au><au>Hsu, Ming-Kuan</au><au>Hsu, Mei-Hui</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design, Synthesis, and Biological Evaluation of Pyrrolo[2,1-c][1,4]benzodiazepine and Indole Conjugates as Anticancer Agents</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2006-02-23</date><risdate>2006</risdate><volume>49</volume><issue>4</issue><spage>1442</spage><epage>1449</epage><pages>1442-1449</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><notes>istex:3F37EA164436417248D3A03A668A8A06859CA9FF</notes><notes>ark:/67375/TPS-1ZX6N2QK-B</notes><notes>ObjectType-Article-2</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-1</notes><notes>content type line 23</notes><notes>ObjectType-Article-1</notes><notes>ObjectType-Feature-2</notes><abstract>A series of novel pyrrolo[2,1-c][1,4]benzodiazepine (PBD) hybrids linked with indole carboxylates is described. These compounds were prepared by linking C-8 of 3 (DC-81) with an indole 2-carbonyl moiety (9) through carbon chain linkers to afford PBD hybrid agents 17−21 in good yields. Preliminary in vivo tests show that these hybrid agents have potent antitumor activity. The cytotoxic studies of the hybrid agents on human melanoma A2058 cells indicate most of the hybrids induced higher cytotoxicity, better DNA-binding ability, an increase in the apoptotic sub-G1 population, and a significant reduction in ΔΨmt relative to compound 3. In addition, DNA flow cytometric analysis shows that hybrids actively induce a marked loss of cells from the G2/M phase of the cell cycle, which progresses to early apoptosis as detected by flow cytometry after double-staining with annexin V and propidium iodide (PI). Thus, we suggest that the hybrid agents are potent inducers of cell apoptosis in A2058 cells.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>16480280</pmid><doi>10.1021/jm050956q</doi><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2006-02, Vol.49 (4), p.1442-1449 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_67662626 |
| source | American Chemical Society:Jisc Collections:American Chemical Society Read & Publish Agreement 2022-2024 (Reading list) |
| subjects | Antineoplastic agents Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Apoptosis Benzodiazepines - chemical synthesis Benzodiazepines - chemistry Benzodiazepines - pharmacology Biological and medical sciences Cell Cycle - drug effects Cell Line, Tumor DNA - chemistry Drug Design Drug Screening Assays, Antitumor General aspects Humans Indoles - chemical synthesis Indoles - chemistry Indoles - pharmacology Medical sciences Melanoma Membrane Potentials - drug effects Mitochondrial Membranes - drug effects Mitochondrial Membranes - physiology Models, Molecular Pharmacology. Drug treatments Pyrroles - chemical synthesis Pyrroles - chemistry Pyrroles - pharmacology Structure-Activity Relationship |
| title | Design, Synthesis, and Biological Evaluation of Pyrrolo[2,1-c][1,4]benzodiazepine and Indole Conjugates as Anticancer Agents |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-09-21T16%3A53%3A45IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Design,%20Synthesis,%20and%20Biological%20Evaluation%20of%20Pyrrolo%5B2,1-c%5D%5B1,4%5Dbenzodiazepine%20and%20Indole%20Conjugates%20as%20Anticancer%20Agents&rft.jtitle=Journal%20of%20medicinal%20chemistry&rft.au=Wang,%20Jeh-Jeng&rft.date=2006-02-23&rft.volume=49&rft.issue=4&rft.spage=1442&rft.epage=1449&rft.pages=1442-1449&rft.issn=0022-2623&rft.eissn=1520-4804&rft.coden=JMCMAR&rft_id=info:doi/10.1021/jm050956q&rft_dat=%3Cproquest_cross%3E67662626%3C/proquest_cross%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-a412t-1e85ac870ec212508fb6a7688b0749dc2963b8b1ddae3f5f362fc7efd21be5893%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=19393217&rft_id=info:pmid/16480280&rfr_iscdi=true |