Mechanism-Guided Design and Synthesis of a Mitochondria-Targeting Artemisinin Analogue with Enhanced Anticancer Activity
Understanding the mechanism of action (MOA) of bioactive natural products will guide endeavor to improve their cellular activities. Artemisinin and its derivatives inhibit cancer cell proliferation, yet with much lower efficiencies than their roles in killing malaria parasites. To improve their effi...
Gespeichert in:
| Veröffentlicht in: | Angewandte Chemie International Edition 2016-10, Vol.55 (44), p.13770-13774 |
|---|---|
| Hauptverfasser: | , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 13774 |
|---|---|
| container_issue | 44 |
| container_start_page | 13770 |
| container_title | Angewandte Chemie International Edition |
| container_volume | 55 |
| creator | Zhang, Chong-Jing Wang, Jigang Zhang, Jianbin Lee, Yew Mun Feng, Guangxue Lim, Teck Kwang Shen, Han-Ming Lin, Qingsong Liu, Bin |
| description | Understanding the mechanism of action (MOA) of bioactive natural products will guide endeavor to improve their cellular activities. Artemisinin and its derivatives inhibit cancer cell proliferation, yet with much lower efficiencies than their roles in killing malaria parasites. To improve their efficacies on cancer cells, we studied the MOA of artemisinin using chemical proteomics and found that free heme could directly activate artemisinin. We then designed and synthesized a derivative, ART‐TPP, which is capable of targeting the drug to mitochondria where free heme is synthesized. Remarkably, ART‐TPP exerted more potent inhibition than its parent compound to cancer cells. A clickable probe ART‐TPP‐Alk was also employed to confirm that the attachment of the TPP group could label more mitochondrial proteins than that for the ART derivative without TPP (AP1). This work shows the importance of MOA study, which enables us to optimize the design of natural drug analogues to improve their biological activities.
A mechanism of action (MOA) study by chemical proteomics indicates that free heme plays a decisive role in the activation of artemisinin in cancer cells. Guided by this MOA, a mitochondria targeting analogue (ART‐TPP; see picture) was developed that shows remarkable anticancer activities. |
| doi_str_mv | 10.1002/anie.201607303 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_journals_1907284528</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>4221679761</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4763-c59b65500657726de54c6f4874be2568924f9aa8bb274d758c65a964d2d44dd53</originalsourceid><addsrcrecordid>eNqFkU1PGzEURa2qFVBg22VlqetJPf6e5RTSgAQUBFUlNpbH9iSmiYfankL-PY5Co67alZ-lc4-e3gXgQ40mNUL4sw7eTTCqORIEkTfgoGa4rogQ5G2ZKSGVkKzeB-9Teii8lIjvgX0sBGokIQfg-dKZRZGkVTUbvXUWnrrk5wHqYOHtOuRF-SY49FDDS58HsxiCjV5XdzrOXfZhDtuY3conH3yAbdDLYT46-OTzAk5DUZvibEP2ZjNG2Jrsf_u8PgLver1M7vj1PQTfv07vTs6qi2-z85P2ojJUcFIZ1nScMYQ4EwJz6xg1vKdS0M5hxmWDad9oLbsOC2oFk4Yz3XBqsaXUWkYOwaet9zEOv0aXsnoYxljWTKpukMCSMiz_SUmCeLkqIoWabCkTh5Si69Vj9Csd16pGalOH2tShdnWUwMdX7ditnN3hf-5fgGYLPPmlW_9Hp9qr8-nf8mqb9Sm7511Wx5-KCyKY-nE1Uzf3zfX9zS1SX8gL59uldQ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1830615203</pqid></control><display><type>article</type><title>Mechanism-Guided Design and Synthesis of a Mitochondria-Targeting Artemisinin Analogue with Enhanced Anticancer Activity</title><source>Wiley Online Library Journals Frontfile Complete</source><creator>Zhang, Chong-Jing ; Wang, Jigang ; Zhang, Jianbin ; Lee, Yew Mun ; Feng, Guangxue ; Lim, Teck Kwang ; Shen, Han-Ming ; Lin, Qingsong ; Liu, Bin</creator><creatorcontrib>Zhang, Chong-Jing ; Wang, Jigang ; Zhang, Jianbin ; Lee, Yew Mun ; Feng, Guangxue ; Lim, Teck Kwang ; Shen, Han-Ming ; Lin, Qingsong ; Liu, Bin</creatorcontrib><description>Understanding the mechanism of action (MOA) of bioactive natural products will guide endeavor to improve their cellular activities. Artemisinin and its derivatives inhibit cancer cell proliferation, yet with much lower efficiencies than their roles in killing malaria parasites. To improve their efficacies on cancer cells, we studied the MOA of artemisinin using chemical proteomics and found that free heme could directly activate artemisinin. We then designed and synthesized a derivative, ART‐TPP, which is capable of targeting the drug to mitochondria where free heme is synthesized. Remarkably, ART‐TPP exerted more potent inhibition than its parent compound to cancer cells. A clickable probe ART‐TPP‐Alk was also employed to confirm that the attachment of the TPP group could label more mitochondrial proteins than that for the ART derivative without TPP (AP1). This work shows the importance of MOA study, which enables us to optimize the design of natural drug analogues to improve their biological activities.
A mechanism of action (MOA) study by chemical proteomics indicates that free heme plays a decisive role in the activation of artemisinin in cancer cells. Guided by this MOA, a mitochondria targeting analogue (ART‐TPP; see picture) was developed that shows remarkable anticancer activities.</description><edition>International ed. in English</edition><identifier>ISSN: 1433-7851</identifier><identifier>EISSN: 1521-3773</identifier><identifier>DOI: 10.1002/anie.201607303</identifier><identifier>PMID: 27709833</identifier><identifier>CODEN: ACIEAY</identifier><language>eng</language><publisher>Germany: Blackwell Publishing Ltd</publisher><subject>Analogs ; anticancer activity ; Anticancer properties ; Antitumor activity ; Artemisinin ; Attachment ; Biocompatibility ; Biomedical materials ; Cancer ; Cell proliferation ; Derivatives ; Design ; Design improvements ; Design optimization ; drug delivery ; Drug development ; fluorescent probe ; Heme ; Inhibition ; Malaria ; Mitochondria ; mitochondria targeting ; Natural products ; Parasites ; Proteins ; Proteomics ; Surgical implants ; Transcription factors ; triphenylphosphonium ; Vector-borne diseases</subject><ispartof>Angewandte Chemie International Edition, 2016-10, Vol.55 (44), p.13770-13774</ispartof><rights>2016 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim</rights><rights>2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.</rights><rights>2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4763-c59b65500657726de54c6f4874be2568924f9aa8bb274d758c65a964d2d44dd53</citedby><cites>FETCH-LOGICAL-c4763-c59b65500657726de54c6f4874be2568924f9aa8bb274d758c65a964d2d44dd53</cites><orcidid>0000-0003-4529-4906</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fanie.201607303$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fanie.201607303$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27709833$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Chong-Jing</creatorcontrib><creatorcontrib>Wang, Jigang</creatorcontrib><creatorcontrib>Zhang, Jianbin</creatorcontrib><creatorcontrib>Lee, Yew Mun</creatorcontrib><creatorcontrib>Feng, Guangxue</creatorcontrib><creatorcontrib>Lim, Teck Kwang</creatorcontrib><creatorcontrib>Shen, Han-Ming</creatorcontrib><creatorcontrib>Lin, Qingsong</creatorcontrib><creatorcontrib>Liu, Bin</creatorcontrib><title>Mechanism-Guided Design and Synthesis of a Mitochondria-Targeting Artemisinin Analogue with Enhanced Anticancer Activity</title><title>Angewandte Chemie International Edition</title><addtitle>Angew. Chem. Int. Ed</addtitle><description>Understanding the mechanism of action (MOA) of bioactive natural products will guide endeavor to improve their cellular activities. Artemisinin and its derivatives inhibit cancer cell proliferation, yet with much lower efficiencies than their roles in killing malaria parasites. To improve their efficacies on cancer cells, we studied the MOA of artemisinin using chemical proteomics and found that free heme could directly activate artemisinin. We then designed and synthesized a derivative, ART‐TPP, which is capable of targeting the drug to mitochondria where free heme is synthesized. Remarkably, ART‐TPP exerted more potent inhibition than its parent compound to cancer cells. A clickable probe ART‐TPP‐Alk was also employed to confirm that the attachment of the TPP group could label more mitochondrial proteins than that for the ART derivative without TPP (AP1). This work shows the importance of MOA study, which enables us to optimize the design of natural drug analogues to improve their biological activities.
A mechanism of action (MOA) study by chemical proteomics indicates that free heme plays a decisive role in the activation of artemisinin in cancer cells. Guided by this MOA, a mitochondria targeting analogue (ART‐TPP; see picture) was developed that shows remarkable anticancer activities.</description><subject>Analogs</subject><subject>anticancer activity</subject><subject>Anticancer properties</subject><subject>Antitumor activity</subject><subject>Artemisinin</subject><subject>Attachment</subject><subject>Biocompatibility</subject><subject>Biomedical materials</subject><subject>Cancer</subject><subject>Cell proliferation</subject><subject>Derivatives</subject><subject>Design</subject><subject>Design improvements</subject><subject>Design optimization</subject><subject>drug delivery</subject><subject>Drug development</subject><subject>fluorescent probe</subject><subject>Heme</subject><subject>Inhibition</subject><subject>Malaria</subject><subject>Mitochondria</subject><subject>mitochondria targeting</subject><subject>Natural products</subject><subject>Parasites</subject><subject>Proteins</subject><subject>Proteomics</subject><subject>Surgical implants</subject><subject>Transcription factors</subject><subject>triphenylphosphonium</subject><subject>Vector-borne diseases</subject><issn>1433-7851</issn><issn>1521-3773</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><recordid>eNqFkU1PGzEURa2qFVBg22VlqetJPf6e5RTSgAQUBFUlNpbH9iSmiYfankL-PY5Co67alZ-lc4-e3gXgQ40mNUL4sw7eTTCqORIEkTfgoGa4rogQ5G2ZKSGVkKzeB-9Teii8lIjvgX0sBGokIQfg-dKZRZGkVTUbvXUWnrrk5wHqYOHtOuRF-SY49FDDS58HsxiCjV5XdzrOXfZhDtuY3conH3yAbdDLYT46-OTzAk5DUZvibEP2ZjNG2Jrsf_u8PgLver1M7vj1PQTfv07vTs6qi2-z85P2ojJUcFIZ1nScMYQ4EwJz6xg1vKdS0M5hxmWDad9oLbsOC2oFk4Yz3XBqsaXUWkYOwaet9zEOv0aXsnoYxljWTKpukMCSMiz_SUmCeLkqIoWabCkTh5Si69Vj9Csd16pGalOH2tShdnWUwMdX7ditnN3hf-5fgGYLPPmlW_9Hp9qr8-nf8mqb9Sm7511Wx5-KCyKY-nE1Uzf3zfX9zS1SX8gL59uldQ</recordid><startdate>20161024</startdate><enddate>20161024</enddate><creator>Zhang, Chong-Jing</creator><creator>Wang, Jigang</creator><creator>Zhang, Jianbin</creator><creator>Lee, Yew Mun</creator><creator>Feng, Guangxue</creator><creator>Lim, Teck Kwang</creator><creator>Shen, Han-Ming</creator><creator>Lin, Qingsong</creator><creator>Liu, Bin</creator><general>Blackwell Publishing Ltd</general><general>Wiley Subscription Services, Inc</general><scope>BSCLL</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TM</scope><scope>K9.</scope><orcidid>https://orcid.org/0000-0003-4529-4906</orcidid></search><sort><creationdate>20161024</creationdate><title>Mechanism-Guided Design and Synthesis of a Mitochondria-Targeting Artemisinin Analogue with Enhanced Anticancer Activity</title><author>Zhang, Chong-Jing ; Wang, Jigang ; Zhang, Jianbin ; Lee, Yew Mun ; Feng, Guangxue ; Lim, Teck Kwang ; Shen, Han-Ming ; Lin, Qingsong ; Liu, Bin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4763-c59b65500657726de54c6f4874be2568924f9aa8bb274d758c65a964d2d44dd53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Analogs</topic><topic>anticancer activity</topic><topic>Anticancer properties</topic><topic>Antitumor activity</topic><topic>Artemisinin</topic><topic>Attachment</topic><topic>Biocompatibility</topic><topic>Biomedical materials</topic><topic>Cancer</topic><topic>Cell proliferation</topic><topic>Derivatives</topic><topic>Design</topic><topic>Design improvements</topic><topic>Design optimization</topic><topic>drug delivery</topic><topic>Drug development</topic><topic>fluorescent probe</topic><topic>Heme</topic><topic>Inhibition</topic><topic>Malaria</topic><topic>Mitochondria</topic><topic>mitochondria targeting</topic><topic>Natural products</topic><topic>Parasites</topic><topic>Proteins</topic><topic>Proteomics</topic><topic>Surgical implants</topic><topic>Transcription factors</topic><topic>triphenylphosphonium</topic><topic>Vector-borne diseases</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Chong-Jing</creatorcontrib><creatorcontrib>Wang, Jigang</creatorcontrib><creatorcontrib>Zhang, Jianbin</creatorcontrib><creatorcontrib>Lee, Yew Mun</creatorcontrib><creatorcontrib>Feng, Guangxue</creatorcontrib><creatorcontrib>Lim, Teck Kwang</creatorcontrib><creatorcontrib>Shen, Han-Ming</creatorcontrib><creatorcontrib>Lin, Qingsong</creatorcontrib><creatorcontrib>Liu, Bin</creatorcontrib><collection>Istex</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><jtitle>Angewandte Chemie International Edition</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Chong-Jing</au><au>Wang, Jigang</au><au>Zhang, Jianbin</au><au>Lee, Yew Mun</au><au>Feng, Guangxue</au><au>Lim, Teck Kwang</au><au>Shen, Han-Ming</au><au>Lin, Qingsong</au><au>Liu, Bin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mechanism-Guided Design and Synthesis of a Mitochondria-Targeting Artemisinin Analogue with Enhanced Anticancer Activity</atitle><jtitle>Angewandte Chemie International Edition</jtitle><addtitle>Angew. Chem. Int. Ed</addtitle><date>2016-10-24</date><risdate>2016</risdate><volume>55</volume><issue>44</issue><spage>13770</spage><epage>13774</epage><pages>13770-13774</pages><issn>1433-7851</issn><eissn>1521-3773</eissn><coden>ACIEAY</coden><abstract>Understanding the mechanism of action (MOA) of bioactive natural products will guide endeavor to improve their cellular activities. Artemisinin and its derivatives inhibit cancer cell proliferation, yet with much lower efficiencies than their roles in killing malaria parasites. To improve their efficacies on cancer cells, we studied the MOA of artemisinin using chemical proteomics and found that free heme could directly activate artemisinin. We then designed and synthesized a derivative, ART‐TPP, which is capable of targeting the drug to mitochondria where free heme is synthesized. Remarkably, ART‐TPP exerted more potent inhibition than its parent compound to cancer cells. A clickable probe ART‐TPP‐Alk was also employed to confirm that the attachment of the TPP group could label more mitochondrial proteins than that for the ART derivative without TPP (AP1). This work shows the importance of MOA study, which enables us to optimize the design of natural drug analogues to improve their biological activities.
A mechanism of action (MOA) study by chemical proteomics indicates that free heme plays a decisive role in the activation of artemisinin in cancer cells. Guided by this MOA, a mitochondria targeting analogue (ART‐TPP; see picture) was developed that shows remarkable anticancer activities.</abstract><cop>Germany</cop><pub>Blackwell Publishing Ltd</pub><pmid>27709833</pmid><doi>10.1002/anie.201607303</doi><tpages>5</tpages><edition>International ed. in English</edition><orcidid>https://orcid.org/0000-0003-4529-4906</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1433-7851 |
| ispartof | Angewandte Chemie International Edition, 2016-10, Vol.55 (44), p.13770-13774 |
| issn | 1433-7851 1521-3773 |
| language | eng |
| recordid | cdi_proquest_journals_1907284528 |
| source | Wiley Online Library Journals Frontfile Complete |
| subjects | Analogs anticancer activity Anticancer properties Antitumor activity Artemisinin Attachment Biocompatibility Biomedical materials Cancer Cell proliferation Derivatives Design Design improvements Design optimization drug delivery Drug development fluorescent probe Heme Inhibition Malaria Mitochondria mitochondria targeting Natural products Parasites Proteins Proteomics Surgical implants Transcription factors triphenylphosphonium Vector-borne diseases |
| title | Mechanism-Guided Design and Synthesis of a Mitochondria-Targeting Artemisinin Analogue with Enhanced Anticancer Activity |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-04T22%3A22%3A32IST&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=Mechanism-Guided%20Design%20and%20Synthesis%20of%20a%20Mitochondria-Targeting%20Artemisinin%20Analogue%20with%20Enhanced%20Anticancer%20Activity&rft.jtitle=Angewandte%20Chemie%20International%20Edition&rft.au=Zhang,%20Chong-Jing&rft.date=2016-10-24&rft.volume=55&rft.issue=44&rft.spage=13770&rft.epage=13774&rft.pages=13770-13774&rft.issn=1433-7851&rft.eissn=1521-3773&rft.coden=ACIEAY&rft_id=info:doi/10.1002/anie.201607303&rft_dat=%3Cproquest_cross%3E4221679761%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1830615203&rft_id=info:pmid/27709833&rfr_iscdi=true |