Synthesis and biological evaluation of a folate-targeted rhaponticin conjugate
Viability of FR-positive KB cells after exposure to FRHA or parental RHA or the RHA derivative (compound 2 or compound 4) with increasing concentrations in the presence or absence of 0.01mM FA (as a competitor) at 37°C for 48h. To improve the therapeutic effect of rhaponticin (RHA), a folate recepto...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2013-01, Vol.21 (1), p.178-185 |
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| creator | Liang, Xuhua Sun, Yang Zeng, Wenyuan Liu, Lusha Ma, Xuan Zhao, Yingyong Fan, Jun |
| description | Viability of FR-positive KB cells after exposure to FRHA or parental RHA or the RHA derivative (compound 2 or compound 4) with increasing concentrations in the presence or absence of 0.01mM FA (as a competitor) at 37°C for 48h.
To improve the therapeutic effect of rhaponticin (RHA), a folate receptor (FR) targeted RHA conjugate was synthesized by utilizing a hydrophilic peptide spacer linked to folic acid (FA) via a releasable disulfide linker. This water-soluble conjugate was found to retain high affinity for FR-positive cells, and it produced specific, dose-responsive activity in vitro. Treatment of FRHA with a reducing agent indicated that the amino-reactive derivative of RHA would be released spontaneously following disulfide bond reduction within the endosomes. FRHA also proved to be active predominantly specific against FR-positive syngeneic and xenograft models in vivo, and possible curative activity resulted with minimal to moderate toxicity. The FRHA conjugate greatly enhanced the therapeutic effects and reduced the toxicity of RHA. In conclusion, FRHA represents a folate-targeted chemotherapeutic that can produce potent activity against established sc tumors. Hence, this report has a great significance in pharmacology and clinical medicine as well as methodology. |
| doi_str_mv | 10.1016/j.bmc.2012.10.044 |
| format | Article |
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To improve the therapeutic effect of rhaponticin (RHA), a folate receptor (FR) targeted RHA conjugate was synthesized by utilizing a hydrophilic peptide spacer linked to folic acid (FA) via a releasable disulfide linker. This water-soluble conjugate was found to retain high affinity for FR-positive cells, and it produced specific, dose-responsive activity in vitro. Treatment of FRHA with a reducing agent indicated that the amino-reactive derivative of RHA would be released spontaneously following disulfide bond reduction within the endosomes. FRHA also proved to be active predominantly specific against FR-positive syngeneic and xenograft models in vivo, and possible curative activity resulted with minimal to moderate toxicity. The FRHA conjugate greatly enhanced the therapeutic effects and reduced the toxicity of RHA. In conclusion, FRHA represents a folate-targeted chemotherapeutic that can produce potent activity against established sc tumors. Hence, this report has a great significance in pharmacology and clinical medicine as well as methodology.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2012.10.044</identifier><identifier>PMID: 23177726</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Animals ; Anticancer ; Antineoplastic Agents - blood ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - therapeutic use ; Cell Line, Tumor ; chemotherapy ; Disulfide bonds ; endosomes ; Folate receptor ; Folate Receptors, GPI-Anchored - metabolism ; Folic acid ; Folic Acid - analogs & derivatives ; Folic Acid - blood ; Folic Acid - therapeutic use ; Humans ; hydrophilicity ; medicine ; Mice ; Mice, Inbred BALB C ; neoplasms ; Neoplasms - drug therapy ; Neoplasms - metabolism ; Pharmacology ; Reducing agents ; Rhaponticin (RHA) ; Spacer ; Stilbenes - blood ; Stilbenes - chemistry ; Stilbenes - therapeutic use ; Targeted therapeutics ; Toxicity ; Tumors ; Xenografts</subject><ispartof>Bioorganic & medicinal chemistry, 2013-01, Vol.21 (1), p.178-185</ispartof><rights>2012 Elsevier Ltd</rights><rights>Copyright © 2012 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c443t-d66da4cb62c8779225f74cff7f8a56e0117a99b529cc5c1c1d5b24bc9ca314e93</citedby><cites>FETCH-LOGICAL-c443t-d66da4cb62c8779225f74cff7f8a56e0117a99b529cc5c1c1d5b24bc9ca314e93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmc.2012.10.044$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>315,782,786,3552,4026,27930,27931,27932,46002</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23177726$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liang, Xuhua</creatorcontrib><creatorcontrib>Sun, Yang</creatorcontrib><creatorcontrib>Zeng, Wenyuan</creatorcontrib><creatorcontrib>Liu, Lusha</creatorcontrib><creatorcontrib>Ma, Xuan</creatorcontrib><creatorcontrib>Zhao, Yingyong</creatorcontrib><creatorcontrib>Fan, Jun</creatorcontrib><title>Synthesis and biological evaluation of a folate-targeted rhaponticin conjugate</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>Viability of FR-positive KB cells after exposure to FRHA or parental RHA or the RHA derivative (compound 2 or compound 4) with increasing concentrations in the presence or absence of 0.01mM FA (as a competitor) at 37°C for 48h.
To improve the therapeutic effect of rhaponticin (RHA), a folate receptor (FR) targeted RHA conjugate was synthesized by utilizing a hydrophilic peptide spacer linked to folic acid (FA) via a releasable disulfide linker. This water-soluble conjugate was found to retain high affinity for FR-positive cells, and it produced specific, dose-responsive activity in vitro. Treatment of FRHA with a reducing agent indicated that the amino-reactive derivative of RHA would be released spontaneously following disulfide bond reduction within the endosomes. FRHA also proved to be active predominantly specific against FR-positive syngeneic and xenograft models in vivo, and possible curative activity resulted with minimal to moderate toxicity. The FRHA conjugate greatly enhanced the therapeutic effects and reduced the toxicity of RHA. In conclusion, FRHA represents a folate-targeted chemotherapeutic that can produce potent activity against established sc tumors. Hence, this report has a great significance in pharmacology and clinical medicine as well as methodology.</description><subject>Animals</subject><subject>Anticancer</subject><subject>Antineoplastic Agents - blood</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Cell Line, Tumor</subject><subject>chemotherapy</subject><subject>Disulfide bonds</subject><subject>endosomes</subject><subject>Folate receptor</subject><subject>Folate Receptors, GPI-Anchored - metabolism</subject><subject>Folic acid</subject><subject>Folic Acid - analogs & derivatives</subject><subject>Folic Acid - blood</subject><subject>Folic Acid - therapeutic use</subject><subject>Humans</subject><subject>hydrophilicity</subject><subject>medicine</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>neoplasms</subject><subject>Neoplasms - drug therapy</subject><subject>Neoplasms - metabolism</subject><subject>Pharmacology</subject><subject>Reducing agents</subject><subject>Rhaponticin (RHA)</subject><subject>Spacer</subject><subject>Stilbenes - blood</subject><subject>Stilbenes - chemistry</subject><subject>Stilbenes - therapeutic use</subject><subject>Targeted therapeutics</subject><subject>Toxicity</subject><subject>Tumors</subject><subject>Xenografts</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkMFu1DAQhi0EokvhAbhAjlyy9TiOHYsTqmhBqsqh9Gw5k8nWq2y82E6lvj1epXCEkzWeb37NfIy9B74FDupiv-0PuBUcRKm3XMoXbANSybppDLxkG25UV_POqDP2JqU951xIA6_ZmWhAay3Uht3ePc35gZJPlZuHqvdhCjuPbqro0U2Lyz7MVRgrV41hcpnq7OKOMg1VfHDHMGePfq4wzPtlV9pv2avRTYnePb_n7P7q68_Lb_XNj-vvl19uapSyyfWg1OAk9kpgp7URoh21xHHUY-daRRxAO2P6VhjEFgFhaHshezToGpBkmnP2ac09xvBroZTtwSekaXIzhSVZaDkvF-pO_x8VWuimEaorKKwoxpBSpNEeoz-4-GSB25Nxu7fFuD0ZP30V42Xmw3P80h9o-DvxR3EBPq7A6IJ1u-iTvb8rCWVDAL4Sn1eCirFHT9Em9DQjDT4SZjsE_48FfgOJ7ZpG</recordid><startdate>20130101</startdate><enddate>20130101</enddate><creator>Liang, Xuhua</creator><creator>Sun, Yang</creator><creator>Zeng, Wenyuan</creator><creator>Liu, Lusha</creator><creator>Ma, Xuan</creator><creator>Zhao, Yingyong</creator><creator>Fan, Jun</creator><general>Elsevier Ltd</general><scope>FBQ</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></search><sort><creationdate>20130101</creationdate><title>Synthesis and biological evaluation of a folate-targeted rhaponticin conjugate</title><author>Liang, Xuhua ; Sun, Yang ; Zeng, Wenyuan ; Liu, Lusha ; Ma, Xuan ; Zhao, Yingyong ; Fan, Jun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c443t-d66da4cb62c8779225f74cff7f8a56e0117a99b529cc5c1c1d5b24bc9ca314e93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Anticancer</topic><topic>Antineoplastic Agents - blood</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Cell Line, Tumor</topic><topic>chemotherapy</topic><topic>Disulfide bonds</topic><topic>endosomes</topic><topic>Folate receptor</topic><topic>Folate Receptors, GPI-Anchored - metabolism</topic><topic>Folic acid</topic><topic>Folic Acid - analogs & derivatives</topic><topic>Folic Acid - blood</topic><topic>Folic Acid - therapeutic use</topic><topic>Humans</topic><topic>hydrophilicity</topic><topic>medicine</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>neoplasms</topic><topic>Neoplasms - drug therapy</topic><topic>Neoplasms - metabolism</topic><topic>Pharmacology</topic><topic>Reducing agents</topic><topic>Rhaponticin (RHA)</topic><topic>Spacer</topic><topic>Stilbenes - blood</topic><topic>Stilbenes - chemistry</topic><topic>Stilbenes - therapeutic use</topic><topic>Targeted therapeutics</topic><topic>Toxicity</topic><topic>Tumors</topic><topic>Xenografts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liang, Xuhua</creatorcontrib><creatorcontrib>Sun, Yang</creatorcontrib><creatorcontrib>Zeng, Wenyuan</creatorcontrib><creatorcontrib>Liu, Lusha</creatorcontrib><creatorcontrib>Ma, Xuan</creatorcontrib><creatorcontrib>Zhao, Yingyong</creatorcontrib><creatorcontrib>Fan, Jun</creatorcontrib><collection>AGRIS</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><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liang, Xuhua</au><au>Sun, Yang</au><au>Zeng, Wenyuan</au><au>Liu, Lusha</au><au>Ma, Xuan</au><au>Zhao, Yingyong</au><au>Fan, Jun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and biological evaluation of a folate-targeted rhaponticin conjugate</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2013-01-01</date><risdate>2013</risdate><volume>21</volume><issue>1</issue><spage>178</spage><epage>185</epage><pages>178-185</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>Viability of FR-positive KB cells after exposure to FRHA or parental RHA or the RHA derivative (compound 2 or compound 4) with increasing concentrations in the presence or absence of 0.01mM FA (as a competitor) at 37°C for 48h.
To improve the therapeutic effect of rhaponticin (RHA), a folate receptor (FR) targeted RHA conjugate was synthesized by utilizing a hydrophilic peptide spacer linked to folic acid (FA) via a releasable disulfide linker. This water-soluble conjugate was found to retain high affinity for FR-positive cells, and it produced specific, dose-responsive activity in vitro. Treatment of FRHA with a reducing agent indicated that the amino-reactive derivative of RHA would be released spontaneously following disulfide bond reduction within the endosomes. FRHA also proved to be active predominantly specific against FR-positive syngeneic and xenograft models in vivo, and possible curative activity resulted with minimal to moderate toxicity. The FRHA conjugate greatly enhanced the therapeutic effects and reduced the toxicity of RHA. In conclusion, FRHA represents a folate-targeted chemotherapeutic that can produce potent activity against established sc tumors. Hence, this report has a great significance in pharmacology and clinical medicine as well as methodology.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>23177726</pmid><doi>10.1016/j.bmc.2012.10.044</doi><tpages>8</tpages></addata></record> |
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| subjects | Animals Anticancer Antineoplastic Agents - blood Antineoplastic Agents - chemistry Antineoplastic Agents - therapeutic use Cell Line, Tumor chemotherapy Disulfide bonds endosomes Folate receptor Folate Receptors, GPI-Anchored - metabolism Folic acid Folic Acid - analogs & derivatives Folic Acid - blood Folic Acid - therapeutic use Humans hydrophilicity medicine Mice Mice, Inbred BALB C neoplasms Neoplasms - drug therapy Neoplasms - metabolism Pharmacology Reducing agents Rhaponticin (RHA) Spacer Stilbenes - blood Stilbenes - chemistry Stilbenes - therapeutic use Targeted therapeutics Toxicity Tumors Xenografts |
| title | Synthesis and biological evaluation of a folate-targeted rhaponticin conjugate |
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