Synthesis and Characterization of a Cobalamin−Colchicine Conjugate as a Novel Tumor-Targeted Cytotoxin
Colchicine was derivatized at C7 with p-alkoxyacetophenone and conjugated to cobalamin (vitamin B12) through an acid-labile hydrazone linker. The cobalamin moiety leads to preferential uptake of the cobalamin−colchicine prodrug by cancer cells, whereupon the hydrazone linker undergoes hydrolysis in...
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| Veröffentlicht in: | Journal of organic chemistry 2004-12, Vol.69 (26), p.8987-8996 |
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| container_end_page | 8996 |
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| container_issue | 26 |
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| container_title | Journal of organic chemistry |
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| creator | Bagnato, Joshua D Eilers, Alanna L Horton, Robert A Grissom, Charles B |
| description | Colchicine was derivatized at C7 with p-alkoxyacetophenone and conjugated to cobalamin (vitamin B12) through an acid-labile hydrazone linker. The cobalamin moiety leads to preferential uptake of the cobalamin−colchicine prodrug by cancer cells, whereupon the hydrazone linker undergoes hydrolysis in the lysosome to unmask colchicine, which acts as a potent cytotoxin by stabilizing microtubules and causing cell death. The bioconjugate is stable in cell culture media and at neutral pH but undergoes hydrolysis with a half-life of 138 min at pH 4.5. The colchicine−cobalamin bioconjugate exhibits nanomolar LC50 values against breast, brain, and melanoma cancer cell lines in culture. Attachment of colchicine to cobalamin is expected to increase the therapeutic index of the drug by limiting the side effects caused by the current nonselective administration of tubulin-targeted chemotherapeutic drugs. |
| doi_str_mv | 10.1021/jo049953w |
| format | Article |
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The cobalamin moiety leads to preferential uptake of the cobalamin−colchicine prodrug by cancer cells, whereupon the hydrazone linker undergoes hydrolysis in the lysosome to unmask colchicine, which acts as a potent cytotoxin by stabilizing microtubules and causing cell death. The bioconjugate is stable in cell culture media and at neutral pH but undergoes hydrolysis with a half-life of 138 min at pH 4.5. The colchicine−cobalamin bioconjugate exhibits nanomolar LC50 values against breast, brain, and melanoma cancer cell lines in culture. 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Org. Chem</addtitle><description>Colchicine was derivatized at C7 with p-alkoxyacetophenone and conjugated to cobalamin (vitamin B12) through an acid-labile hydrazone linker. The cobalamin moiety leads to preferential uptake of the cobalamin−colchicine prodrug by cancer cells, whereupon the hydrazone linker undergoes hydrolysis in the lysosome to unmask colchicine, which acts as a potent cytotoxin by stabilizing microtubules and causing cell death. The bioconjugate is stable in cell culture media and at neutral pH but undergoes hydrolysis with a half-life of 138 min at pH 4.5. The colchicine−cobalamin bioconjugate exhibits nanomolar LC50 values against breast, brain, and melanoma cancer cell lines in culture. Attachment of colchicine to cobalamin is expected to increase the therapeutic index of the drug by limiting the side effects caused by the current nonselective administration of tubulin-targeted chemotherapeutic drugs.</description><subject>Alicyclic compounds</subject><subject>Alicyclic compounds, terpenoids, prostaglandins, steroids</subject><subject>Cell Line, Tumor</subject><subject>Chemistry</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Colchicine - chemistry</subject><subject>Cytotoxins - chemical synthesis</subject><subject>Cytotoxins - chemistry</subject><subject>Cytotoxins - pharmacokinetics</subject><subject>Cytotoxins - pharmacology</subject><subject>Exact sciences and technology</subject><subject>Half-Life</subject><subject>Humans</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Organic chemistry</subject><subject>Preparations and properties</subject><subject>Vitamin B 12 - chemistry</subject><issn>0022-3263</issn><issn>1520-6904</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkM-O0zAQhy0EYsvCgRdAuXDgEBjbcRIfUcSflVaA1MKBSzRxxluX1F7ZLmx5As77iDwJWbXaXpjLSDPf_DT6GHvO4TUHwd9sAlRaK_nrAVtwJaCsNVQP2QJAiFKKWp6xJyltYC6l1GN2xlUNWktYsPVy7_OakksF-rHo1hjRZIruN2YXfBFsgUUXBpxw6_zfP7ddmMzaGedpHvvN7gozFThfF5_CT5qK1W4bYrnCeEWZ5sB9DjncOP-UPbI4JXp27Ofs6_t3q-5jefn5w0X39rLEqmpyWQHnY90CCmNbBVS1JFtujQWLnGsrkQZuCASSHoeGRkIOdpBj1dhBDyjP2atDrokhpUi2v45ui3Hfc-jvbPX3tmb2xYG93g1bGk_kUc8MvDwCmAxONqI3Lp24WtaqFndceeBcynRzv8f4o68b2ah-9WXZy-_fRLPUsm9PuWjS_M8u-lnJfx78B5HDkEU</recordid><startdate>20041224</startdate><enddate>20041224</enddate><creator>Bagnato, Joshua D</creator><creator>Eilers, Alanna L</creator><creator>Horton, Robert A</creator><creator>Grissom, Charles B</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></search><sort><creationdate>20041224</creationdate><title>Synthesis and Characterization of a Cobalamin−Colchicine Conjugate as a Novel Tumor-Targeted Cytotoxin</title><author>Bagnato, Joshua D ; Eilers, Alanna L ; Horton, Robert A ; Grissom, Charles B</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a447t-4011d680a2cf850e48e381fcf0fa119f3aeb1ce02ae9db7edea10fb3d47fb9ba3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Alicyclic compounds</topic><topic>Alicyclic compounds, terpenoids, prostaglandins, steroids</topic><topic>Cell Line, Tumor</topic><topic>Chemistry</topic><topic>Chromatography, High Pressure Liquid</topic><topic>Colchicine - chemistry</topic><topic>Cytotoxins - chemical synthesis</topic><topic>Cytotoxins - chemistry</topic><topic>Cytotoxins - pharmacokinetics</topic><topic>Cytotoxins - pharmacology</topic><topic>Exact sciences and technology</topic><topic>Half-Life</topic><topic>Humans</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>Organic chemistry</topic><topic>Preparations and properties</topic><topic>Vitamin B 12 - chemistry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bagnato, Joshua D</creatorcontrib><creatorcontrib>Eilers, Alanna L</creatorcontrib><creatorcontrib>Horton, Robert A</creatorcontrib><creatorcontrib>Grissom, Charles B</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><jtitle>Journal of organic chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bagnato, Joshua D</au><au>Eilers, Alanna L</au><au>Horton, Robert A</au><au>Grissom, Charles B</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and Characterization of a Cobalamin−Colchicine Conjugate as a Novel Tumor-Targeted Cytotoxin</atitle><jtitle>Journal of organic chemistry</jtitle><addtitle>J. Org. Chem</addtitle><date>2004-12-24</date><risdate>2004</risdate><volume>69</volume><issue>26</issue><spage>8987</spage><epage>8996</epage><pages>8987-8996</pages><issn>0022-3263</issn><eissn>1520-6904</eissn><coden>JOCEAH</coden><abstract>Colchicine was derivatized at C7 with p-alkoxyacetophenone and conjugated to cobalamin (vitamin B12) through an acid-labile hydrazone linker. The cobalamin moiety leads to preferential uptake of the cobalamin−colchicine prodrug by cancer cells, whereupon the hydrazone linker undergoes hydrolysis in the lysosome to unmask colchicine, which acts as a potent cytotoxin by stabilizing microtubules and causing cell death. The bioconjugate is stable in cell culture media and at neutral pH but undergoes hydrolysis with a half-life of 138 min at pH 4.5. The colchicine−cobalamin bioconjugate exhibits nanomolar LC50 values against breast, brain, and melanoma cancer cell lines in culture. 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| ispartof | Journal of organic chemistry, 2004-12, Vol.69 (26), p.8987-8996 |
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| source | MEDLINE; ACS Publications |
| subjects | Alicyclic compounds Alicyclic compounds, terpenoids, prostaglandins, steroids Cell Line, Tumor Chemistry Chromatography, High Pressure Liquid Colchicine - chemistry Cytotoxins - chemical synthesis Cytotoxins - chemistry Cytotoxins - pharmacokinetics Cytotoxins - pharmacology Exact sciences and technology Half-Life Humans Magnetic Resonance Spectroscopy Organic chemistry Preparations and properties Vitamin B 12 - chemistry |
| title | Synthesis and Characterization of a Cobalamin−Colchicine Conjugate as a Novel Tumor-Targeted Cytotoxin |
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