Colchitaxel, a coupled compound made from microtubule inhibitors colchicine and paclitaxel
Background<p>Tumor promoters enhance tumor yield in experimental animals without directly affecting the DNA of the cell. Promoters may play a role in the development of cancer, as humans are exposed to them in the environment. In work based on computer-assisted microscopy and sophisticated cla...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Beilstein-Institut
2006-06-01
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| Series: | Beilstein Journal of Organic Chemistry |
| Online Access: | https://doi.org/10.1186/1860-5397-2-13 |
| _version_ | 1818445091148136448 |
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| author | Karunananda Bombuwala Thomas Kinstle Vladimir Popik Sonal O. Uppal James B. Olesen Jose Viña Carol A. Heckman |
| author_facet | Karunananda Bombuwala Thomas Kinstle Vladimir Popik Sonal O. Uppal James B. Olesen Jose Viña Carol A. Heckman |
| author_sort | Karunananda Bombuwala |
| collection | DOAJ |
| description | Background<p>Tumor promoters enhance tumor yield in experimental animals without directly affecting the DNA of the cell. Promoters may play a role in the development of cancer, as humans are exposed to them in the environment. In work based on computer-assisted microscopy and sophisticated classification methods, we showed that cells could be classified by reference to a database of known normal and cancerous cell phenotypes. Promoters caused loss of properties specific to normal cells and gain of properties of cancer cells. Other compounds, including colchicine, had a similar effect. Colchicine given together with paclitaxel, however, caused cells to adopt properties of normal cells. This provided a rationale for tests of microtubule inhibitor combinations in cancer patients. The combination of a depolymerizing and a stabilizing agent is a superior anti-tumor treatment. The biological basis of the effect is not understood.</p><p>Results</p><p>A single compound containing both colchicine and paclitaxel structures was synthesized. Colchicine is an alkaloid with a trimethoxyphenyl ring (ring A), a ring with an acetamide linkage (ring B), and a tropolone ring (ring C). Although rings A and C are important for tubulin-binding activity, the acetamide linkage on ring B could be replaced by an amide containing a glutamate linker. Alteration of the C-7 site on paclitaxel similarly had little or no inhibitory effect on its biological activity. The linker was attached to this position. The coupled compound, colchitaxel (1), had some of the same effects on microtubules as the combination of starting compounds. It also caused shortening and fragmentation of the + end protein cap.</p><p>Conclusion</p><p>Since microtubule inhibitor combinations give results unlike those obtained with either inhibitor alone, it is important to determine how such combinations affect cell shape and growth. Colchitaxel shows a subset of the effects of the inhibitor combination. Thus, it may be able to bind the relevant cellular target of the combination. It will be useful to determine the basis of the shape reversal effect and possibly, the reasons for therapeutic efficacy of microtubule inhibitor combinations.</p> |
| first_indexed | 2024-12-14T19:26:19Z |
| format | Article |
| id | doaj.art-32e97f442cec4b1abd7e7b39e1783d8f |
| institution | Directory Open Access Journal |
| issn | 1860-5397 |
| language | English |
| last_indexed | 2024-12-14T19:26:19Z |
| publishDate | 2006-06-01 |
| publisher | Beilstein-Institut |
| record_format | Article |
| series | Beilstein Journal of Organic Chemistry |
| spelling | doaj.art-32e97f442cec4b1abd7e7b39e1783d8f2022-12-21T22:50:12ZengBeilstein-InstitutBeilstein Journal of Organic Chemistry1860-53972006-06-01211310.1186/1860-5397-2-131860-5397-2-13Colchitaxel, a coupled compound made from microtubule inhibitors colchicine and paclitaxelKarunananda Bombuwala0Thomas Kinstle1Vladimir Popik2Sonal O. Uppal3James B. Olesen4Jose Viña5Carol A. Heckman6Department of Chemistry, Bowling Green State University, Bowling Green, OH 43403, USADepartment of Chemistry, Bowling Green State University, Bowling Green, OH 43403, USADepartment of Chemistry, Bowling Green State University, Bowling Green, OH 43403, USADepartment of Chemistry, Bowling Green State University, Bowling Green, OH 43403, USABiology Department, Ball State University, Muncie, IN 47306, USAScientific Volume Imaging BV, Alexanderlaan 14, 1213 XS Hilversum, The NetherlandsCenter for Microscopy & Microanalysis, Bowling Green State University, Bowling Green, OH 43403, USABackground<p>Tumor promoters enhance tumor yield in experimental animals without directly affecting the DNA of the cell. Promoters may play a role in the development of cancer, as humans are exposed to them in the environment. In work based on computer-assisted microscopy and sophisticated classification methods, we showed that cells could be classified by reference to a database of known normal and cancerous cell phenotypes. Promoters caused loss of properties specific to normal cells and gain of properties of cancer cells. Other compounds, including colchicine, had a similar effect. Colchicine given together with paclitaxel, however, caused cells to adopt properties of normal cells. This provided a rationale for tests of microtubule inhibitor combinations in cancer patients. The combination of a depolymerizing and a stabilizing agent is a superior anti-tumor treatment. The biological basis of the effect is not understood.</p><p>Results</p><p>A single compound containing both colchicine and paclitaxel structures was synthesized. Colchicine is an alkaloid with a trimethoxyphenyl ring (ring A), a ring with an acetamide linkage (ring B), and a tropolone ring (ring C). Although rings A and C are important for tubulin-binding activity, the acetamide linkage on ring B could be replaced by an amide containing a glutamate linker. Alteration of the C-7 site on paclitaxel similarly had little or no inhibitory effect on its biological activity. The linker was attached to this position. The coupled compound, colchitaxel (1), had some of the same effects on microtubules as the combination of starting compounds. It also caused shortening and fragmentation of the + end protein cap.</p><p>Conclusion</p><p>Since microtubule inhibitor combinations give results unlike those obtained with either inhibitor alone, it is important to determine how such combinations affect cell shape and growth. Colchitaxel shows a subset of the effects of the inhibitor combination. Thus, it may be able to bind the relevant cellular target of the combination. It will be useful to determine the basis of the shape reversal effect and possibly, the reasons for therapeutic efficacy of microtubule inhibitor combinations.</p>https://doi.org/10.1186/1860-5397-2-13 |
| spellingShingle | Karunananda Bombuwala Thomas Kinstle Vladimir Popik Sonal O. Uppal James B. Olesen Jose Viña Carol A. Heckman Colchitaxel, a coupled compound made from microtubule inhibitors colchicine and paclitaxel Beilstein Journal of Organic Chemistry |
| title | Colchitaxel, a coupled compound made from microtubule inhibitors colchicine and paclitaxel |
| title_full | Colchitaxel, a coupled compound made from microtubule inhibitors colchicine and paclitaxel |
| title_fullStr | Colchitaxel, a coupled compound made from microtubule inhibitors colchicine and paclitaxel |
| title_full_unstemmed | Colchitaxel, a coupled compound made from microtubule inhibitors colchicine and paclitaxel |
| title_short | Colchitaxel, a coupled compound made from microtubule inhibitors colchicine and paclitaxel |
| title_sort | colchitaxel a coupled compound made from microtubule inhibitors colchicine and paclitaxel |
| url | https://doi.org/10.1186/1860-5397-2-13 |
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