Antiproliferative Activity and Molecular Docking of Novel Double-Modified Colchicine Derivatives
Microtubules are tubulin polymer structures, which are indispensable for cell growth and division. Its constituent protein β-tubulin has been a common drug target for various diseases including cancer. Colchicine has been used to treat gout, but it has also been an investigational anticance...
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MDPI AG
2018-11-01
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| Online Access: | https://www.mdpi.com/2073-4409/7/11/192 |
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| author | Urszula Majcher Greta Klejborowska Mahshad Moshari Ewa Maj Joanna Wietrzyk Franz Bartl Jack A. Tuszynski Adam Huczyński |
| author_facet | Urszula Majcher Greta Klejborowska Mahshad Moshari Ewa Maj Joanna Wietrzyk Franz Bartl Jack A. Tuszynski Adam Huczyński |
| author_sort | Urszula Majcher |
| collection | DOAJ |
| description | Microtubules are tubulin polymer structures, which are indispensable for cell growth and division. Its constituent protein β-tubulin has been a common drug target for various diseases including cancer. Colchicine has been used to treat gout, but it has also been an investigational anticancer agent with a known antimitotic effect on cells. However, the use of colchicine as well as many of its derivatives in long-term treatment is hampered by their high toxicity. To create more potent anticancer agents, three novel double-modified colchicine derivatives have been obtained by structural modifications in C-4 and C-10 positions. The binding affinities of these derivatives of colchicine with respect to eight different isotypes of human β-tubulin have been calculated using docking methods. In vitro cytotoxicity has been evaluated against four human tumor cell lines (A549, MCF-7, LoVo and LoVo/DX). Computer simulations predicted the binding modes of these compounds and hence the key residues involved in the interactions between tubulin and the colchicine derivatives. Two of the obtained derivatives, 4-bromothiocolchicine and 4-iodothiocolchicine, were shown to be active against three of the investigated cancer cell lines (A549, MCF-7, LoVo) with potency at nanomolar concentrations and a higher relative affinity to tumor cells over normal cells. |
| first_indexed | 2024-03-12T06:50:30Z |
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| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T06:50:30Z |
| publishDate | 2018-11-01 |
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| spelling | doaj.art-bc58cb3dfff04eb3b0d94f1e05f5a24c2023-09-03T00:18:54ZengMDPI AGCells2073-44092018-11-0171119210.3390/cells7110192cells7110192Antiproliferative Activity and Molecular Docking of Novel Double-Modified Colchicine DerivativesUrszula Majcher0Greta Klejborowska1Mahshad Moshari2Ewa Maj3Joanna Wietrzyk4Franz Bartl5Jack A. Tuszynski6Adam Huczyński7Department of Bioorganic Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614 Poznan, PolandDepartment of Bioorganic Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614 Poznan, PolandDepartment of Chemistry, University of Alberta, Edmonton, AB T6G 1Z2, CanadaHirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53-114 Wrocław, PolandHirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53-114 Wrocław, PolandInstitut für Biologie, AG Biophysikalische Chemie, Humboldt Universität zu Berlin, Invalidenstr, 42, 10099 Berlin, GermanyDepartment of Oncology, University of Alberta, Edmonton, AB T6G 1Z2, CanadaDepartment of Bioorganic Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614 Poznan, PolandMicrotubules are tubulin polymer structures, which are indispensable for cell growth and division. Its constituent protein β-tubulin has been a common drug target for various diseases including cancer. Colchicine has been used to treat gout, but it has also been an investigational anticancer agent with a known antimitotic effect on cells. However, the use of colchicine as well as many of its derivatives in long-term treatment is hampered by their high toxicity. To create more potent anticancer agents, three novel double-modified colchicine derivatives have been obtained by structural modifications in C-4 and C-10 positions. The binding affinities of these derivatives of colchicine with respect to eight different isotypes of human β-tubulin have been calculated using docking methods. In vitro cytotoxicity has been evaluated against four human tumor cell lines (A549, MCF-7, LoVo and LoVo/DX). Computer simulations predicted the binding modes of these compounds and hence the key residues involved in the interactions between tubulin and the colchicine derivatives. Two of the obtained derivatives, 4-bromothiocolchicine and 4-iodothiocolchicine, were shown to be active against three of the investigated cancer cell lines (A549, MCF-7, LoVo) with potency at nanomolar concentrations and a higher relative affinity to tumor cells over normal cells.https://www.mdpi.com/2073-4409/7/11/192colchicine binding site inhibitorβ-tubulin affinityantimitotic agentantiproliferative activitythiocolchicine |
| spellingShingle | Urszula Majcher Greta Klejborowska Mahshad Moshari Ewa Maj Joanna Wietrzyk Franz Bartl Jack A. Tuszynski Adam Huczyński Antiproliferative Activity and Molecular Docking of Novel Double-Modified Colchicine Derivatives Cells colchicine binding site inhibitor β-tubulin affinity antimitotic agent antiproliferative activity thiocolchicine |
| title | Antiproliferative Activity and Molecular Docking of Novel Double-Modified Colchicine Derivatives |
| title_full | Antiproliferative Activity and Molecular Docking of Novel Double-Modified Colchicine Derivatives |
| title_fullStr | Antiproliferative Activity and Molecular Docking of Novel Double-Modified Colchicine Derivatives |
| title_full_unstemmed | Antiproliferative Activity and Molecular Docking of Novel Double-Modified Colchicine Derivatives |
| title_short | Antiproliferative Activity and Molecular Docking of Novel Double-Modified Colchicine Derivatives |
| title_sort | antiproliferative activity and molecular docking of novel double modified colchicine derivatives |
| topic | colchicine binding site inhibitor β-tubulin affinity antimitotic agent antiproliferative activity thiocolchicine |
| url | https://www.mdpi.com/2073-4409/7/11/192 |
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