Synthesis and Biological Evaluation of Novel Triple-Modified Colchicine Derivatives as Potent Tubulin-Targeting Anticancer Agents
Specific modifications of colchicine followed by synthesis of its analogues have been tested in vitro with the objective of lowering colchicine toxicity. Our previous studies have clearly shown the anticancer potential of double-modified colchicine derivatives in C-7 and C-10 positions. Here, a seri...
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| Format: | Article |
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MDPI AG
2018-11-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/7/11/216 |
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| author | Urszula Majcher Greta Klejborowska Magdalena Kaik Ewa Maj Joanna Wietrzyk Mahshad Moshari Jordane Preto Jack A. Tuszynski Adam Huczyński |
| author_facet | Urszula Majcher Greta Klejborowska Magdalena Kaik Ewa Maj Joanna Wietrzyk Mahshad Moshari Jordane Preto Jack A. Tuszynski Adam Huczyński |
| author_sort | Urszula Majcher |
| collection | DOAJ |
| description | Specific modifications of colchicine followed by synthesis of its analogues have been tested in vitro with the objective of lowering colchicine toxicity. Our previous studies have clearly shown the anticancer potential of double-modified colchicine derivatives in C-7 and C-10 positions. Here, a series of novel triple-modified colchicine derivatives is reported. They have been obtained following a four-step strategy. In vitro cytotoxicity of these compounds has been evaluated against four human tumor cell lines (A549, MCF-7, LoVo, and LoVo/DX). Additionally, the mode of binding of the synthesized compounds was evaluated in silico using molecular docking to a 3D structure of β-tubulin based on crystallographic data from the Protein Data Bank and homology methodology. Binding free energy estimates, binding poses, and MlogP values of the compounds were obtained. All triple-modified colchicine derivatives were shown to be active at nanomolar concentrations against three of the investigated cancer cell lines (A549, MCF-7, LoVo). Four of them also showed higher potency against tumor cells over normal cells as confirmed by their high selectivity index values. A vast majority of the synthesized derivatives exhibited several times higher cytotoxicity than colchicine, doxorubicin, and cisplatin. |
| first_indexed | 2024-03-12T19:31:57Z |
| format | Article |
| id | doaj.art-d90acafa95da486eb8b4778010df8387 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T19:31:57Z |
| publishDate | 2018-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-d90acafa95da486eb8b4778010df83872023-08-02T04:28:43ZengMDPI AGCells2073-44092018-11-0171121610.3390/cells7110216cells7110216Synthesis and Biological Evaluation of Novel Triple-Modified Colchicine Derivatives as Potent Tubulin-Targeting Anticancer AgentsUrszula Majcher0Greta Klejborowska1Magdalena Kaik2Ewa Maj3Joanna Wietrzyk4Mahshad Moshari5Jordane Preto6Jack A. Tuszynski7Adam Huczyński8Department 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 Bioorganic Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614 Poznan, PolandHirszfeld 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, PolandDepertment of Chemistry, University of Alberta, Edmonton, AB T6G 1Z2, CanadaDepertment of Oncology, University of Alberta, Edmonton, AB T6G 1Z2, CanadaDepertment of Oncology, University of Alberta, Edmonton, AB T6G 1Z2, CanadaDepartment of Bioorganic Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614 Poznan, PolandSpecific modifications of colchicine followed by synthesis of its analogues have been tested in vitro with the objective of lowering colchicine toxicity. Our previous studies have clearly shown the anticancer potential of double-modified colchicine derivatives in C-7 and C-10 positions. Here, a series of novel triple-modified colchicine derivatives is reported. They have been obtained following a four-step strategy. In vitro cytotoxicity of these compounds has been evaluated against four human tumor cell lines (A549, MCF-7, LoVo, and LoVo/DX). Additionally, the mode of binding of the synthesized compounds was evaluated in silico using molecular docking to a 3D structure of β-tubulin based on crystallographic data from the Protein Data Bank and homology methodology. Binding free energy estimates, binding poses, and MlogP values of the compounds were obtained. All triple-modified colchicine derivatives were shown to be active at nanomolar concentrations against three of the investigated cancer cell lines (A549, MCF-7, LoVo). Four of them also showed higher potency against tumor cells over normal cells as confirmed by their high selectivity index values. A vast majority of the synthesized derivatives exhibited several times higher cytotoxicity than colchicine, doxorubicin, and cisplatin.https://www.mdpi.com/2073-4409/7/11/216colchicine binding site inhibitortubulin-targeting agentantimitotic agentantiproliferative activitythiocolchicinenatural compounds |
| spellingShingle | Urszula Majcher Greta Klejborowska Magdalena Kaik Ewa Maj Joanna Wietrzyk Mahshad Moshari Jordane Preto Jack A. Tuszynski Adam Huczyński Synthesis and Biological Evaluation of Novel Triple-Modified Colchicine Derivatives as Potent Tubulin-Targeting Anticancer Agents Cells colchicine binding site inhibitor tubulin-targeting agent antimitotic agent antiproliferative activity thiocolchicine natural compounds |
| title | Synthesis and Biological Evaluation of Novel Triple-Modified Colchicine Derivatives as Potent Tubulin-Targeting Anticancer Agents |
| title_full | Synthesis and Biological Evaluation of Novel Triple-Modified Colchicine Derivatives as Potent Tubulin-Targeting Anticancer Agents |
| title_fullStr | Synthesis and Biological Evaluation of Novel Triple-Modified Colchicine Derivatives as Potent Tubulin-Targeting Anticancer Agents |
| title_full_unstemmed | Synthesis and Biological Evaluation of Novel Triple-Modified Colchicine Derivatives as Potent Tubulin-Targeting Anticancer Agents |
| title_short | Synthesis and Biological Evaluation of Novel Triple-Modified Colchicine Derivatives as Potent Tubulin-Targeting Anticancer Agents |
| title_sort | synthesis and biological evaluation of novel triple modified colchicine derivatives as potent tubulin targeting anticancer agents |
| topic | colchicine binding site inhibitor tubulin-targeting agent antimitotic agent antiproliferative activity thiocolchicine natural compounds |
| url | https://www.mdpi.com/2073-4409/7/11/216 |
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