Synthesis, antiproliferative activity and molecular docking of thiocolchicine urethanes

• Published in: Bioorganic chemistry 2018-12, Vol.81, p.553-566
• Main Authors: Majcher, Urszula, Urbaniak, Alicja, Maj, Ewa, Moshari, Mahshad, Delgado, Magdalena, Wietrzyk, Joanna, Bartl, Franz, Chambers, Timothy C., Tuszynski, Jack A., Huczyński, Adam
• Format: Article
• Language: English
• Subjects: Anticancer agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Colchicine - analogs & derivatives; Colchicine - chemical synthesis; Colchicine - chemistry; Colchicine - pharmacology; Colchicine binding site inhibitors (CBSI); Colchicine derivatives; Drug Design; Drug Screening Assays, Antitumor; Humans; Mitosis - drug effects; Mitotic inhibitor; Models, Molecular; Molecular Docking Simulation; Neoplasms - drug therapy; Neoplasms - metabolism; Tubulin; Tubulin - metabolism; Tubulin Modulators - chemical synthesis; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology; Urethane - analogs & derivatives; Urethane - chemical synthesis; Urethane - pharmacology
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2018.09.004

[Display omitted] •Successful synthesis of a series of carbamate derivatives of 7-deacetyl-10-thiocolchicine as anticancer agents.•Screening of the synthesized compounds against cancer cell lines: A549, MCF-7, LoVo, LoVo/DX and normal BALB/3T3 cells.•Synthesized several novel thiocolchicines for SAR.•Compounds 7 and 14 identified as the most active with high selectivity.•Mode of action demonstrated in silico to involve the colchicine binding site. A number of naturally occurring compounds such as paclitaxel, vinblastine, combretastatin, and colchicine exert their therapeutic effect by changing the dynamics of tubulin and its polymer form, microtubules. The identification of tubulin as a potential target for anticancer drugs has led to extensive research followed by clinical development of numerous compounds from several families. In this paper we report on the design, synthesis and in vitro evaluation of a group of thiocolchicine derivatives, modified at ring-B, labelled here compounds 4–14. These compounds have been obtained in a simple reaction of 7-deacetyl-10-thiocolchicine 3 with eleven different alcohols in the presence of triphosgene. These novel agents have been checked for anti-proliferative activity against four human cancer cell lines and their mode of action has been confirmed as colchicine binding site inhibition (CBSI) using molecular docking. Molecular simulations provided rational tubulin binding models for the tested compounds. On the basis of in vitro tests, derivatives 4–8 and 14 demonstrated the highest potency against MCF-7, LoVo and A549 tumor cell lines (IC50 values = 0.009–0.014 μM). They were more potent and characterized by a higher selectivity index than several standard chemotherapeutics including cisplatin and doxorubicin as well as unmodified colchicine. Further, studies revealed that colchicine and its several derivatives arrested MCF-7 cells in mitosis, while its selected derivatives caused microtubule depolymerization.