Abstract
Two novel C(7)-derivatives of natural anticancer agent colchicine were designed with the purpose to study their ability to induce tubulin clustering in cancer cells. The compounds were synthesized via amidation of N-deacetylcolchicine and Steglich esterification. The conjugate of colchicine with the guanosine derivative possesses moderate cytotoxicity to these cells (EC50 = 13.7 µmol L−1) inducing the depolymerization of microtubules of human lung carcinoma A549 cells but does not stimulate the formation of tubulin clusters. The colchicine conjugate with the biphenyl moiety causes a strong tubulin clustering comparable to that of anticancer agent tubuloclustin. This effect was observed for the first time for the colchicine derivative bearing no substituent at the acetyl group capable of forming hydrogen bonds with target protein.
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The authors are grateful to the DAAD German Academic Exchange Service and coworkers of the Laboratory of Cell Motility at the University of Rostock (Germany), especially to Birgit Wobith for methodic help.
This work was financially supported by the Russian Foundation for Basic Research (Project No. 18-33-01121_mol_a (study of compound 3)) and Russian Science Foundation (Project No. 19-13-00084 (study of compound 2)).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2222—2227, November, 2020.
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Nurieva, E.V., Zefirov, N.A., Temnyakova, N.S. et al. C(7)-Derivatives of colchicine with guanosine and biphenyl moieties: molecular modeling, synthesis, and tubulin clustering effect in cancer cells. Russ Chem Bull 69, 2222–2227 (2020). https://doi.org/10.1007/s11172-020-3025-y
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DOI: https://doi.org/10.1007/s11172-020-3025-y