C(7)-Derivatives of colchicine with guanosine and biphenyl moieties: molecular modeling, synthesis, and tubulin clusteri
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Russian Chemical Bulletin, International Edition, Vol. 69, No. 11, pp. 2222—2227, November, 2020
C(7)-Derivatives of colchicine with guanosine and biphenyl moieties: molecular modeling, synthesis, and tubulin clustering effect in cancer cells E. V. Nurieva,a N. A. Zefirov,a,b N. S. Temnyakova,b S. А. Kuznetsov,c and O. N. Zefirovaa,b aDepartment
of Chemistry, M. V. Lomonosov Moscow State University, Build. 3, 1 Leninskie Gory, 119991 Moscow, Russian Federation. E-mail: [email protected] bInstitute of Physiologically Active Compounds, Russian Academy of Sciences, 1 Severnyi proezd, 142432 Chernogolovka, Moscow Region, Russian Federation. E-mail: [email protected] cInstitute of Biological Sciences, University of Rostock, D-18059 Rostock, Germany. E-mail: [email protected] 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 (ЕС50 13.7 mol 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. Key words: colchicine, guanosine, 4-biphenylacetic acid, molecular modeling, tubulin clusters, lung carcinoma A549.
Alkaloid colchicine (1а) isolated from meadows-affron (Colchicum autumnale) is an efficient anticancer agent but is not used in therapy of tumor diseases because of a very high general toxicity.1,2 Colchicine binds the -subunit of cell dimer protein ,-tubulin at the boundary with the -subunit into which the N-acetyl substituent of molecule 1a is exposed.3
R = Ac (1a, colchicine),
(1b, tubuloclustin),
H (1c, N-deacetylcolchicine)
Modification at position С(7) of colchicine usually does not result in activity loss and can be used for the synthesis of the derivatives of the natural molecule having
a lower general toxocity.4,5 For example, tubuloclustin, N-[7-(adamant-2-yloxy)-7-oxoheptanoyl]-N-deacetylcolchicine (1b), is characterized by an improved toxicological profile in vivo compared to colchicine.4 In experiments in vitro, tubuloclustin induces not only inhibition of tubulin polymerization to microtubules (MT) typical of compound 1a but also stimulates the formation of tubulin clusters (see Ref. 6 and references cited therein). This effect is also characteristic of some other С(7)-derivatives of colchicine (see, e.g., Refs 7 and 8). Many of them show a direct correlation between the antiproliferative activity and clustering efficiency, which explains interest in studying reasons for
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