Novel antimitotic agents related to tubuloclustin: synthesis and biological evaluation

• Published in: Molecular diversity Vol. 21; no. 3; pp. 547 - 564
• Main Authors: Zefirova, Olga N., Nurieva, Evgeniya V., Wobith, Birgit, Gogol, Vladimir V., Zefirov, Nikolay A., Ogonkov, Andrei V., Shishov, Dmitrii V., Zefirov, Nikolay S., Kuznetsov, Sergei A.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.08.2017; Springer Nature B.V
• Subjects: Antiviral drugs; Biochemistry; Biomedical and Life Sciences; Chemical compounds; Chemical synthesis; Cytotoxicity; Life Sciences; Lungs; Molecular structure; Organic Chemistry; Original Article; Pharmacy; Polymer Sciences; Combretastatin; Cytotoxicity; Tubuloclustin; Colchicine; Adamantane; Podophyllotoxin
• ISSN: 1381-1991; 1573-501X
• DOI: 10.1007/s11030-017-9739-6

Tubuloclustin [ N -(7-adamant-2-yloxy-7-oxoheptanoyl)- N -deacetylcolchicine], a highly cytotoxic anti-tubulin compound is known for its ability to promote microtubule disassembly followed by the formation of tubulin clusters of unique morphology. Three series of antimitotic agents related to tubuloclustin were designed and synthesized in order to enhance the molecular diversity of “tubuloclustin-like” family of compounds. The series of compounds with modified adamantane moiety was highly potent in cytotoxic effect on human lung carcinoma A549 cells (EC50 = 6–400 nM) and was active in affecting the microtubule arrays and induction of strong tubulin clusterization. In two other sets of compounds, the colchicine moiety of tubuloclustin was replaced by podophyllotoxin or combretastatin A-4. All combretastatin A-4 derivatives displayed noticeable cytotoxic activity ( EC 50 = 0.8 - 1.6 μ M ) but their effect on microtubules depended on the position of the linker attachment. Podophyllotoxin derivatives were also toxic to A549 cells ( EC 50 = 0.38 - 0.50 μ M ) and caused both microtubule depolymerization and some tubulin clustering. The data obtained gave additional evidence that the whole panel of C7-colchicine, podophyllotoxin and combretastatin derivatives could manifest clustering effect, and the strength of this effect correlated with cytotoxic activity of the compounds.