Estradiol dimer inhibits tubulin polymerization and microtubule dynamics

Publication date: Available online 24 May 2018Source: The Journal of Steroid Biochemistry and Molecular BiologyAuthor(s): Michal Jurášek, Markéta Černohorská, Jiří Řehulka, Vojtěch Spiwok, Tetyana Sulimenko, Eduarda Dráberová, Maria Darmostuk, Soňa Gurská, Ivo Frydrych, Renata Buriánová, Tomáš Ruml, Marián Hajdúch, Petr Bartůněk, Pavel Dráber, Petr Džubák, Pavel B. Drašar, David SedlákAbstractMicrotubule dynamics is one of the major targets for new chemotherapeutic agents. This communication presents the synthesis and biological profiling of steroidal dimers based on estradiol, testosterone and pregnenolone bridged by 2,6-bis(azidomethyl)pyridine between D rings. The biological profiling revealed unique properties of the estradiol dimer including cytotoxic activities on a panel of 11 human cell lines, ability to arrest in the G2/M phase of the cell cycle accompanied with the attenuation of DNA/RNA synthesis. Thorough investigation precluded a genomic mechanism of action and revealed that the estradiol dimer acts at the cytoskeletal level by inhibiting tubulin polymerization. Further studies showed that estradiol dimer, but none of the other structurally related dimeric steroids, inhibited assembly of purified tubulin (IC50, 3.6 μM). The estradiol dimer was more potent than 2-methoxyestradiol, an endogenous metabolite of 17β-estradiol and well-studied microtubule polymerization inhibitor with antitumor effects that was evaluated in clinical trials...
Source: The Journal of Steroid Biochemistry and Molecular Biology - Category: Biochemistry Source Type: research