Crystal Structures, Molecular Docking and In Vitro Investigations of Two 4-Substituted 2-(5,5-dimethyl-3-styrylcyclohex-2-enylidene)malononitrile Derivatives as Potential Topoisomerase II Inhibitors
Martina I. Peeva,
Maya G. Georgieva,
Aneliya A. Balacheva,
Maria Ponticelli,
Ivan P. Bogdanov,
Tsonko Kolev,
Luigi Milella,
Hans-Georg Stammler,
Nikolay T. Tzvetkov
Affiliations
Martina I. Peeva
Department of Biochemical Pharmacology & Drug Design, Institute of Molecular Biology “Roumen Tsanev”, Bulgarian Academy of Sciences (BAS), Acad. G. Bonchev Str., bl. 21, 1113 Sofia, Bulgaria
Maya G. Georgieva
Department of Biochemical Pharmacology & Drug Design, Institute of Molecular Biology “Roumen Tsanev”, Bulgarian Academy of Sciences (BAS), Acad. G. Bonchev Str., bl. 21, 1113 Sofia, Bulgaria
Aneliya A. Balacheva
Department of Biochemical Pharmacology & Drug Design, Institute of Molecular Biology “Roumen Tsanev”, Bulgarian Academy of Sciences (BAS), Acad. G. Bonchev Str., bl. 21, 1113 Sofia, Bulgaria
Maria Ponticelli
Department of Science, University of Basilicata, Via dell’Ateneo Lucano 10, 85100 Potenza, Italy
Ivan P. Bogdanov
Department of Biochemical Pharmacology & Drug Design, Institute of Molecular Biology “Roumen Tsanev”, Bulgarian Academy of Sciences (BAS), Acad. G. Bonchev Str., bl. 21, 1113 Sofia, Bulgaria
Tsonko Kolev
Department of Biochemical Pharmacology & Drug Design, Institute of Molecular Biology “Roumen Tsanev”, Bulgarian Academy of Sciences (BAS), Acad. G. Bonchev Str., bl. 21, 1113 Sofia, Bulgaria
Luigi Milella
Department of Science, University of Basilicata, Via dell’Ateneo Lucano 10, 85100 Potenza, Italy
Hans-Georg Stammler
Department of Chemistry, University of Bielefeld, Universitätsstr. 25, 33615 Bielefeld, Germany
Nikolay T. Tzvetkov
Department of Biochemical Pharmacology & Drug Design, Institute of Molecular Biology “Roumen Tsanev”, Bulgarian Academy of Sciences (BAS), Acad. G. Bonchev Str., bl. 21, 1113 Sofia, Bulgaria
Type II topoisomerases (TOP2s) play a key role in altering the DNA topology by transiently cleaving both strands of a DNA duplex. Therefore, increased TOP2 activity is associated with many cancers. Herein, we present the synthesis, structural characterization, virtual screening, and structural exploration, as well as evaluation of the antiproliferative effects of two new 4-substituted 2-(5,5-dimethyl-3-styrylcyclohex-2-enylidene)malononitrile derivatives with potential application in the drug design of isoform-specific TOP2 inhibitors. Both compounds 1 and 2 were verified by ESI-TOF-MS, NMR, and single-crystal X-ray diffraction (SCXRD) analysis. Furthermore, we applied our recently proposed SCXRD/HYdrogen DEsolvation (HYDE) technology platform in order to perform molecular modeling, virtual screening, and structural exploration with 1 and 2. For this purpose, we used the crystal structure of human TOP2β complexed to DNA and the anticancer drug etoposide. Moreover, we further evaluated the antiproliferative activity of 1 and 2 on human hepatocarcinoma HepG2 cells and compared the observed effects with those of the reference hTOP2β inhibitor etoposide. Based on the obtained results, compounds 1 and 2 showed a virtually higher binding affinity (Ki HYDE values) over etoposide towards hTOP2β but lower antiproliferative activity compared to those of etoposide.
