Synthesis and biological activity of 4-amino-3-chloro-1H-pyrrole-2,5-diones

• Published in: In silico pharmacology Vol. 7; no. 1; pp. 1 - 10
• Main Authors: Kuznietsova, Halyna M., Hurmach, Vasyl V., Bychko, Andriy V., Tykhoniuk, Olena I., Milokhov, Demyd S., Khilya, Olga V., Volovenko, Yulian M., Rybalchenko, Volodymyr K.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 10-04-2019; Springer Nature B.V
• Subjects: Anticancer properties; Binding; Biological activity; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Cell membranes; Cellular and Medical Topics; Computational Science and Engineering; Current voltage characteristics; Domains; Growth factors; In vivo methods and tests; Inhibitors; Kinases; Lipids; Medicinal Chemistry; Membranes; Molecular docking; Molecular dynamics; Organic chemistry; Original Research; Pharmacology/Toxicology; Physiological; Receptors; Resistance; Synthesis; Tyrosine; VEGFR2; Cyclic current–voltage characteristics; 5-Dione derivatives; pyrrole-2; Bilayer lipid membranes; EGFR; 4-Amino-3-chloro-1
• ISSN: 2193-9616; 2193-9616
• DOI: 10.1007/s40203-019-0051-2

4-Amino-3-chloro-1
H
-pyrrole-2,5-dione derivatives were designed and synthesized as potential tyrosine kinase inhibitors. One of them has been shown to inhibit growth of cancer cell lines and in vivo tumors. To determine the impact of side groups on biological activity the ability of different 4-amino-3-chloro-1
H
-pyrrole-2,5-diones to interact with ATP-binding domains of growth factor receptors and with model cell membranes were aimed to be discovered. The methods of molecular docking, short-molecular dynamics (in silico) and non-steady cyclic current–voltage characteristics (in vitro) were used. Five 4-amino-3-chloro-1
H
-pyrrole-2,5-diones were synthesized from 3,4-dichloro-1
H
-pyrrole-2,5-diones. All of them demonstrated the potential ability to form complexes with ATP-binding domains of EGFR and VEGFR2. These complexes were more stable compared to those with ANP. 4-Amino-3-chloro-1
H
-pyrrole-2,5-diones while interact with different bilayer lipid membranes caused an increase of their specific conductance and electric capacity, demonstrating the certain disturbance in lipid packing. Obtained data allowed us to suggest that proposed chemicals can interact with the surface of lipid bilayer, do likely intercalate into the membrane and form stable complexes with EGFR and VEGFR2. So, the prospect of developed chemicals to be effective EGFR and VEGFR2 inhibitors and therefore realize antitumor activity was concluded.