Novel Phthalic-Based Anticancer Tyrosine Kinase Inhibitors: Design, Synthesis and Biological Activity.

In this work, fragments of isophthalic and terephthalic acids are proposed as a structural scaffold to develop potential inhibitors of protein kinases. Novel isophthalic and terephthalic acid derivatives were designed as type-2 protein kinase inhibitors, synthesized and subjected to physicochemical characterization. The screening of their cytotoxic actions against a panel of cell lines derived from different types of tumors (liver, renal, breast and lung carcinomas, as well as chronic myelogenous and promyelocytic leukemia) and normal human B lymphocyte, for the sake of comparison, was performed. Compound 5 showed the highest inhibitory activity against four cancer cell lines, K562, HL-60, MCF-7 and HepG2 (IC50 = 3.42, 7.04, 4.91 and 8.84 µM, respectively). Isophthalic derivative 9 revealed a high potency against EGFR and HER2, at the levels of 90% and 64%, respectively, being comparable to lapatinib at 10 µM. In general, tumor cell cultures were more sensitive to isophthalic acid derivatives than to terephthalic acid ones. In cell cycle studies, isophthalic analogue 5 showed a pronounced dose-dependent effect, and with the increase in its concentration up to 10.0 µM, the number of living cells decreased to 38.66%, while necrosis reached 16.38%. The considered isophthalic compounds had a similar docking performance to that of sorafenib against the VEGFR-2 (PDB id: 4asd, 3wze). The correct binding of compounds 11 and 14 with VEGFR-2 was validated using MD simulations and MM-GPSA calculations.

Synthesis, In Vitro and In Silico Anticancer Activity of New 4-Methylbenzamide Derivatives Containing 2,6-Substituted Purines as Potential Protein Kinases Inhibitors.

A novel class of potential protein kinase inhibitors 7-16 was synthesized in high yields using various substituted purines. The most promising compounds, 7 and 10, exhibited inhibitory activity against seven cancer cell lines. The IC50 values for compounds 7 and 10 were 2.27 and 2.53 µM for K562 cells, 1.42 and 1.52 µM for HL-60 cells, and 4.56 and 24.77 µM for OKP-GS cells, respectively. In addition, compounds 7 and 10 dose-dependently induced the apoptosis and cell cycle arrest at G2/M phase, preventing the cell division of OKP-GS cells. Compounds 7, 9, and 10 showed 36-45% inhibitory activity against PDGFRα and PDGFRß at the concentration of 1 µM. Molecular modeling experiments showed that obtained compounds could bind to PDGFRα as either type 1 (compound 7, ATP-competitive) or type 2 (compound 10, allosteric) inhibitors, depending on the substituent in the amide part of the molecule.

Synthesis, Biological Activities and Docking Studies of Novel 4-(Arylaminomethyl)benzamide Derivatives as Potential Tyrosine Kinase Inhibitors.

A number of new compounds containing the 4-(aminomethyl)benzamide fragment as a linker were designed and synthesized, and their biological activities were evaluated as potential anticancer agents. The cytotoxicity activity of the designed compounds was studied in two hematological and five solid cell lines in comparison with the reference drugs. Targeted structures against eight receptor tyrosine kinases including EGFR, HER-2, HER-4, IGF1R, InsR, KDR, PDGFRa, and PDGFRb were investigated. The majority of the compounds showed a potent inhibitory activity against the tested kinases. The analogues 11 and 13 with the (trifluoromethyl)benzene ring in the amide or amine moiety of the molecule were proven to be highly potent against EGFR, with 91% and 92% inhibition at 10 nM, respectively. The docking of synthesized target compounds for nine protein kinases contained in the Protein Data Bank (PDB) database was carried out. The molecular modeling results for analogue 10 showed that the use of the 4-(aminomethyl)benzamide as a flexible linker leads to a favorable overall geometry of the molecule, which allows one to bypass the bulk isoleucine residue and provides the necessary binding to the active center of the T315I-mutant Abl (PDB: 3QRJ).