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 showed the highest inhibitory activity against four cancer cell lines, K562, HL-60, MCF-7 and HepG2 (IC = 3.42, 7.04, 4.91 and 8.84 µM, respectively). Isophthalic derivative 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 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 and with VEGFR-2 was validated using MD simulations and MM-GPSA calculations.