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

被引:5
|
作者
Kalinichenko, Elena [1 ]
Faryna, Aliaksandr [1 ]
Bozhok, Tatyana [1 ]
Golyakovich, Anna [1 ]
Panibrat, Alesya [1 ]
机构
[1] Natl Acad Sci Belarus, Inst Bioorgan Chem, 5-2 Acad VF Kuprevich St, Minsk 220141, BELARUS
关键词
terephthalic and isophthalic derivatives; anticancer activity; protein kinase inhibitors; VEGFR; cellular apoptosis; ROS; MM-PBSA; MM-GBSA; molecular docking; AUTOPHAGY; IMATINIB; MECHANISMS; MUTATIONS; SUNITINIB; LAPATINIB; APOPTOSIS; ARREST;
D O I
10.3390/cimb45030117
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 mu M, 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 mu M. 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 mu M, 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.
引用
收藏
页码:1820 / 1842
页数:23
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