Abstract
Imatinib (IMT) is the first-in-class BCR-ABL commercial tyrosine kinase inhibitor (TKI). However, the resistance and toxicity associated with the use of IMT highlight the importance of the search for new TKIs. In this context, heterocyclic systems, such as quinoline, which is present as a pharmacophore in the structure of the TKI inhibitor bosutinib (BST), have been widely applied. Thus, this work aimed to obtain new hybrids of imatinib containing quinoline moieties and evaluate them against K562 cells. The compounds were synthesized with a high purity degree. Among the produced molecules, the inhibitor 4-methyl-N3-(4-(pyridin-3-yl)pyrimidin-2-yl)-N1-(quinolin-4-yl)benzene-1,3-diamine (2g) showed a suitable reduction in cell viability, with a CC50 value of 0.9 µM (IMT, CC50 = 0.08 µM). Molecular docking results suggest that the interaction between the most active inhibitor 2g and the BCR-ABL1 enzyme occurs at the bosutinib binding site through a competitive inhibition mechanism. Despite being less potent and selective than IMT, 2g is a suitable prototype for use in the search for new drugs against chronic myeloid leukemia (CML), especially in patients with acquired resistance to IMT.
Highlights
Introduction published maps and institutional affilTargeted therapy is the standard treatment for chronic myeloid leukemia (CML)
The results indicated that the presence of one additional nitrogen atom in quinazoline did not increase its selectivity for the BCR-ABL1 enzyme since no additional hydrogen bonding was observed
Compound 2h is the only molecule that presents a phenylaminopyrimidine pyridine (PAPP) skeleton connected to the C-2 carbon of quinoline, unlike the other compounds, in which this substitution occurred at the C-4 carbon
Summary
K562 (ATCC® CRL243 TM): the cells used in this work were extracted from the bone marrow of a 53-year-old female patient who had CML (ATCC: The Global Bioresource Center b). CRL2029 TM): the cells used in this work were a healthy human cell line obtained from the renal epithelium of a fetus and transformed with adenovirus 5 DNA (ATCC: The. Global Bioresource Center c). The K562 strain was grown in RPMI-1640 medium (R8758, Sigma-Aldrich, St. Louis, MO, USA) according to the provider’s recommendations and the literature [27,28]. WSS-1 cells were cultured in high-glucose DMEM (Vitrocell) according to the provider’s recommendations (ATCC: The Global Bioresource Center c). All cell lines were grown in a cell culture bottle with a 0.22 μm pore membrane filter on the lid, allowing the circulation of CO2. WSS-1 cells grew adherently, while cells of the K562 strain grew in suspension. All cell lines were routinely evaluated before freezing for storage in liquid nitrogen in the vapor phase for the detection of mycoplasma
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