Imatinib derivatives as inhibitors of K562 cells in chronic myeloid leukemia

Abstract

Imatinib was the first representative of the class of Breakpoint cluster region-Abelson murine leukemia viral oncogene homolog (BCR-ABL) tyrosine kinase inhibitors used for the treatment of chronic myeloid leukemia. Second-generation and third-generation drugs have been introduced in this therapy, affording increased patient survival. However, all BCR-ABL tyrosine kinase inhibitors have been shown to induce resistance, necessitating a search for new therapeutic options. The sunitinib, another tyrosine kinase inhibitor used in the treatment of renal cell carcinoma and gastrointestinal stromal tumors is an isatin derivative. Isatin nucleus is highly versatile for the preparation of new substances, and several tyrosine kinase inhibitors examples have been obtained using it. This work aimed to design, synthesize, and biological evaluation of new compounds using the K562 cell line, which constitutively expresses the active BCR-ABL enzyme. Three new series of imatinib derivatives have been planned from the imatinib, and all have a phenylaminopyrimidine group as the main pharmacophore. Sunitinib was used as a structural prototype to planning the series 1 (8a–e) of hybrids between sunitinib and imatinib. Series 2 and 3 are 2-oxo-2-phenyacetamide and 2,2-difluoro-2-phenylacetamide derivatives, respectively. Isatins were used as the starting materials for all series. Compounds were synthesized using simple methodologies and were obtained in high purities. The compounds were tested against K562 cells, and four showed a reduction in cell viability, with EC50 values ranging from 0.37 to 2.02 μM, some of which are close to the imatinib standard (0.21 µM).