Synthesis, molecular modeling, and biological evaluation of novel imatinib derivatives as anticancer agents.

Fulya Günay,Ömer Tahir Günkara,Zuhal Turgut,Özlem Ulucan,Yuk Yin Ng,Sevcan Balta

doi:10.3906/kim-2107-23

Fulya Günay, Ömer Tahir Günkara + Show 4 more

Open Access

https://doi.org/10.3906/kim-2107-23

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Abstract

Different derivatives of imatinib were synthesized by a 3-step reaction method. The structures of the new compounds were characterized by spectroscopic methods. For quantitative evaluation of the biological activity of the compounds, MTT assays were performed, where four BCR-ABL negative leukemic cell lines (Jurkat, Reh, Nalm-6 and Molt-4), one BCR-ABL positive cell line (K562), and one non-leukemic cell line (Hek293T) were incubated with various concentrations of the derivatives. Although imatinib was specifically designed for the BCR-ABL protein, our results showed that it was also effective on BCR-ABL negative cell lines except for Reh cell line. Compound 9 showed lowest IC50 values against Nalm-6 cells as 1.639 μM, also the values of Compound 10 for each cell were very close to imatinib. Molecular docking simulations suggest that except for compound 6, the compounds prefer a DFG-out conformation of the ABL kinase domain. Among them, compound 10 has the highest affinity for ABL kinase domain that is close to the affinity of imatinib. The common rings between compound 10 and imatinib adopt exactly the same conformation and same type of interactions in the ATP binding site with the ABL kinase domain.

Highlights

Imatinib mesylate (Fig1) is the first generation of FDA approved protein-tyrosine kinase inhibitor (Gleevec®, STI-571), especially specific to target c-ABL and BCR-ABL gene products
The general procedure for the synthesis of novel imatinib derivatives is outlined in Scheme 1
As an cyclic secondary amine group; 2-(1-piperazinyl)pyrimidine was used for preparation of compound 4a. (Because pyrimidine and its derivatives are found in nucleobases which composed DNA and RNA and they have broad spectrum of biological effects including anticancer activities [38], it was used as an aryl piperasine group in compound 5 and 7.) And 1-(2,3,4-trimethoxybenzyl)piperazine dihydrochloride was used for preparation of compound 4b as an aryl piperazine group, in compounds 6 and 10. (It was selected due to its immunomodulating [39] and antineoplastic [40] properties.)

Summary

Introduction

Imatinib mesylate (Fig1) is the first generation of FDA approved protein-tyrosine kinase inhibitor (Gleevec®, STI-571), especially specific to target c-ABL (the Abelson proto-oncogene) and BCR-ABL (the Breakpoint cluster region) gene products. With the discovery of imatinib mesylate, it has almost revolutionized the treatment of chronic myelogenous leukemia (CML). It has become the standard of care for treating patients with metastatic gastrointestinal stromal tumors [1]. Imatinib contains 2-(phenylamino)pyrimidine heterocycle core that functions for targeting BCR-ABL activity leading to decrease tyrosine kinase activity; methyl group on this core occupies the selectivity to BCR-ABL; aryl piperazine core increases oral bioavailability and pyrimidine core occupies cellular activity [3]. There are flow-based [16,17,18], polymer-supported [20], coppercatalyzed [21], palladium catalyzed [22], BrettPhos-catalyzed [23,24] methods for synthesizing imatinib

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Conclusion