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Medicinal Chemistry Research

, Volume 26, Issue 11, pp 2929–2941 | Cite as

Imatinib derivatives as inhibitors of K562 cells in chronic myeloid leukemia

  • Liviane D. Azevedo
  • Mônica M. Bastos
  • Flávia C. Vasconcelos
  • Lucas V. B. Hoelz
  • Floriano P. S. Junior
  • Rafael F. Dantas
  • Ana C. M. de Almeida
  • Andressa Paula de Oliveira
  • Larissa C. Gomes
  • Raquel C. Maia
  • Nubia Boechat
Original Research

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 (8ae) 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).

Keywords

Tyrosine kinase inhibitors Imatinib Sunitinib Isatin Phenylacetamide 

Notes

Acknowledgements

We are grateful to Coordination for the Improvement of Higher Education Personnel (CAPES), National Council for Scientific and Technological Development (CNPq) and Foundation for Research Support of the State of Rio de Janeiro (FAPERJ) for funding this work.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

44_2017_1993_MOESM1_ESM.doc (56 kb)
Supplementary Information

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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Liviane D. Azevedo
    • 1
    • 2
  • Mônica M. Bastos
    • 1
    • 2
  • Flávia C. Vasconcelos
    • 3
  • Lucas V. B. Hoelz
    • 1
  • Floriano P. S. Junior
    • 4
  • Rafael F. Dantas
    • 4
  • Ana C. M. de Almeida
    • 4
  • Andressa Paula de Oliveira
    • 1
    • 2
  • Larissa C. Gomes
    • 1
    • 5
  • Raquel C. Maia
    • 3
  • Nubia Boechat
    • 1
    • 2
  1. 1.Departamento de Síntese de Fármacos, Fundação Oswaldo CruzInstituto de Tecnologia em Fármacos, Farmanguinhos - FiocruzRio de JaneiroBrazil
  2. 2.Programa de Pós-Graduação em Farmacologia e Química Medicinal – ICB-UFRJ, CCSBloco J, Ilha do FundãoRio de JaneiroBrazil
  3. 3.Laboratório de Hemato-Oncologia Celular e Molecular, Instituto Nacional do Câncer, INCAHospital do Câncer I, Praça da Cruz Vermelha, CentroRio de JaneiroBrazil
  4. 4.Laboratório de Bioquímica Experimental e Computacional de FármacosFundação Oswaldo Cruz, Instituto Oswaldo CruzRio de JaneiroBrazil
  5. 5.PROBIN - Abeu - Centro Universitário UNIABEUBelford RoxoBrazil

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