Imatinib derivatives as inhibitors of K562 cells in chronic myeloid leukemia
- 275 Downloads
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).
KeywordsTyrosine kinase inhibitors Imatinib Sunitinib Isatin Phenylacetamide
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.
- Abraham SA, Hopcroft LEM, Carrick E, Drotar ME, Dunn K, Williamson AJK, Korfi K, Baquero P, Park LE, Scott MT, Pellicano F, Pierce A, Copland M, Nourse C, Grimmond SM, Vetrie D, Whetton AD, Holyoake TL (2016) Dual targeting of p53 and c-MYC selectively eliminates leukemic stem cells. Nature 534:341–346. doi: 10.1038/nature18288 CrossRefPubMedPubMedCentralGoogle Scholar
- Aslam NA, Babu SA, Rani S, Mahajan S, Solanki J, Yasuda M, Baba A (2015) Diastereoselective construction of 3-aminooxindoles with adjacent stereocenters: stereocontrolled addition of γ-Substituted allylindiums to isatin ketimines. Eur J Org Chem 2015:4168–4189. doi: 10.1002/ejoc.201500340 CrossRefGoogle Scholar
- Azevedo LD, Bastos MM, Oliveira AP, Boechat N (2017) Sínteses e propriedades de fármacos inibidores da tirosina quinase BCR-ABL, utilizados no tratamento da leucemia mieloide crônica. Química Nova. doi: 10.21577/0100-4042.20170027 (In press)
- Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, Cervantes F, Clark RE, Cortes JE, Guilhot F, Hjorth-Hansen H, Hughes TP, Kantarjian HM, Kim DW, Larson RA, Lipton JH, Mahon FX, Martinelli G, Mayer J, Muller MC, Niederwieser D, Pane F, Radich JP, Rousselot P, Saglio G, Saubele S, Schiffer C, Silver R, Simonsson B, Steegmann JL, Goldman JM, Hehlmann R (2013) European leukemia net recommendations for the management of chronic myeloid leukemia: 2013. Blood 122:872–884. doi: 10.1182/blood-2013-05-501569 CrossRefPubMedPubMedCentralGoogle Scholar
- Bennett JH (1845) Case of hypertrophy of the spleen and liver in which death took place from suppuration of the blood. Edin Med Surg J 64:413–423Google Scholar
- Boechat N, Kover WB, Bastos MM, Pinto AC, Maciel LC, Mayer LMU, Silva FSQ, SÁ PM, Mendonça JS, Wardell SMSV, Arruda MSL (2008) N-Acyl-3,3-difluoro-2-oxoindoles as versatile intermediates for the preparation of different 2,2-difluorophenylacetic derivatives. Journal of the Brazilian Chemical Society 19:445–457CrossRefGoogle Scholar
- Boechat N, Kover WB, Bastos MM, Romeiro NC, Silva ASC, Santos FC, Valverde AL, Azevedo MLG, Wollinger W, Souza TML, Souza SLO, Frugulhetti ICPP (2007) Design, synthesis, and biological evaluation of new 3-hydroxy-2-oxo-3-trifluoromethylindole as potential HIV-1 reverse transcriptase inhibitors. Med Chem Res 15:492–510. doi: 10.1007/s00044-007-9004-0 CrossRefGoogle Scholar
- Boechat N, Pinto AC (2000) Gem-difluoro derivative of phenylacetamide and phenylacetic acid and their pharmaceutical uses. US6034266 (A) filled 17 Sept 1996, issued 7 Mar 2000Google Scholar
- Choi HG, Sim T, Gray N, Zhou W, Chang JW, Zhang J, Weisberg E (2010) Fused heterocyclic compounds and their uses. WO2010144909 (A1) filled 14 Jun 2010, issued 16 Dec 2010Google Scholar
- Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, Capdeville R, Talpaz M (2001) Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 14:1038–1042. doi: 10.1056/NEJM200104053441402 CrossRefGoogle Scholar
- Feng Z, Chen X, Liu H, Meng C (2013) Amine pyrimidine derivates, and production method thereof, and medicament composition and use. CN101423513 B filled 29 Oct 2007, issued 27 Mar 2013Google Scholar
- Jeankumar VU, Alokam R, Sridevi JP, Suryadevara P, Matikonda SS, Peddi S, Alvala SSM, Yogeeswari P, Sriram D (2014) Discovery and structure optimization of a series of isatin derivatives as Mycobacterium tuberculosis chorismate mutase inhibitors. Chem Biol Drug Des 83:498–506. doi: 10.1111/cbdd.12265 CrossRefPubMedGoogle Scholar
- Majid SJ, Ahmad RM (2015) Chronic myeloid leukemia manifesting on palate: a rare case report with a brief review of literature. Int J Curr Res 7:13996–13999Google Scholar
- NCCN Clinical Practice Guidelines in Oncology. Chronic Myelogenous Leukemia (2017) 105. http://www.nccn.org/professionals/physician_gls/pdf/cml.pdf. Accessed 1 Jan 2017
- Neves BJ, Dantas RF, Senger MR, Melo-Filho CC, Valente WC, de Almeida AC, Rezende-Neto JM, Lima EF, Paveley R, Furnham N, Muratov E, Kamentsky L, Carpenter AE, Braga RC, Silva-Junior FP, Andrade CH (2016) Discovery of new anti-schistosomal hits by integration of qsar-based virtual screening and high content screening. J Med Chem 15:7075–7088. doi: 10.1021/acs.jmedchem.5b02038 CrossRefGoogle Scholar
- Obafemi CA, Taiwo FO, Iwalewa EO, Akinpelu DA (2012) Synthesis, antibacterial and anti-inflammatory activities of some 2-phenylglyoxylic acid derivatives. Int J Life Sci Pharma Res 2:22–36Google Scholar