Imatinib derivatives as inhibitors of K562 cells in chronic myeloid leukemia

Azevedo, Liviane D. de; Bastos, Mônica M.; Vasconcelos, Flavia da Cunha; Hoelz, Lucas Villas Bôas; Floriano, P. S.; Dantas, Rafael Ferreira; Almeida, Ana C. M. de; Oliveira, Andresa Pereira de; Gomes, Larissa C.; Maia, Raquel Ciuvalschi; Boechat, Núbia

doi:10.1007/s00044-017-1993-8

Cited by 14 publications

(14 citation statements)

References 44 publications

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“…As mutations in the BCR-Abl-1 enzyme domain can occur, cases of resistance have emerged in the treatment with TKIs, compromising its effectiveness [10,11]. In continuation of the work by our group to develop new imatinib analogs [12,13], in this work, we designed a series of imatinib 1,2,3-triazole analogs 1a,b and 2a-j (Figure 1). The 1,2,3-triazoles are heterocyclic compounds, consisting of a five-membered ring, containing two carbon atoms and three nitrogen atoms [14].…”

Section: Introductionmentioning

confidence: 99%

(Phenylamino)pyrimidine-1,2,3-triazole derivatives as analogs of imatinib: searching for novel compounds against chronic myeloid leukemia

Pimentel

Hoelz

Canzian

et al. 2021

Beilstein J. Org. Chem.

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The enzyme tyrosine kinase BCR-Abl-1 is the main molecular target in the treatment of chronic myeloid leukemia and can be competitively inhibited by tyrosine kinase inhibitors such as imatinib. New potential competitive inhibitors were synthesized using the (phenylamino)pyrimidine-pyridine (PAPP) group as a pharmacophoric fragment, and these compounds were biologically evaluated. The synthesis of twelve new compounds was performed in three steps and assisted by microwave irradiation in a 1,3-dipolar cycloaddition to obtain 1,2,3-triazole derivatives substituted on carbon C-4 of the triazole nucleus. All compounds were evaluated for their inhibitory activities against a chronic myeloid leukemia cell line (K562) that expresses the enzyme tyrosine kinase BCR-Abl-1 and against healthy cells (WSS-1) to observe their selectivity. Three compounds showed promising results, with IC50 values between 1.0 and 7.3 μM, and were subjected to molecular docking studies. The results suggest that such compounds can interact at the same binding site as imatinib, probably sharing a competitive inhibition mechanism. One compound showed the greatest interaction affinity for BCR-Abl-1 in the docking studies.

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Section: Introductionmentioning

confidence: 99%

(Phenylamino)pyrimidine-1,2,3-triazole derivatives as analogs of imatinib: searching for novel compounds against chronic myeloid leukemia

Pimentel

Hoelz

Canzian

et al. 2021

Beilstein J. Org. Chem.

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“…The series 1a–e has hybrid molecules developed from IMB and sunitinib, another TK inhibitor. The molecules of series 2a–e have 2-oxo-2-phenylacetamides, the ones of series 3a–e have 3,2-difluoro-2-phenylacetamides, and isatins were used as starting molecules in all series (Azevedo et al ., 2017).…”

Section: Discussionmentioning

confidence: 99%

“…1) and the derivatives ( 1a–c, 1e, 2a–e and 3a–e – Fig. 2) were provided by Dr Núbia Boechat from the Laboratório de Síntese Orgânica – Instituto de Tecnologia em Fármacos/Fundação Oswaldo Cruz (Farmanguinhos/Fiocruz) (Rio de Janeiro, Rio de Janeiro, Brazil) and synthesized as reported (Azevedo et al ., 2017). Stock solutions in dimethyl sulfoxide were prepared w/v with the final concentration never exceeding 0.6%, which does not exert mammalian host cell toxicity as reported (Timm et al ., 2014).…”

Section: Methodsmentioning

confidence: 99%

Repurposing strategies for Chagas disease therapy: the effect of imatinib and derivatives againstTrypanosoma cruzi

et al. 2019

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Chagas disease (CD) is a neglected parasitic condition endemic in the Americas caused by Trypanosoma cruzi. Patients present an acute phase that may or not be symptomatic, followed by lifelong chronic stage, mostly indeterminate, or with cardiac and/or digestive progressive lesions. Benznidazole (BZ) and nifurtimox are the only drugs approved for treatment but not effective in the late chronic phase and many strains of the parasite are naturally resistant. New alternative therapy is required to address this serious public health issue. Repositioning and combination represent faster, and cheaper trial strategies encouraged for neglected diseases. The effect of imatinib (IMB), a tyrosine kinase inhibitor designed for use in neoplasias, was assessed in vitro on T. cruzi and mammalian host cells. In comparison with BZ, IMB was moderately active against different strains and forms of the parasite. The combination IMB + BZ in fixed-ratio proportions was additive. Novel 14 derivatives of IMB were screened and a 3,2-difluoro-2-phenylacetamide (3e) was as potent as BZ on T. cruzi but had low selectivity index. The results demonstrate the importance of phenotypic assays, encourage the improvement of IMB derivatives to reach selectivity and testify to the use of repurposing and combination in drug screening for CD.

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“…By continuing the work that the group has been developing to obtain new imatinib analogs [12][13][14][15][16][17][18], in this work, we designed a series of imatinib 1,2,3-triazole analogs 1a-b and 2a-j (Figure 1). The choice of a 1,2,3-triazole ring is associated with both 4 chemical and metabolic stability [19,20] and with the possibility of providing new compounds capable of circumventing resistance in cancer treatment with TKI [21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

Phenylamino pyrimidine-1,2,3-triazole derivatives as analogs of imatinib: searching for novel compounds against chronic myeloid leukemia

Pimentel¹,

Hoelz²,

Canzian³

et al. 2021

Preprint

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The enzyme tyrosine kinase Bcr-Abl-1 is the main molecular target in the treatment of chronic myeloid leukemia and can be competitively inhibited by tyrosine kinase inhibitors such as imatinib. New potential competitive inhibitors were synthesized using the phenylamino pyrimidine pyridine (PAPP) group as a pharmacophoric fragment, and these compounds were biologically evaluated. The synthesis of the twelve new compounds was performed in three steps and assisted by microwave irradiation in a 1,3-dipolar cycloaddition to obtain 1,2,3-triazole derivatives substituted on carbon C-4 of the triazole nucleus. All of them had their inhibitory activities evaluated against a chronic myeloid leukemia cell line (K562) that expresses the enzyme tyrosine kinase Bcr-Abl-1 and against healthy cells (WSS-1) to observe their selectivity. Three compounds had promising results, showing an IC50 between 1.0 and 7.3 mM, and were subjected to molecular docking studies. This result suggests that such compounds can interact at the same binding site as imatinib, probably sharing a competitive inhibition mechanism. One of them showed the greatest interaction affinity for Bcr-Abl-1 in the docking studies.

show abstract

Imatinib derivatives as inhibitors of K562 cells in chronic myeloid leukemia

Cited by 14 publications

References 44 publications

(Phenylamino)pyrimidine-1,2,3-triazole derivatives as analogs of imatinib: searching for novel compounds against chronic myeloid leukemia

(Phenylamino)pyrimidine-1,2,3-triazole derivatives as analogs of imatinib: searching for novel compounds against chronic myeloid leukemia

Repurposing strategies for Chagas disease therapy: the effect of imatinib and derivatives againstTrypanosoma cruzi

Phenylamino pyrimidine-1,2,3-triazole derivatives as analogs of imatinib: searching for novel compounds against chronic myeloid leukemia

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