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

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) gr...

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Vydané v:Beilstein journal of organic chemistry Ročník 17; číslo 1; s. 2260 - 2269
Hlavní autori: Pimentel, Luiz Claudio Ferreira, Hoelz, Lucas Villas Boas, Canzian, Henayle Fernandes, Branco, Frederico Silva Castelo, de Oliveira, Andressa Paula, Campos, Vinicius Rangel, Júnior, Floriano Paes Silva, Dantas, Rafael Ferreira, Resende, Jackson Antônio Lamounier Camargos, Cunha, Anna Claudia, Boechat, Nubia, Bastos, Mônica Macedo
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: Germany Beilstein-Institut zur Föerderung der Chemischen Wissenschaften 01.09.2021
Beilstein-Institut
Predmet:
(phenylamino)pyrimidine-pyridine
1,2,3-triazole
1,3-dipolar cycloaddition
BCR-ABL protein
Binding sites
Chemistry
Chromosomes
Chronic myeloid leukemia
Confidence intervals
Cytotoxicity
Design
Enzymes
Full Research Paper
Fusion protein
Imatinib
Kinases
Leukemia
Mutation
Myeloid leukemia
Protein-tyrosine kinase
Triazoles
(phenylamino)pyrimidine-pyridine
chronic myeloid leukemia
imatinib
1,2,3-triazole
1,3-dipolar cycloaddition
ISSN:1860-5397, 2195-951X, 1860-5397
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Shrnutí: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 IC 50 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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ISSN:1860-5397
2195-951X
1860-5397
DOI:10.3762/bjoc.17.144