Flavonoid Derivatives Targeting BCR-ABL Kinase: Semisynthesis, Molecular Dynamic Simulations and Enzymatic Inhibition

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2021-09-01

Autores

Ribeiro, Rayssa
Eloy, Mariana A.
Francisco, Carla S.
Javarini, Clara L.
Ayusso, Gabriela M. [UNESP]
Fonseca, Victor Da Rocha
Romão, Wanderson
Regasini, Luis O. [UNESP]
Araujo, Sheila C.
Almeida, Michell O.

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Resumo

Background: Natural products have been universally approached in the research of novel trends useful to detail the essential paths of the life sciences and as a strategy for pharmacothera-peutics. Objective: This work focuses on further modification to the 6-hydroxy-flavanone building block aiming to obtain improved BCR-ABL kinase inhibitors. Methods: Ether derivatives were obtained from Williamson synthesis and triazole from Mi-crowave-assisted click reaction. Chemical structures were finely characterized through IR,1H and13 C NMR and HRMS. They were tested for their inhibitory activity against BCR-ABL kinase. Results: Two inhibitors bearing a triazole ring as a pharmacophoric bridge demonstrated the strongest kinase inhibition at IC50 value of 364 nM (compound 3j) and 275 nM (compound 3k). Conclusion: 6-hydroxy-flavanone skeleton can be considered as a promising core for BCR-ABL kinase inhibitors.

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6-hydroxy-flavanone skeleton, BCR-ABL kinase inhibitors, Chronic myeloid leukemia, Semisynthesis, Triazole, Williamson synthesis

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Current Topics in Medicinal Chemistry, v. 21, n. 22, p. 1999-2017, 2021.

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