Spirooxadiazoline-oxindoles derived from imatinib show antimyeloproliferative potential in K562 cells.

Autor: de Azevedo LD; Departamento de Síntese Orgânica, Fundação Oswaldo Cruz, Farmanguinhos, Rio de Janeiro, Brasil., Leite DI; Departamento de Síntese Orgânica, Fundação Oswaldo Cruz, Farmanguinhos, Rio de Janeiro, Brasil., de Oliveira AP; Departamento de Síntese Orgânica, Fundação Oswaldo Cruz, Farmanguinhos, Rio de Janeiro, Brasil., Junior FPS; Fundação Oswaldo Cruz, Laboratório de Bioquímica Experimental e Computacional de Fármacos, Instituto Oswaldo Cruz, Rio de Janeiro, Brasil., Dantas RF; Fundação Oswaldo Cruz, Laboratório de Bioquímica Experimental e Computacional de Fármacos, Instituto Oswaldo Cruz, Rio de Janeiro, Brasil., Bastos MM; Departamento de Síntese Orgânica, Fundação Oswaldo Cruz, Farmanguinhos, Rio de Janeiro, Brasil., Boechat N; Departamento de Síntese Orgânica, Fundação Oswaldo Cruz, Farmanguinhos, Rio de Janeiro, Brasil., Pimentel LCF; Departamento de Síntese Orgânica, Fundação Oswaldo Cruz, Farmanguinhos, Rio de Janeiro, Brasil.
Jazyk: angličtina
Zdroj: Archiv der Pharmazie [Arch Pharm (Weinheim)] 2024 Aug; Vol. 357 (8), pp. e2400029. Date of Electronic Publication: 2024 Apr 16.
DOI: 10.1002/ardp.202400029
Abstrakt: Imatinib mesylate was the first representative BCR-ABL1 tyrosine kinase inhibitor (TKI) class for the treatment of chronic myeloid leukemia. Despite the revolution promoted by TKIs in the treatment of this pathology, a resistance mechanism occurs against all BCR-ABL1 inhibitors, necessitating a constant search for new therapeutic options. To develop new antimyeloproliferative substances, we applied a medicinal chemistry tool known as molecular hybridization to design 25 new substances. These compounds were synthesized and biologically evaluated against K562 cells, which express BCR-ABL1, a constitutively active tyrosine kinase enzyme, as well as in WSS-1 cells (healthy cells). The new compounds are conjugated hybrids that contain phenylamino-pyrimidine-pyridine (PAPP) and an isatin backbone, which are the main pharmacophoric fragments of imatinib and sunitinib, respectively. A spiro-oxindole nucleus was used as a linker because it occurs in many compounds with antimyeloproliferative activity. Compounds 2a, 2b, 3c, 4c, and 4e showed promise, as they inhibited cell viability by between 45% and 61% at a concentration of 10 µM. The CC 50 of the most active substances was determined to be within 0.8-9.8 µM.
(© 2024 Deutsche Pharmazeutische Gesellschaft.)
Databáze: MEDLINE
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