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

PAPP chronic myeloid leukemia imatinib spiro‐oxindoles tyrosine kinase inhibitors

Journal

Archiv der Pharmazie
ISSN: 1521-4184
Titre abrégé: Arch Pharm (Weinheim)
Pays: Germany
ID NLM: 0330167

Informations de publication

Date de publication:
16 Apr 2024
Historique:
revised: 15 03 2024
received: 10 01 2024
accepted: 29 03 2024
medline: 17 4 2024
pubmed: 17 4 2024
entrez: 16 4 2024
Statut: aheadofprint

Résumé

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

Identifiants

pubmed: 38627294
doi: 10.1002/ardp.202400029
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

e2400029

Subventions

Organisme : Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro
Organisme : Conselho Nacional de Desenvolvimento Científico e Tecnológico

Informations de copyright

© 2024 Deutsche Pharmazeutische Gesellschaft.

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Auteurs

Liviane D de Azevedo (LD)

Departamento de Síntese Orgânica, Fundação Oswaldo Cruz, Farmanguinhos, Rio de Janeiro, Brasil.

Debora I Leite (DI)

Departamento de Síntese Orgânica, Fundação Oswaldo Cruz, Farmanguinhos, Rio de Janeiro, Brasil.

Andressa P de Oliveira (AP)

Departamento de Síntese Orgânica, Fundação Oswaldo Cruz, Farmanguinhos, Rio de Janeiro, Brasil.

Floriano P S Junior (FPS)

Fundação Oswaldo Cruz, Laboratório de Bioquímica Experimental e Computacional de Fármacos, Instituto Oswaldo Cruz, Rio de Janeiro, Brasil.

Rafael F Dantas (RF)

Fundação Oswaldo Cruz, Laboratório de Bioquímica Experimental e Computacional de Fármacos, Instituto Oswaldo Cruz, Rio de Janeiro, Brasil.

Monica M Bastos (MM)

Departamento de Síntese Orgânica, Fundação Oswaldo Cruz, Farmanguinhos, Rio de Janeiro, Brasil.

Nubia Boechat (N)

Departamento de Síntese Orgânica, Fundação Oswaldo Cruz, Farmanguinhos, Rio de Janeiro, Brasil.

Luiz C F Pimentel (LCF)

Departamento de Síntese Orgânica, Fundação Oswaldo Cruz, Farmanguinhos, Rio de Janeiro, Brasil.

Classifications MeSH