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Spirooxadiazoline-oxindoles derived from imatinib show antimyeloproliferative potential in K562 cells.
- Source :
-
Archiv der Pharmazie [Arch Pharm (Weinheim)] 2024 Aug; Vol. 357 (8), pp. e2400029. Date of Electronic Publication: 2024 Apr 16. - Publication Year :
- 2024
-
Abstract
- 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 <subscript>50</subscript> of the most active substances was determined to be within 0.8-9.8 µM.<br /> (© 2024 Deutsche Pharmazeutische Gesellschaft.)
- Subjects :
- Humans
K562 Cells
Structure-Activity Relationship
Protein Kinase Inhibitors pharmacology
Protein Kinase Inhibitors chemical synthesis
Protein Kinase Inhibitors chemistry
Cell Proliferation drug effects
Molecular Structure
Dose-Response Relationship, Drug
Fusion Proteins, bcr-abl antagonists & inhibitors
Fusion Proteins, bcr-abl metabolism
Spiro Compounds pharmacology
Spiro Compounds chemistry
Spiro Compounds chemical synthesis
Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy
Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology
Drug Screening Assays, Antitumor
Imatinib Mesylate pharmacology
Oxindoles pharmacology
Oxindoles chemical synthesis
Oxindoles chemistry
Antineoplastic Agents pharmacology
Antineoplastic Agents chemical synthesis
Antineoplastic Agents chemistry
Cell Survival drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1521-4184
- Volume :
- 357
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Archiv der Pharmazie
- Publication Type :
- Academic Journal
- Accession number :
- 38627294
- Full Text :
- https://doi.org/10.1002/ardp.202400029