期刊
MOLECULES
卷 27, 期 3, 页码 -出版社
MDPI
DOI: 10.3390/molecules27030750
关键词
tyrosine kinase inhibitors; imatinib; K562; A549; PAPP and isatin
资金
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior-Brasil (CAPES) [001]
- Foundations for Research of the State of Rio de Janeiro (FAPERJ) [E-26/202.805/2017]
- National Council of R&D of Brazil (CNPq) [306193/2018-3, 304059/2018-8]
This study synthesized ten novel analogs containing isatins and the phenylamino-pyrimidine pyridine (PAPP) skeleton and evaluated their antiproliferative ability. The results suggest that several of these analogs exhibit stronger inhibitory effects against lung cancer and can be used as prototypes for the development of more effective anti-lung cancer drugs.
Tyrosine kinase enzymes are among the primary molecular targets for the treatment of some human neoplasms, such as those in lung cancer and chronic myeloid leukemia. Mutations in the enzyme domain can cause resistance and new inhibitors capable of circumventing these mutations are highly desired. The objective of this work was to synthesize and evaluate the antiproliferative ability of ten new analogs that contain isatins and the phenylamino-pyrimidine pyridine (PAPP) skeleton, the main pharmacophore group of imatinib. The 1,2,3-triazole core was used as a spacer in the derivatives through a click chemistry reaction and gave good yields. All the analogs were tested against A549 and K562 cells, lung cancer and chronic myeloid leukemia (CML) cell lines, respectively. In A549 cells, the 3,3-difluorinated compound (3a), the 5-chloro-3,3-difluorinated compound (3c) and the 5-bromo-3,3-difluorinated compound (3d) showed IC50 values of 7.2, 6.4, and 7.3 mu M, respectively, and were all more potent than imatinib (IC50 of 65.4 mu M). In K562 cells, the 3,3-difluoro-5-methylated compound (3b) decreased cell viability to 57.5% and, at 10 mu M, showed an IC50 value of 35.8 mu M (imatinib, IC50 = 0.08 mu M). The results suggest that 3a, 3c, and 3d can be used as prototypes for the development of more potent and selective derivatives against lung cancer.
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