New pyrimidine derivatives as potential agents against hepatocellular carcinoma: design, synthesis, and and biological evaluations.
1/5 보강
[BACKGROUND] Sorafenib is a tyrosine kinase inhibitor (TKI) used to treat hepatocellular carcinoma (HCC), but this drug causes clinically significant toxicities in approximately 50% of patients.
APA
Bertrand J, Montorfano I, et al. (2026). New pyrimidine derivatives as potential agents against hepatocellular carcinoma: design, synthesis, and and biological evaluations.. Frontiers in pharmacology, 17, 1745214. https://doi.org/10.3389/fphar.2026.1745214
MLA
Bertrand J, et al.. "New pyrimidine derivatives as potential agents against hepatocellular carcinoma: design, synthesis, and and biological evaluations.." Frontiers in pharmacology, vol. 17, 2026, pp. 1745214.
PMID
41693770 ↗
Abstract 한글 요약
[BACKGROUND] Sorafenib is a tyrosine kinase inhibitor (TKI) used to treat hepatocellular carcinoma (HCC), but this drug causes clinically significant toxicities in approximately 50% of patients. Given the high frequency and severity of these side effects, it is necessary to develop new, safer drugs to treat this cancer.
[PURPOSE] Novel 2,6,9-trisubstituted pyrimidine derivatives were synthesised and evaluated as potential antitumour agents for HCC.
[MATERIALS AND METHODS] Twelve compounds () were obtained by a four-step synthetic procedure using a simple and efficient methodology in which two key reactions were promoted by microwave irradiation. Subsequently, compounds were evaluated for cytotoxic activity against the HCC cell line HepG2 and other cell lines; in the HepG2 xenograft tumour model; and (docking and dynamic simulations).
[RESULTS AND DISCUSSION] Compound proved to be the most promising of this series (IC = 5.6 µM), as well as being more index selective than sorafenib and with lower cytotoxicity in Vero cells (18.92 µM). In addition, was further evaluated in Huh-7 cells and demonstrated selectivity for HCC. Docking studies on the proposed targets, VEGFR-2 and B-raf, indicated that could bind to them with binding energies and interaction patterns similar to those of sorafenib. The interaction pattern at the VEGFR-2 binding site was corroborated by dynamic studies over 100 ns. A possible mechanism of -induced HepG2 cell death was investigated. Experiments on caspases-3, -7, -8, -9, Apaf-1, Cyt-c, ERK1/2, and p53 showed that they were all activated, whereas Bcl-2 was inhibited by in HepG2 cells. Furthermore, induced the accumulation of reactive oxygen species (ROS) in HepG2 cells. These results suggest that apoptosis in HepG2 was caused by: (i) a caspase-dependent pathway and (ii) changes in the cellular levels of Bcl-2 family proteins and ROS. In addition, attenuated the growth of HepG2 xenograft tumours in mice at a dose of 1 mg/kg for 3 weeks.
[CONCLUSION] Based on these results, this pyrimidine derivative could be an interesting compound for the design of new agents against HCC.
[PURPOSE] Novel 2,6,9-trisubstituted pyrimidine derivatives were synthesised and evaluated as potential antitumour agents for HCC.
[MATERIALS AND METHODS] Twelve compounds () were obtained by a four-step synthetic procedure using a simple and efficient methodology in which two key reactions were promoted by microwave irradiation. Subsequently, compounds were evaluated for cytotoxic activity against the HCC cell line HepG2 and other cell lines; in the HepG2 xenograft tumour model; and (docking and dynamic simulations).
[RESULTS AND DISCUSSION] Compound proved to be the most promising of this series (IC = 5.6 µM), as well as being more index selective than sorafenib and with lower cytotoxicity in Vero cells (18.92 µM). In addition, was further evaluated in Huh-7 cells and demonstrated selectivity for HCC. Docking studies on the proposed targets, VEGFR-2 and B-raf, indicated that could bind to them with binding energies and interaction patterns similar to those of sorafenib. The interaction pattern at the VEGFR-2 binding site was corroborated by dynamic studies over 100 ns. A possible mechanism of -induced HepG2 cell death was investigated. Experiments on caspases-3, -7, -8, -9, Apaf-1, Cyt-c, ERK1/2, and p53 showed that they were all activated, whereas Bcl-2 was inhibited by in HepG2 cells. Furthermore, induced the accumulation of reactive oxygen species (ROS) in HepG2 cells. These results suggest that apoptosis in HepG2 was caused by: (i) a caspase-dependent pathway and (ii) changes in the cellular levels of Bcl-2 family proteins and ROS. In addition, attenuated the growth of HepG2 xenograft tumours in mice at a dose of 1 mg/kg for 3 weeks.
[CONCLUSION] Based on these results, this pyrimidine derivative could be an interesting compound for the design of new agents against HCC.