Design, synthesis, and antitumor activity of novel compounds based on 1,2,4-triazolophthalazine scaffold: Apoptosis-inductive and PCAF-inhibitory effects.
Bioorg Chem
; 101: 104019, 2020 08.
Article
en En
| MEDLINE
| ID: mdl-32615465
The antitumor activity of newly synthesised triazolophthalazines (L-45 analogues) 10-32 was evaluated in human hepatocellular carcinoma (HePG-2), breast cancer (MCF-7), prostate cancer (PC3), and colorectal carcinoma (HCT-116) cells. Compounds 17, 18, 25, and 32 showed potent antitumor activity (IC50, 2.83-13.97 µM), similar to doxorubicin (IC50, 4.17-8.87 µM) and afatinib (IC50, 5.4-11.4 µM). HePG2 was inhibited by compounds 10, 17, 18, 25, 26, and 32 (IC50, 3.06-10.5 µM), similar to doxorubicin (IC50, 4.50 µM) and afatinib (IC50, 5.4 µM). HCT-116 and MCF-7 were susceptible to compounds 10, 17, 18, 25, and 32 (IC50, 2.83-10.36 and 5.69-11.36 µM, respectively), similar to doxorubicin and afatinib (IC50 = 5.23 and 4.17, and 11.4 and 7.1 µM, respectively). Compounds 17, 25, and 32 exerted potent activities against PC3 (IC50, 7.56-12.28 µM) compared with doxorubicin (IC50, 8.87 µM) and afatinib (IC50 7.7 µM). Compounds 17 and 32 were the strongest PCAF inhibitors (IC50, 5.31 and 10.30 µM, respectively) and compounds 18 and 25 exhibited modest IC50 values (17.09 and 32.96 µM, respectively) compared with bromosporine (IC50, 5.00 µM). Compound 17 was cytotoxic to HePG2 cells (IC50, 3.06 µM), inducing apoptosis in the pre-G phase and arresting the cell cycle in the G2/M phase. Molecular docking for the most active PCAF inhibitors (17 and 32) was performed.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Ftalazinas
/
Triazoles
/
Diseño de Fármacos
/
Apoptosis
/
Factores de Transcripción p300-CBP
/
Antineoplásicos
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Bioorg Chem
Año:
2020
Tipo del documento:
Article
País de afiliación:
Egipto