Discovery of phthalazino[1,2-b]-quinazolinone derivatives as multi-target HDAC inhibitors for the treatment of hepatocellular carcinoma via activating the p53 signal pathway

In view of histone deacetylases (HDACs) as a promising target for cancer therapy, a series of phthalazino [1,2-b]-quinazolinone units were hybrided with ortho-aminoanilide or hydroxamic acid to serve as multitarget HDAC inhibitors for the treatment of solid tumors. Among the target compounds, 8h possessed nano-molar IC50 values toward the tested cancer cells and HDAC subtypes, which was more potent than the HDAC inhibitor SAHA (vorinostat). Mechanism study revealed that compound 8h could suppress the HepG2 cell proliferation via prompting the acetylation of histone 3 (H3) and a-tubulin, and activating the p53 signal pathway as designed. In addition, compound 8h exhibited much stronger in vivo antitumor efficacy than SAHA in the HepG2 xenograft tumor model with negligible toxicity. As a novel multi-target HDAC inhibitor, compound 8h deserves further development as a potential anticancer agent. (c) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

This study identified compound 8h as a potent multitarget HDAC inhibitor with nano-molar IC50 values against cancer cells and HDAC subtypes. Compound 8h effectively suppressed HepG2 cell proliferation through the acetylation of histone 3 (H3), activation of the p53 signal pathway, and exhibited superior in vivo antitumor efficacy compared to SAHA.