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
Abstract
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 multi-target HDAC inhibitors for the treatment of solid tumors. Among the target compounds, 8h possessed nano-molar IC 50 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 α-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.
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The majority of hydroxamate HDACi have a propensity to act in a pan-inhibitory fashion.
“The majority of hydroxamate HDACi have a propensity to act in a pan-inhibitory fashion (Figure 6A) [42–49].”
From Medicinal chemistry advances in targeting class I histone deacetylases (2023) · cites this paper as [48]
Trichostatin A, fimepinostat, and quisinostat all inhibit HDACs 1-3 in the picomolar range despite having different linkers.
“For example, trichostatin A contains a chain of sp2-hybridized carbons for a linker while fimepinostat and quisinostat contain pyrimidines as linkers, yet all 3 molecules inhibit HDACs 1–3 in the picomolar range (Figure 6A) [43, 44, 48].”
From Medicinal chemistry advances in targeting class I histone deacetylases (2023) · cites this paper as [48]
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Medicinal chemistry advances in targeting class I histone deacetylases
Abdallah, D. I., de Araujo, E. D., Patel, N. H., Hasan, L. S., Moriggl, R., Krämer, O. H., & Gunning, P. T. (2023) · Exploration of Targeted Anti-tumor Therapy · doi:10.37349/etat.2023.00166 · Cited by 15 · see citing works
“An interesting observation is the presence of free-amine and N-heterocycles in the cap region across multiple inhibitors (e.g., fimepinostat, quisinostat, HDAC-IN-30, and pracinostat), which may be contributing to increased affinity towards HDAC.”
Background
- Authors
- Liu, Q., Zhang, B., Wang, Y., Wang, X., & Gou, S.
- Affiliations
- Southeast University (CN)
- Venue
- European Journal of Medicinal Chemistry
- Publisher
- Elsevier BV
- Published
- 2022-02
- Volume
- 229
- Pages
- 114058
- ISSN
- 0223-5234 (ISSN-L)
- OpenAlex
- W4200328003
- Cited by
- 49
- References
- 4
- Citations by year
- 2026: 3 · 2025: 19 · 2024: 9 · 2023: 13 · 2022: 5
- FWCI
- 2.20
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- European Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Physical Sciences › Chemistry › Organic Chemistry › Quinazolinone synthesis and applications
- Keywords
- histone deacetylase inhibitors, hepatocellular carcinoma, p53 pathway, histone H3 acetylation, alpha-tubulin acetylation, HepG2 cells, vorinostat, anticancer activity
- MeSH terms
- Vorinostat, Acetylation, Animals, Antineoplastic Agents, Drug Screening Assays, Antitumor, Carcinoma, Hepatocellular, Histone Deacetylases, Histones, Humans, Hydroxamic Acids, Liver Neoplasms, Male, Phthalazines, Structure-Activity Relationship, Tubulin, Signal Transduction, Tumor Suppressor Protein p53, Cell Line, Tumor, Cell Proliferation, Mice, Quinazolinones, Histone Deacetylase Inhibitors, Molecular Docking Simulation
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