Design, synthesis and antitumor activities of phthalazinone derivatives as PARP-1 inhibitors and PARP-1/HDAC-1 inhibitors.
Bioorg Chem
; 151: 107556, 2024 Oct.
Article
en En
| MEDLINE
| ID: mdl-39068717
ABSTRACT
In recent years, poly(ADP-ribose)polymerase-1 (PARP-1) and histone deacetylase (HDAC) have emerged as significant targets in tumor therapy, garnering widespread attention. In this study, we designed and synthesized two novel phthalazinone PARP-1 inhibitors and dual PARP-1/HDAC-1 inhibitors, named DLC-1-46 containing dithiocarboxylate fragments and DLC-47-63 containing hydroxamic acid fragments, and evaluated their inhibitory activities on enzymes and cells. Among the PARP-1 inhibitors, most compounds exhibited high inhibitory activity against the PARP-1 enzyme, with DLC-1-6 being particularly notable, showing IC50 values <0.2â¯nM. Notably, DLC-1 demonstrated significant anti-proliferative activity, with IC50 values for inhibiting the proliferation of MDA-MB-436, MDA-MB-231, and MCF-7 cells reaching 0.08, 26.39, and 1.01⯵M, respectively. Further investigation revealed that DLC-1 arrested MDA-MB-231 cells in the G1 phase and induced apoptosis in a dose-dependent manner. Among the designed dual PARP-1/HDAC-1 inhibitors, several compounds exhibited potent dual-target inhibitory activity, with DLC-49 displaying IC50 values of 0.53â¯nM and 17â¯nM for PARP-1 and HDAC-1, respectively. DLC-50 demonstrated the most potent anti-proliferative activity, with IC50 values for inhibiting the proliferation of MDA-MB-436, MDA-MB-231, and MCF-7 cells at 0.30, 2.70, and 2.41⯵M, respectively. Cell cycle arrest and apoptosis assays indicated that DLC-50 arrested the cell cycle in the G2 phase and induced apoptosis in HCT-116 cells. Our findings present a novel avenue for further exploration of PARP-1 inhibitors and dual PARP-1/HDAC-1 inhibitors.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Ftalazinas
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Ensayos de Selección de Medicamentos Antitumorales
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Diseño de Fármacos
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Proliferación Celular
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Histona Desacetilasa 1
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Inhibidores de Histona Desacetilasas
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Inhibidores de Poli(ADP-Ribosa) Polimerasas
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Poli(ADP-Ribosa) Polimerasa-1
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Antineoplásicos
Límite:
Humans
Idioma:
En
Revista:
Bioorg Chem
Año:
2024
Tipo del documento:
Article
País de afiliación:
China