Carbamoylation at C-8 position of natural 3-arylcoumarin scaffold for the discovery of novel PARP-1 inhibitors with potent anticancer activity.
Eur J Med Chem
; 277: 116726, 2024 Nov 05.
Article
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| MEDLINE
| ID: mdl-39116535
ABSTRACT
Structural modification based on natural privileged scaffolds has proven to be an attractive approach to generate potential antitumor candidates with high potency and specific targeting. As a continuation of our efforts to identify potent PARP-1 inhibitors, natural 3-arylcoumarin scaffold was served as the starting point for the construction of novel structural unit for PARP-1 inhibition. Herein, a series of novel 8-carbamyl-3-arylcoumarin derivatives were designed and synthesized. The antiproliferative activities of target compounds against four BRCA-mutated cancer cells (SUM149PT, HCC1937, MDA-MB-436 and Capan-1) were evaluated. Among them, compound 9b exhibited excellent antiproliferative effects against SUM149PT, HCC1937 and Capan-1 cells with IC50 values of 0.62, 1.91 and 4.26 µM, respectively. Moreover, 9b could significantly inhibit the intracellular PARP-1/2 activity in SUM149PT cells with IC50 values of 2.53 nM and 6.45 nM, respectively. Further mechanism studies revealed that 9b could aggravate DNA double-strand breaks, increase ROS production, decrease mitochondrial membrane potential, arrest cell cycle at G2/M phase and ultimately induce apoptosis in SUM149PT cells. In addition, molecular docking study demonstrated that the binding mode of 9b with PARP-1 was similar to that of niraparib, forming multiple hydrogen bond interactions with the active site of PARP-1. Taken together, these findings suggest that 8-carbamyl-3-arylcoumarin scaffold could serve as an effective structural unit for PARP-1 inhibition and offer a valuable paradigm for the structural modification of natural products.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Ensayos de Selección de Medicamentos Antitumorales
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Cumarinas
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Proliferación Celular
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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:
Eur J Med Chem
Año:
2024
Tipo del documento:
Article
Pais de publicación:
Francia