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Discovery of Novel Apigenin-Piperazine Hybrids as Potent and Selective Poly (ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors for the Treatment of Cancer.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2021 Aug 26; Vol. 64 (16), pp. 12089-12108. Date of Electronic Publication: 2021 Aug 18. - Publication Year :
- 2021
-
Abstract
- Poly (ADP-ribose) polymerase-1 (PARP-1) is a potential target for the discovery of chemosensitizers and anticancer drugs. Amentoflavone ( AMF ) is reported to be a selective PARP-1 inhibitor. Here, structural modifications and trimming of AMF have led to a series of AMF derivatives ( 9a-h ) and apigenin-piperazine/piperidine hybrids ( 14a-p , 15a-p , 17a-h , and 19a-f ), respectively. Among these compounds, 15l exhibited a potent PARP-1 inhibitory effect (IC <subscript>50</subscript> = 14.7 nM) and possessed high selectivity to PARP-1 over PARP-2 (61.2-fold). Molecular dynamics simulation and the cellular thermal shift assay revealed that 15l directly bound to the PARP-1 structure. In in vitro and in vivo studies, 15l showed a potent chemotherapy sensitizing effect against A549 cells and a selective cytotoxic effect toward SK-OV-3 cells through PARP-1 inhibition. 15l·2HCl also displayed good ADME characteristics, pharmacokinetic parameters, and a desirable safety margin. These findings demonstrated that 15l·2HCl may serve as a lead compound for chemosensitizers and the (BRCA-1)-deficient cancer therapy.
- Subjects :
- Animals
Antineoplastic Agents chemical synthesis
Antineoplastic Agents metabolism
Antineoplastic Agents pharmacokinetics
Cell Line, Tumor
Drug Discovery
Female
Flavones chemical synthesis
Flavones metabolism
Flavones pharmacokinetics
Humans
Male
Mice, Inbred BALB C
Mice, Nude
Molecular Docking Simulation
Molecular Dynamics Simulation
Molecular Structure
Piperazines chemical synthesis
Piperazines metabolism
Piperazines pharmacokinetics
Poly (ADP-Ribose) Polymerase-1 metabolism
Poly(ADP-ribose) Polymerase Inhibitors chemical synthesis
Poly(ADP-ribose) Polymerase Inhibitors metabolism
Poly(ADP-ribose) Polymerase Inhibitors pharmacokinetics
Protein Binding
Rats, Sprague-Dawley
Structure-Activity Relationship
Mice
Rats
Antineoplastic Agents therapeutic use
Flavones therapeutic use
Neoplasms drug therapy
Piperazines therapeutic use
Poly (ADP-Ribose) Polymerase-1 antagonists & inhibitors
Poly(ADP-ribose) Polymerase Inhibitors therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 64
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 34404206
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.1c00735