Design, Synthesis, and Biological Evaluation of a Series of Benzo[de][1,7]naphthyridin-7(8H)-ones Bearing a Functionalized Longer Chain Appendage as Novel PARP1 Inhibitors

Abstract

A series of benzo[de][1,7]naphthyridin-7(8H)-ones possessing a functionalized long-chain appendage have been designed and evaluated as novel PARP1 inhibitors. The initial effort led to the first-generation PARP1 inhibitor 26 bearing a terminal phthalazin-1(2H)-one framework and showing remarkably high PARP1 inhibitory activity (0.31 nM) but only moderate potency in the cell. Further effort generated the second-generation lead 41, showing high potency against both the PARP1 enzyme and BRCA-deficient cells, especially for the BRCA1-deficient MDA-MB-436 cells (CC50 < 0.26 nM). Mechanistic studies revealed that the new PARP1 inhibitors significantly inhibited H2O2-triggered PARylation in SKOV3 cells, induced cellular accumulation of DNA double-strand breaks, and impaired cell-cycle progression in BRCA2-deficient cells. Significant potentiation on the cytotoxicity of Temozolomide was also observed. The unique structural character and exceptionally high potency of 41 made it stand out as a promising drug candidate worthy for further evaluation.

Stepwise development of structure–activity relationship of diverse PARP-1 inhibitors through comparative and validatedin silico modeling techniques and molecular dynamics simulation

“…Nevertheless, other parts of these molecules diverted from each other to a considerable extent depending on structural variation to access different interacting amino acid residues (Figure 3(A)). For example, bound ligand of PDB id 4HHY (Ye et al, 2013) formed hydrogen bond interaction with Arg217, whereas none of other ligands interacted with this amino acid. The terminal parts of most of these ligands were rather located far from this amino acid residue.…”

“…The nicotinamide binding site of the substrate was close to L helix as well as c and d strands. Six reported ligand-bound PARP-1 crystal structures (PDB Ids: 4HHY (Ye et al, 2013), 3L3M (Penning et al, 2010), 3L3L , 2RD6, 4L6S (Gangloff et al, 2013), and 3GN7) were aligned with each other by the help of Align Protein Structure tool of Maestro. Analyses of the aligned structures revealed that all ligands are superimposed with each other almost perfectly with respect to their nicotinamide-mimicking moieties (Figure 3(A)).…”

“…In order to substantiate these facts, the docked poses of the compounds were analyzed on the basis of Site Maps generated at the active site of the PARP-1 enzyme. Six aligned X-ray crystal structures of human PARP-1 (PDB Ids: 4HHY (Ye et al, 2013), 3L3 M (Penning et al, 2010), 3L3L , 2RD6, 4L6S (Gangloff et al, 2013), and 3GN7) were used to generate SiteMaps. The ligand bound pocket of these protein structures showed the highest druggability (SiteScore: 1.037, Dscore; 1.050, size: 339 and volume: 1173.06).…”

“…4HHZ (Ye et al, 2013) and hydrophobic interaction in 3L3M and 4HHY. Furthermore, Tyr228 also interacted in a different way with these three compounds (Cpds.…”

“…(A) Binding of nicotinamide residue of NAD + at PARP-1 catalytic site; (B) Binding interaction of bound ligand of PDB id 3L3M(Penning et al, 2010); and (C) Binding interaction of bound ligand of PDB id 4HHY(Ye et al, 2013).…”