Discovery and SAR of novel, potent and selective hexahydrobenzonaphthyridinone inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1)

Torrisi, Caterina; Bisbocci, Monica; Ingenito, Raffaele; Ontoria, Jesus M.; Rowley, Michael; Schultz‐Fademrecht, Carsten; Toniatti, Carlo; Jones, Philip

doi:10.1016/j.bmcl.2009.12.002

Cited by 10 publications

(4 citation statements)

References 15 publications

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“…All the newly synthesized benzo[ de ][1,7]naphthyridin-7(8 H )-ones were evaluated for their ability to inhibit PARP1 enzymatic activity. , The clinical compound 3 was used as the reference compound, and our data were identical to that reported . First, compounds 10 – 13 with a bicyclic amino group attached to the N1 of benzo[ de ][1,7]naphthyridin-7(8 H )-one core through a 2-oxo-ethyl (acetamide) linker were prepared to increase molecular flexibility.…”

Section: Resultsmentioning

confidence: 98%

“…We recently found that replacement of the catechol function in 5 with a lactam led to benzo[de] [1,7]naphthyridin-7(8H)-ones 6 that were completely inactive at any of dopamine receptors. Interestingly, Torrisi and coauthors 40 recently reported that compound 6 with an N-acyl group (e.g., R = pyrrolidin-3-yl) displayed onedigit nanomolar PARP1 enzymatic potency but only moderate or no inhibition to the PARylation in whole cells. This result promoted us to switch our focus on the development of novel PARP1 inhibitors bearing the benzo[de] [1,7]naphthyridin-7(8H)-one scaffold with a long-chain appendage as that in clinical compound 3.…”

Section: ■ Introductionmentioning

confidence: 99%

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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

Chen

et al. 2013

J. Med. Chem.

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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.

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Section: Resultsmentioning

confidence: 98%

Section: ■ Introductionmentioning

confidence: 99%

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

Chen

et al. 2013

J. Med. Chem.

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“…The recent discovery of benzo[de] [1,7]naphtyridin-7(8H)-one scaffold as a new pharmacophore capable of interacting with the NAD + binding site [56] has promoted the development of new PARP-1 inhibitors bearing this lactam framework combined with M A N U S C R I P T…”

Section: Figure 4 Comes About Herementioning

confidence: 99%

Phthalazin-1(2H)-one as a remarkable scaffold in drug discovery

Vila

Besada

Costas

et al. 2015

European Journal of Medicinal Chemistry

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“…Two hundred and forty structurally diverse compounds were explored as PARP-1 inhibitors by Merck Research Laboratories Ferrigno et al, 2010;Jones et al, 2009;Orvieto et al, 2009;Pescatore et al, 2010;Scarpelli et al, 2010;Torrisi et al, 2010) and these compounds were selected in the present work. The biological activity value (IC 50 (nM)) was converted to the negative logarithmic scale (pIC 50 = log 10 9 /IC 50 ) and was subsequently used as thedependent variable in different regression analyses (e.g.…”

Section: Data-setmentioning

confidence: 99%

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

Halder

Saha

et al. 2014

Journal of Biomolecular Structure and Dynamics

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Inhibitors of poly (ADP-ribose) polymerase-1 (PARP-1) enzyme are useful for the treatment of various diseases including cancer. Comparative in silico studies were performed on different ligand-based (2D-QSAR, Kernel-based partial least square (KPLS) analysis, Pharmacophore Search Engine (PHASE) pharmacophore mapping), and structure-based (molecular docking, MM-GBSA analyses, Gaussian-based 3D-QSAR analyses on docked poses) modeling techniques to explore the structure-activity relationship of a diverse set of PARP-1 inhibitors. Two-dimensional (2D)-QSAR highlighted the importance of charge topological index (JGI7), fractional polar surface area (JursFPSA3), and connectivity index (CIC2) along with different molecular fragments. Favorable and unfavorable fingerprints were demonstrated in KPLS analysis, whereas important pharmacophore features (one acceptor, one donor, and two ring aromatic) along with favorable and unfavorable field effects were demonstrated in PHASE-based pharmacophore model. MM-GBSA analyses revealed significance of different polar, non-polar, and solvation energies. Docking-based alignment of ligands was used to perform Gaussian-based 3D-QSAR study that further demonstrated importance of different field effects. Overall, it was found that polar interactions (hydrogen bonding, bridged hydrogen bonding, and pi-cation) play major roles for higher activity. Steric groups increase the total contact surface area but it should have higher fractional polar surface area to adjust solvation energy. Structure-based pharmacophore mapping spotted the positive ionizable feature of ligands as the most important feature for discriminating highly active compounds from inactives. Molecular dynamics simulation, conducted on highly active ligands, described the dynamic behaviors of the protein complexes and supported the interpretations obtained from other modeling analyses. The current study may be useful for designing PARP-1 inhibitors.

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Discovery and SAR of novel, potent and selective hexahydrobenzonaphthyridinone inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1)

Cited by 10 publications

References 15 publications

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

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

Phthalazin-1(2H)-one as a remarkable scaffold in drug discovery

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

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