Discovery of novel quinazoline-2,4(1H,3H)-dione derivatives as potent PARP-2 selective inhibitors. 2017

Hailong Zhao, and Ming Ji, and Guonan Cui, and Jie Zhou, and Fangfang Lai, and Xiaoguang Chen, and Bailing Xu
Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.

The PARP-2 selective inhibitor is important for clarifying specific roles of PARP-2 in the pathophysiological process and developing desired drugs with reduced off-target side effects. In this work, a series of novel quinazoline-2,4(1H,3H)-dione derivatives was designed and synthesized to explore isoform selective PARP inhibitors. As a result, compound 11a (PARP-1 IC50=467nM, PARP-2 IC50=11.5nM, selectivity PARP-1/PARP-2=40.6) was disclosed as the most selective PARP-2 inhibitor with high potency to date. The binding features of compound 11a within PARP-1 and PARP-2 were investigated respectively to provide useful insights for the further construction of new isoform selective inhibitors of PARP-1 and PARP-2 by using CDOCKER program.

UI MeSH Term Description Entries
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D011065 Poly(ADP-ribose) Polymerases Enzymes that catalyze the transfer of multiple ADP-RIBOSE groups from nicotinamide-adenine dinucleotide (NAD) onto protein targets, thus building up a linear or branched homopolymer of repeating ADP-ribose units i.e., POLY ADENOSINE DIPHOSPHATE RIBOSE. ADP-Ribosyltransferase (Polymerizing),Poly ADP Ribose Polymerase,Poly(ADP-Ribose) Synthase,Poly(ADP-ribose) Polymerase,PARP Polymerase,Poly ADP Ribose Transferase,Poly ADP-Ribose Synthase,Poly(ADP-Ribose) Transferase,Poly(ADPR) Polymerase,Poly(ADPribose) Polymerase,Poly ADP Ribose Synthase,Polymerase, PARP,Synthase, Poly ADP-Ribose
D011799 Quinazolines A group of aromatic heterocyclic compounds that contain a bicyclic structure with two fused six-membered aromatic rings, a benzene ring and a pyrimidine ring. Quinazoline
D004791 Enzyme Inhibitors Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D055808 Drug Discovery The process of finding chemicals for potential therapeutic use. Drug Prospecting,Discovery, Drug,Prospecting, Drug
D020128 Inhibitory Concentration 50 The concentration of a compound needed to reduce population growth of organisms, including eukaryotic cells, by 50% in vitro. Though often expressed to denote in vitro antibacterial activity, it is also used as a benchmark for cytotoxicity to eukaryotic cells in culture. IC50,Concentration 50, Inhibitory
D021241 Spectrometry, Mass, Electrospray Ionization A mass spectrometry technique used for analysis of nonvolatile compounds such as proteins and macromolecules. The technique involves preparing electrically charged droplets from analyte molecules dissolved in solvent. The electrically charged droplets enter a vacuum chamber where the solvent is evaporated. Evaporation of solvent reduces the droplet size, thereby increasing the coulombic repulsion within the droplet. As the charged droplets get smaller, the excess charge within them causes them to disintegrate and release analyte molecules. The volatilized analyte molecules are then analyzed by mass spectrometry. ESI Mass Spectrometry,Electrospray Ionization Mass Spectrometry,Mass Spectrometry, ESI,Spectrometry, ESI Mass
D066241 Carbon-13 Magnetic Resonance Spectroscopy Magnetic resonance spectroscopy involving detection of changes in the resonance of carbon-13 nuclei in organic molecules. 13C NMR,Carbon 13 Magnetic Resonance Spectroscopy
D066244 Proton Magnetic Resonance Spectroscopy Spectroscopy technique which measures changes in organic compounds by tracking the spectral energy of absorption of HYDROGEN atoms. 1H NMR,1H-MRS,1H-NMR

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