Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors based on a tetrahydro-1(2H)-isoquinolinone Scaffold: Synthesis, biological evaluation and X-ray crystal structure

Synthesis

Volumn , Issue 9, 2005, Pages 1550-1554

  Peukert, Stefan ^a,b   Schwahn, Uwe ^a   Güssregen, Stefan ^a   Schreuder, Herman ^a   Hofmeister, Armin ^a  

^a SANOFI AVENTIS DEUTSCHLAND GMBH   (Germany)

^b NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH   (United States)

Author keywords

Crystal structure; Isoquinolinones; Medicinal chemistry; PARP inhibitors; Structure activity relationship

Indexed keywords

AMINES; CRYSTAL STRUCTURE; ENZYMES; NITROGEN COMPOUNDS; SYNTHESIS (CHEMICAL); X RAY ANALYSIS;

NICOTINAMIDES; NON-PLANAR RING SYSTEMS; X RAY CRYSTAL STRUCTURE;

ENZYME INHIBITION;

NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE INHIBITOR;

ANIMAL CELL; ARTICLE; BIOLOGICAL ACTIVITY; CRYSTAL STRUCTURE; DRUG STRUCTURE; DRUG SYNTHESIS; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION; X RAY CRYSTALLOGRAPHY;

EID: 20644450130     PISSN: 00397881     EISSN: None     Source Type: Journal    
DOI: 10.1055/s-2005-865324     Document Type: Article

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14. The catalytic fragment of chicken PARP-1 was obtained from Prof. DeMurcia of the Ecole Supérieure de Biotechnology de Strasbourg. Native PARP-1 was crystallized at pH 8.5 with 18% PEG 4000 and 8% i-PrOH as precipitant, following the protocol of Jung et al.: Jung, S.; Miranda, E. A.; De Murcia, J. M.; Niedergang, C.; Delarue, M.; Schulz, G. E.; DeMurcia, G. M. J. Mol. Biol. 1994, 244, 114. Inhibitor complexes were obtained by soaking native crystals with the appropriate inhibitors. The space group and cell dimensions of the crystals obtained were the same as in the published crystal structures. We obtained well diffracting crystals, diffracting to 2.2 and 2.1 Å resolutions, respectively. We did not observe any major differences between our PARP structures and the PARP structures present in the PDB.
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