New poly(ADP-ribose) polymerase-1 inhibitors with antioxidant activity based on 4-carboxamidobenzimidazole-2-ylpyrroline and -tetrahydropyridine nitroxides and their precursors.
4-Carboxamidobenzimidazoles were previously described as PARP inhibitor compounds. Here we report upon 4-carboxamido-1H-benzimidazoles substituted in the 2-position with nitroxides or their amine or hydroxylamine precursors. Among the new molecules, a highly active PARP inhibitor 4h (IC(50) = 14 nM) was identified with antioxidant/radical scavenger activity. We concluded that in most cases sterically hindered amines are better PARP inhibitors than their oxidized form and structural changes in the 2-substituted 4-carboxamido-1H-benzimidazoles (such as N-substitution or changing the position of the carboxamide group) were detrimental to PARP inhibition activity but not to antioxidant activity. These results indicate the advantages of combining an antioxidant nitroxide or nitroxide precursor with a PARP inhibitor molecule to decrease or eliminate the deleterious processes initiated by reactive oxygen and reactive nitrogen species (ROS and RNS). The radical scavenging capability of 4h was demonstrated by EPR study of urine collected after drug administration.
Kálai
Tamás
T
Department of Organic and Medicinal Chemistry, University of Pecs, H-7624 Pecs, Szigeti str. 12, Hungary.
Balog
Mária
M
Szabó
Alíz
A
Gulyás
Gergely
G
Jeko
József
J
Sümegi
Balázs
B
Hideg
Kálmán
K
D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004578:Electron Spin Resonance Spectroscopy; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D051379:Mice; D008810:Mice, Inbred C57BL; D009589:Nitrogen Oxides / Q000737:chemistry / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats
D000975:Antioxidants; D004791:Enzyme Inhibitors; D009589:Nitrogen Oxides; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C499320:PARP1 protein, human; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1