90417-38-2Relevant articles and documents
Studies towards hypoxia-activated prodrugs of PARP inhibitors
Dickson, Benjamin D.,Wong, Way Wua,Wilson, William R.,Hay, Michael P.
, (2019/05/02)
Poly(ADP-ribose)polymerase (PARP) inhibitors (PARPi) have recently been approved for the treatment of breast and ovarian tumors with defects in homologous recombination repair (HRR). Although it has been demonstrated that PARPi also sensitize HRR competent tumors to cytotoxic chemotherapies or radiotherapy, normal cell toxicity has remained an obstacle to their use in this context. Hypoxia-activated prodrugs (HAPs) provide a means to limit exposure of normal cells to active drug, thus adding a layer of tumor selectivity. We have investigated potential HAPs of model PARPi in which we attach a bioreducible “trigger” to the amide nitrogen, thereby blocking key binding interactions. A representative example showed promise in abrogating PARPi enzymatic activity in a biochemical assay, with a ca. 160-fold higher potency of benzyl phthalazinone 4 than the corresponding model HAP 5, but these N-alkylated compounds did not release the PARPi upon one-electron reduction by radiolysis. Therefore, we extended our investigation to include NU1025, a PARPi that contains a phenol distal to the core binding motif. The resulting 2-nitroimidazolyl ether provided modest abrogation of PARPi activity with a ca. seven-fold decrease in potency, but released the PARPi efficiently upon reduction. This investigation of potential prodrug approaches for PARPi has identified a useful prodrug strategy for future exploration.
NEUROLOGICALLY-ACTIVE COMPOUNDS
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Page 117, (2010/02/06)
The present invention relates to neurologically-active compounds, being heterocyclic compounds having two fused 6-membered rings with a nitrogen atom at position 1 and a hydroxy or mercapto group at position 8 with at least one ring being aromatic. Also disclosed are processes for the preparation of these compounds and their use as pharmaceutical or veterinary agents, in particular for the treatment of neurological conditions, more specifically neurodegenerative conditions such as Alzheimer's disease.
Resistance-modifying agents. 5.1 Synthesis and biological properties of quinazolinone inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP)
Griffin, Roger J.,Srinivasan, Sheila,Bowman, Karen
, p. 5247 - 5256 (2007/10/03)
Clinical studies concerning the role of poly(ADP-ribose) polymerase (PARP) in the repair of drug- and radiation-induced DNA damage have been impeded by the poor solubility, lack of potency, and limited specificity of currently available inhibitors. A seri