3177-80-8Relevant 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.
A scaleable formal total synthesis of dehydrogliotoxin
McMahon, Travis C.,Stanley, Sarah,Kazyanskaya, Edward,Hung, Deborah,Wood, John L.
scheme or table, p. 2262 - 2264 (2011/05/05)
A formal total synthesis of the epidithiodiketopiperazine natural product, dehydrogliotoxin (2), utilizing an intramolecular ring closure to form key intermediate 5 is described.
Stereoselective synthesis of tilivalline
Nagasaka, Tatsuo,Koseki, Yuji
, p. 6797 - 6801 (2007/10/03)
Tilivalline 1, a metabolite from Klebsiella pneumoniae var. ocytoca, was easily synthesized in five steps from (S)-proline and 3-(benzyloxy)isatoic anhydride 4g. This synthesis is based on modified Curtius reactions of 3- substituted phthalic anhydrides 11 to 3-substituted isatoic anhydrides 4, conversion of lactams 6 to the acyliminium precursors 7 and stereoselective introduction of indole from the less hindered side of 7.
