We have identified three novel structures for inhibitors of the poly(ADP-ribose) polymerase (PARP), a nuclear enzyme activated by strand breaks in DNA and implicated in DNA repair, apoptosis, organ dysfunction or necrosis., and 4-(1-methyl-1H-pyrrol-2-ylmethylene)-4H-isoquinolin-1,3-dione (BYK204165) inhibited cell-free recombinant human PARP-1 with pIC 50 values of 8. 36, 7.81, 6.40, and 7.35 (pK i 7.97, 7.43, 5.90, and 7.05), and murine PARP-2 with pIC 50 values of 7.50, 7.55, 5.71, and 5.38, respectively. BYK49187, BYK236864, and BYK20370 displayed no selectivity for PARP-1/2, whereas BYK204165 displayed 100-fold selectivity for PARP-1. The IC 50 values for inhibition of poly(ADPribose) synthesis in human lung epithelial A549 and cervical carcinoma C4I cells as well in rat cardiac myoblast H9c2 cells after PARP activation by H 2 O 2 were highly significantly correlated with those at cell-free PARP-1 (r 2 ϭ 0.89 -0.96, P Ͻ 0.001) but less with those at PARP-2 (r 2 ϭ 0.78 -0.84, P Ͻ 0.01). The infarct size caused by coronary artery occlusion and reperfusion in the anesthetized rat was reduced by 22% (P Ͻ 0.05) by treatment with BYK49187 (3 mg/kg i.v. bolus and 3 mg/kg/h i.v. during 2-h reperfusion), whereas the weaker PARP inhibitors, BYK236864 and BYK20370, were not cardioprotective. In conclusion, the imidazoquinolinone BYK49187 is a potent inhibitor of human PARP-1 activity in cell-free and cellular assays in vitro and reduces myocardial infarct size in vivo. The isoquinolindione BYK204165 was found to be 100-fold more selective for PARP-1. Thus, both compounds might be novel and valuable tools for investigating PARP-1-mediated effects.Poly(ADP-ribose) polymerases (PARP) 1 and 2 are abundant nuclear enzymes in eukaryotic cells that have been implicated in the cellular response to DNA damage (Schreiber et al., 2006). PARPs catalyze an energy-consuming reaction by transferring ADP-ribose moieties from the substrate NAD ϩ to nuclear acceptor proteins, including PARP itself, and to existing ADP-ribose adducts on protein, thus forming chains of poly(ADP-ribose) (PAR), to render damaged DNA accessible to the repair system and to maintain cell survival, genomic stability, and mammalian longevity (D'Amours et al., 1999). This beneficial, cytoprotective effect of PARP activity is apparent under conditions of low to modArticle, publication date, and citation information can be found at

Inhibitors of histone deacetylases (HDAC) are currently developed for the treatment of cancer. These include compounds with a sulfur containing head group like depsipeptide, alkylthiols, thiocarboxylates, and trithiocarbonates with a carbonyl group in the alpha-position. In the present investigation, we report on the synthesis and comprehensive SAR analysis of HDAC inhibitors bearing a tri- or dithiocarbonate motif. Such trithiocarbonates are readily accessible from either preformed or in situ prepared alpha-halogenated methylaryl ketones. A HDAC isotype selectivity and a substrate competitive mode-of-action is shown for defined analogues. Exploration of the head group showed the necessity of the dithio-alpha-carbonyl motif for potent HDAC inhibition. Highly potent, substrate competitive HDAC6 selective inhibitors were identified (12ac:IC 50 = 65 nM and K i = 110 nM). Trithiocarbonate analogues with an aminoquinoline-substituted pyridinyl-thienoacetyl cap demonstrate a cytotoxicity profile and potency comparable to that of suberoylanilide hydroxamic acid (SAHA) as an approved cancer drug.

No abstract

No abstract

No abstract

No abstract

Ein Cyclopeptolid, ein Polyen und ein Aminoredukton, Spezies vollkommen unterschiedlicher Biogenese, sind die Komponenten des — insbesondere gegen Staphylococcus aureus — antibiotisch wirksamen Naturstoffs Enopeptin B 1. Die erste Totalsynthese dieser Verbindung einer neuartigen Substanzklasse gelang nun durch geschickte Anwendung des Methodenarsenals der modernen Peptidchemie, wobei die drei Bausteine auf zwei Wegen miteinander kombiniert wurden.

No abstract