Bisindolylpyrrole triggers transient mitochondrial permeability transitions to cause apoptosis in a VDAC1/2 and cyclophilin D-dependent manner via the ANT-associated pore.

Bisindolylpyrrole at 0.1 μM is cytoprotective in 2% FBS that is counteracted by cyclosporin-A (CsA), an inhibitor of cyclophilin-D (CypD). We hypothesized that the cytoprotective effect might be due to transient mitochondrial permeability transition (tPT).

The yeast mitochondrial permeability transition is regulated by reactive oxygen species, endogenous Ca and Cpr3, mediating cell death.

We investigated the properties of the permeability transition pore (PTP) in Saccharomyces cerevisiae in agar-embedded mitochondria (AEM) and agar-embedded cells (AEC) and its role in yeast death. In AEM, ethanol-induced pore opening, as indicated by the release of calcein and mitochondrial membrane depolarization, can be inhibited by CsA, by Cpr3 deficiency, and by the antioxidant glutathione. Notably, the pore opening is inhibited, when mitochondria are preloaded by EGTA or Fluo3 to chelate matrix Ca, or are pretreated with 4-Br A23187 to extract matrix Ca, prior to agar-embedding, or when pore opening is induced in the presence of EGTA; opened pores are re-closed by sequential treatment with CsA, 4-Br A23187 plus EGTA and NADH, indicating endogenous matrix Ca involvement.

A practical method for oxazole synthesis by cycloisomerization of propargyl amides.

[reaction: see text] 2,5-disubstituted and 2,4,5-trisubstituted oxazol-5-yl carbonyl compounds were prepared in good yields by a mild SiO2-mediated cycloisomerization of propargyl amides.

Bisindolylmaleimide I and V inhibit necrosis induced by oxidative stress in a variety of cells including neurons.

Although free radical-mediated necrosis is implicated in many diseases such as neurodegeneration, potent anti-necrotic drugs have not yet been exploited. We found that bisindolylmaleimide I (BMI or GF 109203X), a PKC inhibitor, protected a variety of cells, including neurons, from oxidant-induced necrosis, although calphostin C, another type of PKC inhibitor, and staurosporine, a broad kinase inhibitor, had no such effect. BMI was significantly protective in neuronal cells whereas chronic application of BMI induced neurotoxicity.