The marine alkaloid ascididemin (ASC) was shown to exert cytotoxicity even against multidrug-resistant cancer cells. Here, we address the signaling pathways utilized by ASC to trigger apoptosis in Jurkat leukemia T cells. We show that ASC (0.5-20 lM) induces a mitochondrial pathway that requires the activation of the initiator caspase-2 upstream of mitochondria. ASC-triggered apoptosis occurred independent of CD95, but required mitochondrial dysfunction. The activation of caspase-2 was shown to precede the processing of caspase-8, -9 and -3. The specific caspase-2 inhibitor zVDVADfmk abrogated ASC-induced DNA fragmentation almost completely. Overexpression of Bcl-x L blocked caspase-8 but not caspase-2 processing. Conversely, caspase-2 inhibition strongly reduced caspase-9 activation. As a possible link between caspase-2 and mitochondrial dysfunction, Bid was found to be cleaved by ASC. In addition, JNK was activated by ASC upstream of mitochondria via reactive oxygen species. The specific JNK inhibitor SP600125 partially inhibited caspase-2 and -9 processing as well as cytochrome c release and DNA fragmentation indicating that JNK contributes to, but is not necessary for ASCmediated apoptosis. Thus, ASC triggers a pathway in which early activation of caspase-2 provides a possible link between its DNA-damaging activity and the induction of mitochondrial dysfunction. The activation of JNK contributes to this signaling upstream of mitochondria.
ABSTRACT:The chiroptical properties of calliactine (2) have been studied experimentally as well as by quantum chemical calculations based on density functional theory (DFT). According to the DFT calculations, the four energetically lowest conformers of the title compound lie within a range of 1.1 kcal/mol and are separated from other conformers by an energy gap of nearly 9 kcal/mol. Based on their geometries, the excitation energies and rotational strengths have been calculated using time-dependent DFT (TDDFT) and the dipole velocity formalism. The circular dichroism (CD) spectrum of calliactine has been obtained as a Boltzmann-weighted superposition of the spectra of each of the four structures. By comparison of the calculated and experimental CD spectra, the absolute configuration of calliactine has been elucidated as S.
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