Stereospecific nickel-catalyzed cross-coupling reactions of alkyl Grignard reagents and identification of selective anti-breast-cancer agents.

Alkyl Grignard reagents that contain ß-hydrogen atoms were used in a stereospecific nickel-catalyzed cross-coupling reaction to form C(sp(3))-C(sp(3)) bonds. Aryl Grignard reagents were also utilized to synthesize 1,1-diarylalkanes. Several compounds synthesized by this method exhibited selective inhibition of proliferation of MCF-7 breast cancer cells.

Experimental and theoretical investigation of the scope of enantioselective ketone allylations employing Nakamura's allylzinc-bisoxazoline reagent.

The scope of enantioselective allylations employing Nakamura's allylzinc-bisoxazoline reagent was examined by performing allylations of a selection of readily available ketones. Low-to-moderate ee's were observed, and a computational study was conducted to rationalize the results. Examination of transition structures of previously performed allylations that proceeded with high ee revealed the importance of both local and global control elements in these successful reactions. The ability of density functional theory methods to estimate the enantioselectivity of these asymmetric ketone allylations was established. All allylations that were studied computationally exhibited low (<5 kcal/mol) activation barriers, a result that is consistent with the highly reactive nature of Nakamura's reagent.

Interactions of DNR1 with the apoptotic machinery of Drosophila melanogaster.

Caspases are crucial activators of apoptosis and NF-kappaB signaling in vertebrates and invertebrates. In Drosophila, the caspase-9 counterpart Dronc is essential for most apoptotic death, whereas the caspase-8 homolog Dredd activates NF-kappaB signaling in response to gram-negative bacterial infection. The mechanics of caspase regulation are conserved and include the activities of a family of inhibitor of apoptosis (IAP) proteins. The RING-domain-bearing protein Defense repressor 1 (Dnr1), blocks ectopic Dredd-mediated induction of an NF-kappaB reporter in the Drosophila S2 cell line. In this study, we present novel data indicating that Dnr1 impacts on Dronc-dependent regulation of the apoptotic program. We show that depletion of Dnr1 results in elevated Dronc protein levels, which translates to increased caspase activation and activity upon induction of apoptosis. Conversely, we demonstrate that overexpression of Dnr1 blocks apoptotic caspase activity and prevents induction of apoptosis in tissue culture assays. Furthermore, we show that Dnr1 overexpression significantly reduces Dronc protein levels and identify the domains of Dnr1 necessary for these effects. From these data, we propose that Dnr1 inhibits initiator caspases in S2 cells.