No abstract

Breast cancer gene 1 (BRCA1) contributes to the regulation of centrosome number. We previously identified receptor for activated C kinase 1 (RACK1) as a BRCA1-interacting partner. RACK1, a scaffold protein that interacts with multiple proteins through its seven WD40 domains, directly binds to BRCA1 and localizes to centrosomes. RACK1 knockdown suppresses centriole duplication, whereas RACK1 overexpression causes centriole overduplication in a subset of mammary gland-derived cells. In this study, we showed that RACK1 binds directly to polo-like kinase 1 (PLK1) and Aurora A, and promotes the Aurora A/PLK1 interaction. RACK1 knockdown decreased phosphorylated PLK1 (p-PLK1) level and the centrosomal localization of Aurora A and p-PLK1 in S phase, whereas RACK1 overexpression increased p-PLK1 level and the centrosomal localization of Aurora A and p-PLK1 in interphase, resulting in an increase of cells with abnormal centriole disengagement. Overexpression of cancer-derived RACK1 variants failed to enhance the Aurora A/PLK1 interaction, PLK1 phosphorylation, and the centrosomal localization of p-PLK1. These results suggest that RACK1 functions as a scaffold protein for the activation of PLK1 by Aurora A to promote centriole duplication.

N-Alkylated unsaturated ketonitrones were efficiently synthesized from propargyloxyamines using Cu catalysts. Mechanistic studies suggest that the rearrangement reaction proceeds via Cu-catalyzed intramolecular hydroamination, followed by thermally induced electrocyclic ring opening.

Propynal hydrazones are successfully converted to the corresponding 3-aminoacrylonitriles in the presence of copper catalysts in good to high yields. As an example, (Z)-N-(hex-2-ynylidene)morpholin-4-amine reacted in the presence of 10 mol % Cu(OAc)(2) in acetonitrile at 25 °C to afford (E)-3-morpholinohex-2-enenitrile ((E)-2 h) in 77% yield via C-N bond formation and subsequent β-elimination involving cleavage of N-N and C-H bonds.

Efficient Synthesis of N-Alkylated ,-Unsaturated Ketonitrones via Cu-Catalyzed Rearrangement. -The title compounds are efficiently synthesized from propargyloxyamines. The rearrangement reaction proceeds via Cu-catalyzed intramolecular hydroamination, followed by thermally induced electrocyclic ring opening. The reaction of substrate (V) gives the 3-isoxazoline (VI). The propargyloxyamines and ketonitrones undergo cycloaddition reaction with electron-deficient alkynes [e.g. reaction of (VII)]. -(NAKAMURA*, I.; ONUMA, T.; KANAZAWA, R.; NISHIGAI, Y.; TERADA, M.; Org. Lett. 16 (2014) 16, 4198-4200, http://dx.doi.org/10.1021/ol501889g ; Grad. Sch. Sci., Tohoku Univ., Sendai 980, Japan; Eng.) -B. Bergmann