PTHrP intracrine actions divergently influence breast cancer growth through p27 and LIFR.

The role of parathyroid hormone (PTH)-related protein (PTHrP) in breast cancer remains controversial, with reports of PTHrP inhibiting or promoting primary tumor growth in preclinical studies. Here, we provide insight into these conflicting findings by assessing the role of specific biological domains of PTHrP in tumor progression through stable expression of PTHrP (-36-139aa) or truncated forms with deletion of the nuclear localization sequence (NLS) alone or in combination with the C-terminus. Although the full-length PTHrP molecule (-36-139aa) did not alter tumorigenesis, PTHrP lacking the NLS alone accelerated primary tumor growth by downregulating p27, while PTHrP lacking the NLS and C-terminus repressed tumor growth through p27 induction driven by the tumor suppressor leukemia inhibitory factor receptor (LIFR). Induction of p27 by PTHrP lacking the NLS and C-terminus persisted in bone disseminated cells, but did not prevent metastatic outgrowth, in contrast to the primary tumor site. These data suggest that the PTHrP NLS functions as a tumor suppressor, while the PTHrP C-terminus may act as an oncogenic switch to promote tumor progression through differential regulation of p27 signaling.

Enaminones via ruthenium-catalyzed coupling of thioamides and α-diazocarbonyl compounds.

Enaminones can be prepared via the Rh2(OAc)4-catalyzed coupling of α-diazocarbonyl compounds with thioamides. However, rhodium is the most expensive and least abundant among the dominant precious metals used for catalysis. Furthermore, a very limited substrate scope is known for the intermolecular rhodium catalyzed coupling reaction. Therefore, there is a need to find a more economical catalyst substitute with a broad substrate scope. In this paper, we describe the use of Ru(II) catalysts for the synthesis of enaminones. The reaction can be performed efficiently with the Grubbs first-generation catalyst or [(Ph)3P]3RuCl2 in a sealed tube. Both catalysts are much less expensive than Rh2(OAc)4. Secondary and tertiary thioamides, when reacted with α-diazodiesters, α-diazoketoesters, α-diazodiketones, and α-diazomonoketones give enaminones. Primary thioamides give thiazole derivatives when reacted with α-diazomonoketones. However, with other diazo compounds, primary thioamides also give enaminones. All enaminones are obtained in good yields and with good diastereoselectivity. Accordingly, the method described in this paper is an efficient and economical alternative to the Rh2(OAc)4-catalyzed coupling process.

Ruthenium catalyzed synthesis of enaminones.

The Grubbs first-generation catalyst has been found to be an effective catalyst for the synthesis of enaminones by coupling thioamides with α-diazodicarbonyl compounds. The reaction is successful in converting primary, secondary, and tertiary thioamides into their corresponding enaminones. The reaction is also suitable for the synthesis of chiral enaminones.