Efficacy of the highly selective focal adhesion kinase inhibitor BI 853520 in adenocarcinoma xenograft models is linked to a mesenchymal tumor phenotype.

Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, has attracted interest as a target for pharmacological intervention in malignant diseases. Here, we describe BI 853520, a novel ATP-competitive inhibitor distinguished by high potency and selectivity. In vitro, the compound inhibits FAK autophosphorylation in PC-3 prostate carcinoma cells with an IC of 1 nmol/L and blocks anchorage-independent proliferation of PC-3 cells with an EC of 3 nmol/L, whereas cells grown in conventional surface culture are 1000-fold less sensitive.

A macrocyclic approach to tetracycline natural products. Investigation of transannular alkylations and Michael additions.

A new approach to the tetracycline core structure is presented. The pivotal intermediate is identified as macrocycle III. The two interior bonds (C4a-C12a and C5a-C11a) are to be constructed through sequential transannular Michael additions (III-II) and compression-promoted transannular isoxazole alkylations from intermediate II.

Synthesis of functionalized nitroarylmagnesium halides via an iodine-magnesium exchange.

[reaction: see text] Various nitro-substituted aryl and heteroaryl iodides undergo an iodine-magnesium exchange reaction when treated with PhMgCl leading to nitro-containing magnesium organometallics. These Grignard reagents display an excellent stability at temperatures below -40 degrees C and do not undergo electron-transfer reactions. They react as expected with various electrophiles.

Highly functionalized organomagnesium reagents prepared through halogen-metal exchange.

Organomagnesium reagents occupy a central position in synthetic organic and organometallic chemistry. Recently, the halogen-magnesium exchange has considerably extended the range of functionalized Grignard reagents available for synthetic purposes. Functional groups such as esters, nitriles, iodides, imines, or even nitro groups can be present in a wide range of aromatic and heterocyclic organomagnesium reagents.

A new general preparation of polyfunctional diarylamines by the addition of functionalized arylmagnesium compounds to nitroarenes.

The addition of functionalized arylmagnesium halides to nitroarenes in THF (-20 degrees C, 2 h) provides, after reductive workup (FeCl(2), NaBH(4)), various polyfunctional diarylamines in 63-86% yield. Heterocyclic arylated amines can be prepared by this one-pot procedure. A mechanistic rationale of this reaction is given.