Microwave heating allows regio‐ and enantioselective allylic alkylation to be carried out in air in a few minutes in a convenient one‐pot procedure [Eq. (1)]. The catalytically active molybdenum(0) species was formed in situ from inexpensive [Mo(CO)6] and a chiral ligand.

Poorly vascularized areas of solid tumors contain quiescent cell populations that are resistant to cell cycle-active cancer drugs. The compound VLX600 was recently identified to target quiescent tumor cells and to inhibit mitochondrial respiration. We here performed gene expression analysis in order to characterize the cellular response to VLX600. The compound-specific signature of VLX600 revealed a striking similarity to signatures generated by compounds known to chelate iron. Validation experiments including addition of ferrous and ferric iron in excess, EXAFS measurements, and structure activity relationship analyses showed that VLX600 chelates iron and supported the hypothesis that the biological effects of this compound is due to iron chelation. Compounds that chelate iron possess anti-cancer activity, an effect largely attributed to inhibition of ribonucleotide reductase in proliferating cells. Here we show that iron chelators decrease mitochondrial energy production, an effect poorly tolerated by metabolically stressed tumor cells. These pleiotropic features make iron chelators an attractive option for the treatment of solid tumors containing heterogeneous populations of proliferating and quiescent cells.

Inhibition of lysine specific demethylase 1 (LSD1) has been shown to induce the differentiation of leukemia stem cells in acute myeloid leukemia (AML). Irreversible inhibitors developed from the nonspecific inhibitor tranylcypromine have entered clinical trials; however, the development of effective reversible inhibitors has proved more challenging. Herein, we describe our efforts to identify reversible inhibitors of LSD1 from a high throughput screen and subsequent in silico modeling approaches. From a single hit (12) validated by biochemical and biophysical assays, we describe our efforts to develop acyclic scaffold-hops from GSK-690 (1). A further scaffold modification to a (4-cyanophenyl)glycinamide (e.g., 29a) led to the development of compound 32, with a K value of 32 nM and an EC value of 0.67 μM in a surrogate cellular biomarker assay. Moreover, this derivative does not display the same level of hERG liability as observed with 1 and represents a promising lead for further development.

carboxylic acid esterscarboxylic acid esters (benzene compounds) Q 0530 -093Highly Stereo-and Regioselective Allylations Catalyzed by Mo-Pyridylamide Complexes: Electronic and Steric Effects of the Ligand.-The amide shown in entry D) containing electron-donating substituted pyridine rings is found to be an efficient ligand for the regio-and stereoselective allylation of the malonate (II). The use of ligands bearing electron-withdrawing substituted pyridine rings or alkyl substituted pyridine rings results in reduction of selectivity and yield.

No abstract

Palladium-catalyzed substitution of cyclohex-2-en-1-yl ethyl carbonate with neutral C-, O-, and N-nucleophiles was achieved in 1-2 minutes using microwave flash heating. Enantioselectivities up to 96% were observed. Ionic nucleophiles tended to result in lower ee. With S-nucleophiles problems with the stability of the nucleophile were encountered.

No abstract

No abstract