CAM4066, a specific CK2α kinase inhibitor, is anchored in the cryptic αD pocket outside the active site and inserts a “warhead” into the active site, blocking ATP binding and thereby inhibiting the kinase.

Graphical abstract

We describe the development of a CAM4712, a novel CK2α inhibitor which does not interact with the ATP binding site and shows improved properties over the first-generation inhibitor CAM4066.

The asymmetric synthesis of helicenes … … by a Fischer indolization catalyzed by a SPINOL-derived phosphoric acid is reported by B. List et al. in their Communication on page 5202 ff. The catalyst is designed for long-range control and bears extended p-surfaces at the 3,3'-position. It creates a chiral nanometer-sized pocket, which enables p-p stacking interactions between the substituents and the reactive intermediate. A variety of (di)azahelicenes were obtained with good to excellent yields and enentioselectivities.

MAT2a is a methionine adenosyltransferase that synthesizes the essential metabolite S-adenosylmethionine (SAM) from methionine and ATP. Tumors bearing the co-deletion of p16 and MTAP genes have been shown to be sensitive to MAT2a inhibition, making it an attractive target for treatment of MTAP-deleted cancers. A fragment-based lead generation campaign identified weak but efficient hits binding in a known allosteric site. By use of structure-guided design and systematic SAR exploration, the hits were elaborated through a merging and growing strategy into an arylquinazolinone series of potent MAT2a inhibitors. The selected in vivo tool compound 28 reduced SAM-dependent methylation events in cells and inhibited proliferation of MTAP-null cells in vitro. In vivo studies showed that 28 was able to induce antitumor response in an MTAP knockout HCT116 xenograft model.

Es wird über die erste asymmetrische organokatalytische Synthese von Helicenen berichtet. Eine neue SPINOL‐abgeleitete Phosphorsäure mit ausgedehnten π‐Substituenten katalysiert die asymmetrische Synthese von Helicenen über eine enantioselektive Fischer‐Indolisierung. Eine Vielzahl von Azahelicenen und Diazahelicenen konnte auf diese Weise mit guten bis sehr guten Ausbeuten und Enantioselektivitäten erhalten werden.

The asymmetric synthesis of helicenes … … by a Fischer indolization catalyzed by a SPINOL-derived phosphoric acid is reported by B. List et al. in their Communication on page 5202 ff. The catalyst is designed for long-range control and bears extended p-surfaces at the 3,3'-position. It creates a chiral nanometer-sized pocket, which enables p-p stacking interactions between the substituents and the reactive intermediate. A variety of (di)azahelicenes were obtained with good to excellent yields and enentioselectivities.

Different organic promoters have been successfully employed in asymmetric oxidations with hydrogen peroxide and molecular oxygen as environmentally benign oxidants. In this manuscript, we illustrate developments achieved in this area to access chiral epoxides, sulfoxides, gamma-lactones, alfa-hydroxylated carbonyl compounds, and derivatives thereof