Fragment-Based Discovery of Novel MUS81 Inhibitors.

MUS81 is a structure-selective endonuclease that cleaves various branched DNA structures arising from natural physiological processes such as homologous recombination and mitosis. Due to this, MUS81 is able to relieve replication stress, and its function has been reported to be critical to the survival of many cancers, particularly those with dysfunctional DNA-repair machinery. There is therefore interest in MUS81 as a cancer drug target, yet there are currently few small molecule inhibitors of this enzyme reported, and no liganded crystal structures are available to guide hit optimization. Here we report the fragment-based discovery of novel small molecule MUS81 inhibitors with sub-µM biochemical activity. These inhibitors were used to develop a novel crystal system, providing the first structural insight into the inhibition of MUS81 with small molecules.

Selective Defluorination of Trifluoromethyl Substituents by Conformationally Induced Remote Substitution.

The selective reduction of an aromatic trifluoromethyl substituent to a difluoromethyl substituent may be achieved by base-promoted elimination to form a difluoro-p-quinomethide which is trapped by an intramolecular nucleophile. High yields are obtained when the nucleophilic trap entails the conformationally favoured cyclisation of an aminoisobutyric acid (Aib) derivative. The resulting cyclised difluoromethyl-substituted arylimidazolidinone products are readily converted to versatile difluoromethyl-substituted aldehydes by reduction and hydrolysis. Defluorination is successful on a range of benzenoid (both para and ortho CF3-substituted) and heterocyclic substrates. Double defluorination may likewise be achieved sequentially, or in a single step, from an Aib dipeptide derivative.

Binding of l-kynurenine to X. campestris tryptophan 2,3-dioxygenase.

The kynurenine pathway is the major route of tryptophan metabolism. The first step of this pathway is catalysed by one of two heme-dependent dioxygenase enzymes - tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) - leading initially to the formation of N-formylkynurenine (NFK). In this paper, we present a crystal structure of a bacterial TDO from X. campestris in complex with l-kynurenine, the hydrolysed product of NFK. l-kynurenine is bound at the active site in a similar location to the substrate (l-Trp). Hydrogen bonding interactions with Arg117 and the heme 7-propionate anchor the l-kynurenine molecule into the pocket. A mechanism for the hydrolysis of NFK in the active site is presented.

Triarylmethanes and their Medium-Ring Analogues by Unactivated Truce-Smiles Rearrangement of Benzanilides.

Intramolecular nucleophilic aromatic substitution (Truce-Smiles rearrangement) of the anions of 2-benzyl benzanilides leads to triarylmethanes in an operationally simple manner. The reaction succeeds even without electronic activation of the ring that plays the role of electrophile in the SN Ar reaction, being accelerated instead by the preferred conformation imposed by the tertiary amide tether. The amide substituent of the product may be removed or transformed into alternative functional groups. A ring-expanding variant (n to n+4) of the reaction provided a route to doubly benzo-fused medium ring lactams of 10 or 11 members. Hammett analysis returned a ρ value consistent with the operation of a partially concerted reaction mechanism.