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BAZ2A promotes migration and invasion in prostate cancer. Two chemical probes, the specific BAZ2-ICR, and the BAZ2/BRD9 cross-reactive GSK2801, interfere with the recognition of acetylated lysines in histones by the bromodomains of BAZ2A and of its BAZ2B paralog. The two chemical probes were tested in prostate cancer cell lines with opposite androgen susceptibility. BAZ2-ICR and GSK2801 showed different cellular efficacies in accordance with their unequal selectivity profiles. Concurrent inhibition of BAZ2 and BRD9 did not reproduce the effects observed with GSK2801, indicating possible off-targets for this chemical probe. On the other hand, the single BAZ2 inhibition by BAZ2-ICR did not phenocopy genetic ablation, demonstrating that bromodomain interference is not sufficient to strongly affect BAZ2A functionality and suggesting a PROTAC-based chemical ablation as an alternative optimization strategy and a possible therapeutic approach. In this context, we also present the crystallographic structures of BAZ2A in complex with the above chemical probes. Binding poses of TP-238 and GSK4027, chemical probes for the bromodomain subfamily I, and two ligands of the CBP/EP300 bromodomains identify additional headgroups for the development of BAZ2A ligands.

WHO recognizes Rehabilitation as an essential element in improving health outcomes in the twenty-first century. The SARS-CoV-2 pandemic has been a continuous challenge, there have been constant changes in the way of dealing with the disease. The impact of the pandemic is observed in the volume increase of consultations that have been carried out from the Intensive Care Medicine Service, as well as the number of sessions and techniques used in the treatments of hospitalized patients. The pandemic has revealed that the rehabilitation services work is now more essential than ever., La OMS reconoce a la Rehabilitación como un elemento esencial para mejorar los resultados de la salud del siglo XXI. La pandemia por SARS-CoV-2 ha supuesto un continuo reto, se han ido sucediendo cambios constantes en la forma de afrontar la enfermedad. El impacto que ha supuesto la pandemia se observa en el incremento del volumen de interconsultas que se nos ha realizado desde el Servicio de Medicina Intensiva, así como el número de sesiones y de técnicas empleadas en los tratamientos de los pacientes ingresados. La pandemia ha revelado que la labor de los servicios de rehabilitación es ahora más esencial que nunca.

A new family of cationic, bidentate (P^N)gold(III) fluoride complexes has been prepared and a detailed characterization of the gold‐fluoride bond has been carried out. Our results correlate with the observed reactivity of the fluoro ligand, which undergoes facile exchange with both cyano and acetylene nucleophiles. The resulting (P^N)arylgold(III)C(sp) complexes have enabled the first study of reductive elimination on (P^N)gold(III) systems, which demonstrated that C(sp2)−C(sp) bond formation occurs at higher rates than those reported for analogous phosphine‐based monodentate systems.

A chelation-assisted oxidative addition of gold(i) into the C-C bond of biphenylene is reported here. The presence of a coordinating group (pyridine, phosphine) in the biphenylene unit enabled the use of readily available gold(i) halide precursors providing a new, straightforward entry towards cyclometalated (N^C^C)- and (P^C)-gold(iii) complexes. Our study, combining spectroscopic and crystallographic data with DFT calculations, showcases the importance of neighboring, weakly coordinating groups towards the successful activation of strained C-C bonds by gold.

Alkene dicarbofunctionalizations enable the streamlined construction of aliphatic structures and have thus been the subject of intense research efforts. Despite significant progress, catalytic asymmetric variants remain scarce. Inspired by the advantages of reductive cross-coupling approaches, we present here a highly efficient asymmetric intermolecular Ni-catalyzed reductive dicarbofunctionalization of alkenes. Two distinct readily available electrophiles, namely, Csp2- and Csp3-halides, are added simultaneously across a variety of olefins (vinyl amides, vinyl boranes, vinyl phosphonates) at room temperature in a highly regio- and enantioselective manner. The reaction, devoid of sensitive organometallic reagents, takes advantage of an in situ generated chiral alkyl Ni(III)-intermediate to ensure a stereodefined outcome in the Csp3–Csp2 bond-forming reaction. An (l)-(+)-isoleucine chiral bisoxazoline ligand and the presence of coordinating sites on the alkene are key for the successful outcome in these “asymmetric radical relayed reductive couplings” (ARRRCs). Further, multiple transformations of the chiral amides obtained in this process showcase the potential of this new methodology for the straightforward assembly of chiral building blocks such as primary and secondary amines and oxazolines, highlighting its synthetic utility.

The X-ray structure of the catalytic domain of the EphA3 tyrosine kinase in complex with a previously reported type II inhibitor was used to design two novel quinoxaline derivatives, inspired by kinase inhibitors that have reached clinical development. These two new compounds were characterized by an array of cell-based assays and gene expression profiling experiments. A global chemical proteomics approach was used to generate the drug-protein interaction profile, which suggested suitable therapeutic indications. Both inhibitors, studied in the context of angiogenesis and in vivo in a relevant lymphoma model, showed high efficacy in the control of tumor size.

The mechanism of the gold-catalyzed oxidative cross-coupling of arenes and alkynes has been studied in detail combining stoichiometric experiments with putative reaction intermediates and DFT calculations. Our data suggest that ligand exchange between the alkyne, the Au(I)-catalyst and the hypervalent iodine reagent is responsible for the formation of both, a Au(I)-acetylide complex as well as a more reactive “non-symmetric” I(III) oxidant, responsible for the crucial Au(I)/Au(III) turnover. Further, the reactivity of the in situ generated Au(III)-acetylide complex is governed by the nature of the anionic ligands transferred by the I(III) oxidant: while halogen ligands remain unreactive, acetato ligands are efficiently displaced by the arene to yield the observed Csp2-Csp cross-coupling products through an irreversible reductive elimination step. Finally, the nature of competitive processes and catalyst deactivation pathways has also been unraveled. This detailed investigation provides insights not only on the specific features of the species involved in oxidative gold-catalyzed cross couplings but also highlights the importance of both ancillary and anionic ligands on the reactivity of the key Au(III) intermediates.

Herein we present the first example of a three-component dicarbofunctionalization of olefins under reductive conditions. Our strategy takes advantage of nickel catalysis to add aryl and alkyl groups across the double bond with remarkable selectivity. The reaction shows broad functional group compatibility and more importantly, it proves to be general in terms of the alkenes that can be functionalized compared to previous dicarbofunctionalization methods. Initial control experiments reveal different activation modes for both electrophiles and the involvement of alkyl radicals throughout the reaction.

Expanding the chemical space and simultaneously ensuring synthetic accessibility is of upmost importance, not only for the discovery of effective binders for novel protein classes but, more importantly, for the development of compounds against hard-to-drug proteins. Here, we present AutoCouple, a de novo approach to computational ligand design focused on the diversity-oriented generation of chemical entities via virtual couplings. In a benchmark application, chemically diverse compounds with low-nanomolar potency for the CBP bromodomain and high selectivity against the BRD4(1) bromodomain were achieved by the synthesis of about 50 derivatives of the original fragment. The binding mode was confirmed by X-ray crystallography, target engagement in cells was demonstrated, and antiproliferative activity was showcased in three cancer cell lines. These results reveal AutoCouple as a useful in silico coupling method to expand the chemical space in hit optimization campaigns resulting in potent, selective, and cell permeable bromodomain ligands.

Motivation and method: Small-molecule inhibitors targeting the adenosine triphosphate (ATP) binding pocket of the catalytic domain of protein kinases have potential to become drugs devoid of (major) side effects, particularly if they bind selectively. Here, the sequences of the 518 human kinases are first mapped onto the structural alignment of 116 kinases of known three-dimensional structure. The multiple structure alignment is then used to encode the known strategies for developing selective inhibitors into a fingerprint. Finally, a network analysis is used to partition the kinases into clusters according to similarity of their fingerprints, i.e. physico-chemical characteristics of the residues responsible for selective binding. Results: For each kinase the network analysis reveals the likelihood to find selective inhibitors targeting the ATP binding site. Systematic guidelines are proposed to develop selective inhibitors. Importantly, the network analysis suggests that the tyrosine kinase EphB4 has high selectivity potential, which is consistent with the selectivity profile of two novel EphB4 inhibitors. Contact: dhuang@bioc.uzh.ch; caflisch@bioc.uzh.ch Supplementary information: Supplementary data are available at Bioinformatics online

The quest for selective C–H functionalization reactions, able to provide new strategic opportunities for the rapid assembly of molecular complexity, represents a major focus of the chemical community. Examples of non-directed, remote Csp3–H activation to forge complex carbon frameworks remain scarce due to the kinetic stability and thus intrinsic challenge associated to the chemo-, regio- and stereoselective functionalization of aliphatic C–H bonds. Here we describe a radical-mediated, directing-group-free regioselective 1,5-hydrogen transfer of unactivated Csp3–H bonds followed by a second Csp2–H functionalization to produce, with exquisite stereoselectivity, a variety of elaborated fused ketones. This study demonstrates that aliphatic acids can be strategically harnessed as 1,2-diradical synthons and that secondary aliphatic C–H bonds can be engaged in stereoselective C–C bond-forming reactions, highlighting the potential of this protocol for target-oriented natural product and pharmaceutical synthesis.

Mutant Estrogen Receptor (ERT2) ligand-binding domain fusions with Cre recombinase are a key tool for spatio-temporally controlled genetic recombination with the Cre/lox system. CreERT2 is efficiently activated in a concentration-dependent manner by the Tamoxifen metabolite trans-4-OH-Tamoxifen (trans-4-OHT). Reproducible and efficient Cre/lox experimentation is hindered by the gradual loss of CreERT2 induction potency upon prolonged storage of dissolved trans-4-OHT, which potentially results from gradual trans-to-cis isomerization or degradation. Here, we combined zebrafish CreERT2 recombination experiments and cell culture assays to document the gradual activity loss of trans-4-OHT and describe the alternative Tamoxifen metabolite Endoxifen as more stable alternative compound. Endoxifen retains potent activation upon prolonged storage (3 months), yet consistently induces half the ERT2 domain fusion activity compared to fresh trans-4-OHT. Using 1HNMR analysis, we reveal that trans-4-OHT isomerization is undetectable upon prolongedstorage in either DMSO or Ethanol, ruling out isomer transformation as cause for the gradual loss of trans-4-OHT activity. We further establish that both trans-4-OHT and Endoxifen are insensitive to light exposure under regular laboratory handling conditions. We attribute the gradual loss of trans-4-OHT potency to precipitation over time, and show that heating of aged trans-4-OHT aliquots reinstates their CreERT2 induction potential. Our data establish Endoxifen as potent and reproducible complementary compound to 4-OHT to control ERT2 domain fusion proteins in vivo, and provide a framework for efficient chemically controlled recombination experiments.

Generally speaking, the aim of this work is to study the (Δ,N) problem (or the degree-number of vertices problem) for double-step digraphs. A digraph is a network consisting of vertices and directed edges (called arcs). In the case of a graph, the edges have no direction. A double-step digraph consists of a set of vertices and arcs of the forms (i ,i +a) and (i ,i+b) , with a and b positive integers called “steps”, that is, there exist arcs from the vertex i to the vertices i+a and i+b (all the operations are modulo ). This digraph is denoted by G (N ; a,b) . The diameter of a graph is the shortest distance between two of the farthest vertices. In the diameter of a digraph, we must consider that the edges have directions. The unilateral distance in a digraph is the minimum distance between the digraph and the converse digraph (obtained by changing the directions of all the arcs). The ( Δ,N) problem has been extensively studied for graphs and digraphs, but not in the case of double-step digraphs considering the unilateral diameter. The problem consists of finding the minimum unilateral diameter D ∗ for a doublestep digraph given a number of vertices N and degree Δ= 2, that is, to find out the two steps of a double-step digraph that minimize the unilateral diameter D ∗ for these number of vertices and degree., Català: En termes generals, l’objectiu d’aquest treball és estudiar el problema (Δ,N)(o problema grau-nombre de vèrtexs) per al cas de digrafs de doble pas. Un digraf és una xarxa constituïda per vèrtexs i arestes dirigides (anomenades arcs). En el cas dels grafs, les arestes no tenen direcció. Un digraf de doble pas consta N de vèrtexs i un conjunt d’arcs de la forma (i,i+a) i (i,i ,+b) , amb a i b enters positius anomenats “passos”, és a dir, que existeixen enllaços des del vèrtex cap els vèrtexs i+a i i+b (les operacions s’han d’entendre sempre en mòdul N ). Aquest digraf es denota G(N;a ,b). El diàmetre d’un graf és la mínima distància possible que hi ha entre dos dels vèrtexs més allunyats entre si. En el diàmetre d’un digraf hem de tenir en compte que els arcs tenen direcció. La distància unilateral en un digraf és el mínim entre la distància en el digraf i en el digraf convers (obtingut canviant totes les direccions dels arcs). El problema ( Δ,N) ha estat molt estudiat en grafs i en digrafs, però no en el cas dels digrafs de doble pas considerant el diàmetre unilateral. El problema consisteix a trobar el mínim diàmetre unilateral D ∗ en digrafs de doble pas, per a un nombre de vèrtexs N i el grau Δ=2 donats, és a dir, trobar quins són els dos passos d’un digraf de doble pas que fan que el diàmetre unilateral D ∗ sigui mínim per a aquests nombre de vèrtexs i grau.

Gold(I) complexes are the most active catalysts for the biscyclopropanation of dienynes to form tetracyclic compounds. PtII and ZnII are also able to promote the biscyclopropanation, although less efficiently. The configurations obtained in all cases with the use of gold(I) catalysts can be explained by the pathway proceeding through anti cyclopropyl gold carbenes. Similar intermediates are most probably involved in reactions catalyzed by RuII and PtII. Two different cyclopropanation pathways have been found; they depend on the structures of the cyclopropyl gold carbenes (anti or syn) and the relative arrangements of the metal carbenes and the alkenes.

Support for the direct route: That cyclobutenes are not necessary intermediates in the skeletal rearrangement of enynes is supported by DFT calculations and kinetic studies. Cyclobutenes may arise from the corresponding syn-cyclopropylgold(I) carbenes

Alkynophilic cationic gold(I) complexes are very active catalysts for reactions of enynes that proceed exclusively through cyclopropyl carbene complexes as intermediates (see scheme). With such catalysts, the first examples of endocyclic skeletal rearrangements under mild conditions have been observed.