Proteasom‐Inhibitoren

The proteasome is a multicatalytic protease complex with an unusual enzyme mechanism. It plays a central role in intracellular protein degradation and its important function in the regulation of the cell cycle makes it an interesting target for cancer therapy. First developed as reagents to elucidate the catalytic functions of the proteasome, several proteasome inhibitors are presently being tested in clinical trials. It appears that proteasome inhibitors of the classes peptidyl boronic acids, peptide epoxyketones, and β‐lactone‐γ‐lactams are particularly effective as anticancer agents.     

Tunable Probes with Direct Fluorescence Signals for the Constitutive and Immunoproteasome

Electrophiles are commonly used for the inhibition of proteases. Notably, inhibitors of the proteasome, a central determinant of cellular survival and a target of several FDA‐approved drugs, are mainly characterized by the reactivity of their electrophilic head groups. We aimed to tune the inhibitory strength of peptidic sulfonate esters by varying the leaving groups. Indeed, proteasome inhibition correlated well with the pK_a of the leaving group. The use of fluorophores as leaving groups enabled us to design probes that release a stoichiometric fluorescence signal upon reaction, thereby directly linking proteasome inactivation to the readout. This principle could be applicable to other sulfonyl fluoride based inhibitors and allows the design of sensitive probes for enzymatic studies.     

Synthesis of Periphery‐Decorated and Core‐Initiated Borane Polyanionic Macromolecules

A new class of globular polybranched macromolecules that contain multiple anionic metallacarborane clusters at the o‐carborane periphery is reported. The water soluble high boron rich containing molecules could be of interest for boron neutron capture therapy (BNCT) as well as for drug delivery. The reinforced electrostatic noncovalent interactions between anionic polyethylene glycol cobaltabisdicarbollide (PEG‐COSAN) branches and the ammonium cation have been shown using ESI‐MS.     

B‐MWW Zeolite: The Case Against Single‐Site Catalysis

Boron‐containing materials have recently been identified as highly selective catalysts for the oxidative dehydrogenation (ODH) of alkanes to olefins. It has previously been demonstrated by several spectroscopic characterization techniques that the surface of these boron‐containing ODH catalysts oxidize and hydrolyze under reaction conditions, forming an amorphous B₂(OH)_xO_(3?x/2) (x=0–6) layer. Yet, the precise nature of the active site(s) remains elusive. In this Communication, we provide a detailed characterization of zeolite MCM‐22 isomorphously substituted with boron (B‐MWW). Using ¹¹B solid‐state NMR spectroscopy, we show that the majority of boron species in B‐MWW exist as isolated BO₃ units, fully incorporated into the zeolite framework. However, this material shows no catalytic activity for ODH of propane to propene. The catalytic inactivity of B‐MWW for ODH of propane falsifies the hypothesis that site‐isolated BO₃ units are the active site in boron‐based catalysts. This observation is at odds with other traditionally studied catalysts like vanadium‐based catalysts and provides an important piece of the mechanistic puzzle.     

Boron‐Double‐Ring Sheet,Fullerene, and Nanotubes: Potential Hydrogen Storage Materials

Similar to carbon‐based graphene, fullerenes and carbon nanotubes, boron atoms can form sheets, fullerenes, and nanotubes. Here we investigate several of these novel boron structures all based on the boron double ring within the framework of density functional theory. The boron sheet is found to be metallic and flat in its ground state. The spherical boron cage containing 180 atoms is also stable and has I symmetry. Stable nanotubes are obtained by rolling up the boron sheet, and all are metallic. The hydrogen storage capacity of boron nanostructures is also explored, and it is found that Li‐decorated boron sheets and nanotubes are potential candidates for hydrogen storage. For Li‐decorated boron sheets, each Li atom can adsorb a maximum of 4 H₂ molecules with g_d=7.892 wt %. The hydrogen gravimetric density increases to g_d=12.309 wt % for the Li‐decorated (0,6) boron nanotube.     

Monobenzofused 1,4‐Azaborines: Synthesis,Characterization, and Discovery of a Unique Coordination Mode

We report the first general synthesis of boron‐substituted monobenzofused 1,4‐azaborines using ring‐closing metathesis of an enamine‐containing diene as a key synthetic strategy. As part of our investigations, we discovered that the B‐C3 moiety in a 1,4‐azaborine can serve uniquely as a η²‐L‐type ligand. This functionality is exemplified by two κ²‐N‐η²‐BC Pt complexes of a boron‐pyridyl‐substituted monobenzofused‐1,4‐azaborine. Single‐crystal X‐ray diffraction analysis of the Pt complexes shows a strong structural contribution from the iminium resonance form of the monobenzofused‐1,4‐azaborine ligand. We also demonstrate that a palladium(0) complex supported by a 1,4‐azaborine‐based phosphine ligand can catalyze hydroboration of 1‐buten‐3‐yne with unique selectivity. In view of the importance of arene–metal π‐interactions in catalytic applications, this work should open new opportunities for ligand design involving the 1,4‐azaborine motif as an arene substitute.     

Ring Expansions of Boroles with Diazo Compounds: Steric Control of C or N Insertion and Aromatic/Nonaromatic Products

Access to novel imine‐substituted 1,2‐azaborinines, as well as highly arylated boracyclohexa‐3,5‐dienes has been developed by ring expansion of boroles with diazoalkanes with varying degrees of steric bulk. The formation of a diazoalkane intermediate is also discussed for the reaction of ortho‐brominated p‐tolyl‐azide with 1,2,3,4,5‐pentaphenylborole. Structural details as well as UV/Vis spectroscopic and cyclic voltammetric data are provided. These boron‐containing heterocycles have the potential to serve as building blocks for boron‐containing materials.     

Monobenzofused 1,4‐Azaborines: Synthesis,Characterization, and Discovery of a Unique Coordination Mode

We report the first general synthesis of boron‐substituted monobenzofused 1,4‐azaborines using ring‐closing metathesis of an enamine‐containing diene as a key synthetic strategy. As part of our investigations, we discovered that the B‐C3 moiety in a 1,4‐azaborine can serve uniquely as a η²‐L‐type ligand. This functionality is exemplified by two κ²‐N‐η²‐BC Pt complexes of a boron‐pyridyl‐substituted monobenzofused‐1,4‐azaborine. Single‐crystal X‐ray diffraction analysis of the Pt complexes shows a strong structural contribution from the iminium resonance form of the monobenzofused‐1,4‐azaborine ligand. We also demonstrate that a palladium(0) complex supported by a 1,4‐azaborine‐based phosphine ligand can catalyze hydroboration of 1‐buten‐3‐yne with unique selectivity. In view of the importance of arene–metal π‐interactions in catalytic applications, this work should open new opportunities for ligand design involving the 1,4‐azaborine motif as an arene substitute.     

Design,Synthesis and Biological Evaluation of Potent Azadipeptide Nitrile Inhibitors and Activity‐Based Probes as Promising Anti‐Trypanosoma brucei Agents

Trypanosoma cruzi and Trypanosoma brucei are parasites that cause Chagas disease and African sleeping sickness, respectively. There is an urgent need for the development of new drugs against both diseases due to the lack of adequate cures and emerging drug resistance. One promising strategy for the discovery of small‐molecule therapeutics against parasitic diseases has been to target the major cysteine proteases such as cruzain for T. cruzi, and rhodesain/TbCatB for T. brucei. Azadipeptide nitriles belong to a novel class of extremely potent cysteine protease inhibitors against papain‐like proteases. We herein report the design, synthesis, and evaluation of a series of azanitrile‐containing compounds, most of which were shown to potently inhibit both recombinant cruzain and rhodesain at low nanomolar/picomolar ranges. A strong correlation between the potency of rhodesain inhibition (i.e., target‐based screening) and trypanocidal activity (i.e., whole‐organism‐based screening) of the compounds was observed. To facilitate detailed studies of this important class of inhibitors, selected hit compounds from our screenings were chemically converted into activity‐based probes (ABPs), which were subsequently used for in situ proteome profiling and cellular localization studies to further elucidate potential cellular targets (on and off) in both the disease‐relevant bloodstream form (BSF) and the insect‐residing procyclic form (PCF) of Trypanosoma brucei. Overall, the inhibitors presented herein show great promise as a new class of anti‐trypanosome agents, which possess better activities than existing drugs. The activity‐based probes generated from this study could also serve as valuable tools for parasite‐based proteome profiling studies, as well as bioimaging agents for studies of cellular uptake and distribution of these drug candidates. Our studies therefore provide a good starting point for further development of these azanitrile‐containing compounds as potential anti‐parasitic agents.     

Recent Progress in the Development of Solid‐State Luminescent o‐Carboranes with Stimuli Responsivity

o‐Carborane, a cluster compound containing boron and adjacent carbon atoms, displays intriguing luminescent properties. Recently, compounds containing o‐carborane units were found to show suppressed aggregation‐induced quenching and intense solid‐state emission; they also show potential for the development of stimuli‐responsive luminochromic materials. In this Minireview, we introduce three kinds of fundamental photochemical properties: aggregation‐induced emission, twisted intramolecular charge transfer in crystals, and environment‐sensitive excimer formation in solids. Based on these properties, several types of luminochromism, such as thermos‐, vapo‐, and mechanochromism, have been discovered. Based mainly on results from recent studies, we illustrate these mechanisms as well as unique luminescent behaviors of o‐carborane derivatives.     

Indolo‐Phakellins as β5‐Specific Noncovalent Proteasome Inhibitors

The proteasome represents an invaluable target for the treatment of cancer and autoimmune disorders. The application of proteasome inhibitors, however, remains limited to blood cancers because their reactive headgroups and peptidic scaffolds convey unfavorable pharmacodynamic properties. Thus, the discovery of more drug‐like lead structures is indispensable. In this study, we present the first structure of the proteasome in complex with an indolo‐phakellin that exhibits a unique noncovalent binding mode unparalleled by all hitherto reported inhibitors. The natural product inspired pentacyclic alkaloid binds solely and specificially into the spacious S3 subpocket of the proteasomal β5 substrate binding channel, gaining major stabilization through halogen bonding with the protein backbone. The presented compound provides an ideal scaffold for the structure‐based design of subunit‐specific nonpeptidic proteasome‐blockers.     

Lysine‐Targeting Covalent Inhibitors

Targeted covalent inhibitors have gained widespread attention in drug discovery as a validated method to circumvent acquired resistance in oncology. This strategy exploits small‐molecule/protein crystal structures to design tightly binding ligands with appropriately positioned electrophilic warheads. Whilst most focus has been on targeting binding‐site cysteine residues, targeting nucleophilic lysine residues can also represent a viable approach to irreversible inhibition. However, owing to the basicity of the ϵ ‐amino group in lysine, this strategy generates a number of specific challenges. Herein, we review the key principles for inhibitor design, give historical examples, and present recent developments that demonstrate the potential of lysine targeting for future drug discovery.     

Rational Design and Identification of a Non‐Peptidic Aggregation Inhibitor of Amyloid‐β Based on a Pharmacophore Motif Obtained from cyclo[‐Lys‐Leu‐Val‐Phe‐Phe‐]

Inhibition of pathogenic protein aggregation may be an important and straightforward therapeutic strategy for curing amyloid diseases. Small‐molecule aggregation inhibitors of Alzheimer’s amyloid‐β (Aβ) are extremely scarce, however, and are mainly restricted to dye‐ and polyphenol‐type compounds that lack drug‐likeness. Based on the structure‐activity relationship of cyclic Aβ16–20 (cyclo‐[KLVFF]), we identified unique pharmacophore motifs comprising side‐chains of Leu², Val³, Phe⁴, and Phe⁵ residues without involvement of the backbone amide bonds to inhibit Aβ aggregation. This finding allowed us to design non‐peptidic, small‐molecule aggregation inhibitors that possess potent activity. These molecules are the first successful non‐peptidic, small‐molecule aggregation inhibitors of amyloids based on rational molecular design.     

A Minimal β‐Lactone Fragment for Selective β5c or β5i Proteasome Inhibitors

Broad‐spectrum proteasome inhibitors are applied as anticancer drugs, whereas selective blockage of the immunoproteasome represents a promising therapeutic rationale for autoimmune diseases. We here aimed at identifying minimal structural elements that confer β5c or β5i selectivity on proteasome inhibitors. Based on the natural product belactosin C, we synthesized two β‐lactones featuring a dimethoxybenzyl moiety and either a methylpropyl (pseudo‐isoleucin) or an isopropyl (pseudo‐valine) P1 side chain. Although the two compounds differ only by one methyl group, the isoleucine analogue is six times more potent for β5i (IC₅₀=14 nM ) than the valine counterpart. Cell culture experiments demonstrate the cell‐permeability of the compounds and X‐ray crystallography data highlight them as minimal fragments that occupy primed and non‐primed pockets of the active sites of the proteasome. Together, these results qualify β‐lactones as a promising lead‐structure motif for potent nonpeptidic proteasome inhibitors with diverse pharmaceutical applications.     

Prediction of Boron–Boron Triple‐Bond Polymers Stabilized by Janus‐Type Bis(N‐heterocyclic) Carbenes

A class of polymeric compounds containing boron–boron triple bonds stabilized by N‐heterocyclic biscarbenes is proposed. Since a triply bonded B₂ is related to its third excited state, the predicted macromolecule would be composed by several units of an electronically excited first‐row homonuclear dimer. Moreover, it is shown that the replacement of biscarbene with N₂ or CO as spacers could change the bonding profile of the boron–boron units to a cumulene‐like structure. Based on these results, different types of diboryne polymers are proposed, which could lead to an unprecedented set of boron materials with distinct physical properties. The novel diboryne macromolecules could be synthesized by the reaction of Janus‐type biscarbenes with tetrabromodiborane, B₂Br₄, and sodium naphthalenide, [Na(C₁₀H₈)], similarly to Braunschweig’s work on the room temperature stable boron–boron triple bond compounds (Science, 2012 , 336, 1420).     

Segmented conjugated macromolecules containing silicon and boron: ADMET synthesis and luminescent properties

Boron‐ and silicon‐containing conjugated homo‐ and copolymers could be synthesized using acyclic diene metathesis (ADMET) condensation of bis‐styryl monomers. Both, tri‐and tetra‐coordinated boron monomers were successfully polymerized forming homopolymers, or random copolymers (if polymerized together with a silicon containing co‐monomer). Polymer molecular weights M_n were measured at ～6000 to 15,000 g/mol (NMR end group analysis) with molecular weight distributions M_w/M_n ～1.8 to 2.2. The polymers absorbed at λ_max ～317 to 406 nm and emitted at λ_max ～370 to 494 nm with fluorescent quantum efficiencies ～24 to 48%. The copolymer with tri‐coordinate boron showed highly efficient fluorescence quenching in the presence of fluoride ions at ratios boron/fluoride ～5/1, demonstrating its potential as anion sensor. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 1707–1718     

Electrophilic Cyanation of Boron Enolates: Efficient Access to Various β‐Ketonitrile Derivatives

The highly efficient electrophilic cyanation of boron enolates using readily available cyanating reagents, N‐cyano‐N‐phenyl‐p‐toluenesulfonamide (NCTS) and p‐toluenesulfonyl cyanide (TsCN), is reported. Various β‐ketonitriles were prepared by this new protocol, which has a remarkably broad substrate scope compared to existing methods. The present method also allowed efficient synthesis of β‐ketonitriles containing a quaternary α‐carbon center. In addition, a preliminary result with the use of a chiral boron enolate for the enantioselective cyanation reaction is described.     

A Versatile Methodology for the Controlled Synthesis of Photoluminescent High‐Boron‐Content Dendrimers

Fluorescent star‐shaped molecules and dendrimers with a 1,3,5‐triphenylbenzene moiety as the core and 3 or 9 carborane derivatives at the periphery, have been prepared in very good yields by following different approaches. One procedure relies on the nucleophilic substitution of Br groups in 1,3,5‐tris(4‐(3‐bromopropoxy)phenyl)benzene with the monolithium salts of methyl and phenyl‐o‐carborane. The second method is the hydrosilylation reactions on the peripheral allyl ether functions of 1,3,5‐tris(4‐allyloxy‐phenyl)benzene and 1,3,5‐tris(4‐(3,4,5‐trisallyloxybenzyloxy)phenyl)benzene with suitable carboranyl‐silanes to produce different generations of dendrimers decorated with carboranyl fragments. This approach is very versatile and allows one to introduce long spacers between the fluorescent cores and the boron clusters, as well as to obtain a high loading of boron clusters. The removal of one boron atom from each cluster leads to high‐boron‐content water‐soluble macromolecules. Thermogravimetric analyses show a higher thermal stability for the three‐functionalized compounds than for those containing 9 clusters. All compounds exhibit photoluminescent properties at room temperature under ultraviolet irradiation with high quantum yields; these depend on the nature of the cluster and the substituent on the C_cluster. Cyclic voltammetry indicates that there is no electronic communication between the core and the peripheral carboranyl fragments. Due to the high boron content of these molecules, we currently focus our research on their biocompatibility, biodistribution in cells cultures, and potential applications for boron neutron capture therapy (BNCT).     

Synthesis of Aminoboronic Acid Derivatives from Amines and Amphoteric Boryl Carbonyl Compounds

Herein, we demonstrate the use of α‐boryl aldehydes and acyl boronates in the synthesis of aminoboronic acid derivatives. This work highlights the untapped potential of boron‐substituted iminium ions and offers insights into the behavior of N‐methyliminodiacetyl (MIDA) boronates during condensation and tautomerization processes. The preparative value of this contribution lies in the demonstration that various amines, including linear and cyclic peptides, can be readily conjugated with boron‐containing fragments. A mild deprotection of amino MIDA‐boronates enables access to α‐ and β‐aminoboronic acids in high chemical yields. This simple process should be applicable to the synthesis of a wide range of bioactive molecules as well as precursors for cross‐coupling reactions.     

Unexpected Correlation Between Boron Chain Condensation and Hydrogen Evolution Reaction (HER) Activity in Highly Active Vanadium Borides: Enabling Predictions

Transition‐metal borides (TMBs) have recently attracted attention as excellent hydrogen evolution (HER) electrocatalysts in bulk crystalline materials. Herein, we show for the first time that VB and V₃B₄ have high electrocatalytic HER activity. Furthermore, we show that the HER activity (in 0.5 m H₂SO₄) increases with increasing boron chain condensation in vanadium borides: Using a ?23 mV overpotential decrement derived from ?0.296 mV (for VB at ?10 mA cm^?2 current density) and ?0.273 mV (for V₃B₄) we accurately predict the overpotential of VB₂ (?0.204 mV) as well as that of unstudied V₂B₃ (?0.250 mV) and hypothetical “V₅B₈” (?0.227 mV). We then derived an exponential equation that predicts the overpotentials of known and hypothetical V_xB_y phases containing at least a boron chain. These results provide a direct correlation between crystal structure and HER activity, thus paving the way for the design of even better electrocatalytic materials through structure–activity relationships.