Vaulted Biaryls in Catalysis: A Structure–Activity Relationship Guided Tour of the Immanent Domain of the VANOL Ligand

The active site in the BOROX catalyst is a chiral polyborate anion (boroxinate) that is assembled in situ from three equivalents of B(OPh)₃ and one of the VANOL ligand by a molecule of substrate. The substrates are bound to the boroxinate by H bonds to oxygen atoms O1–O3. The effects of introducing substituents at each position of the naphthalene core of the VANOL ligand are systematically investigated in an aziridination reaction. Substituents in the 4,4′‐ and 8,8′‐positions have a negative effect on catalyst performance, whereas, substituents in the 7‐ and 7′‐positions have the biggest impact in a positive direction.     

Horseradish Peroxidase Catalyzed Hydrogelation for Biomedical,Biopharmaceutical, and Biofabrication Applications

Horseradish peroxidase (HRP)‐catalyzed hydrogelation has attracted much attention owing to the ease of handling, high biocompatibility, and processability. This review summarizes recent developments, including cutting‐edge research into the use of HRP‐mediated hydrogelation toward biomedical, biopharmaceutical, and biofabrication applications. From the viewpoint of polymer chemistry, the basic chemistry behind hydrogelation, the structure–property relationship, and hybridization of multiple materials by using HRP‐catalyzed hydrogelation are summarized. From the chemical engineering perspective, strategies for controlling hydrogelation kinetics, hydrogel characteristics, and hydrogelation processes are summarized and discussed in detail. Strategies for obtaining biomaterials for medical and pharmaceutical use, and biofabrication for tissue engineering and regenerative medicine emerge by unifying the aspects of HRP‐mediated hydrogelation.     

A Smart Library of Epoxide Hydrolase Variants and the Top Hits for Synthesis of (S)‐β‐Blocker Precursors

Microtuning of the enzyme active pocket has led to a smart library of epoxide hydrolase variants with an expanded substrate spectrum covering a series of typical β‐blocker precursors. Improved activities of 6‐ to 430‐fold were achieved by redesigning the active site at two predicted hot spots. This study represents a breakthrough in protein engineering of epoxide hydrolases and resulted in enhanced activity toward bulky substrates.     

Synthesis and Characterization of Two‐Photon Active Chromophores Based on Tetrathienoacene (TTA) and Dithienothiophene (DTT)

Three new donor–π–donor (D‐π‐D) tetrathienoacene (thieno[2′,3′:4,5]thieno[3,2‐b]thieno[2,3‐d]thiophene (TTA))‐cored chromophores, end‐functionalized with electron‐donating triphenylamine (TPA) groups, were developed and characterized for their two‐photon‐related properties by using both nano‐ and femtosecond laser pulses as the probing tools. TTA‐based chromophores exhibit stronger and more widely dispersed two‐photon absorption (2PA) than those of dithienothiophene (DTT)‐based congeners. As a consequence, the bithiophene‐conjugated TTA chromophore exhibits the highest maximum 2PA cross‐section value (up to 2500 GM) with good thermal stability, and thus, it is the best performing two‐photon chromophore among the studied model compounds. The bithiophene‐conjugated DTT analogue exhibits the second highest maximum two‐photon absorptivity of 1950 GM, which is nearly 7 times larger than that of previously reported DTT‐based chromophores.     

Reactions of a Ruthenium Complex with Substituted N‐Propargyl Pyrroles

In an investigation into the chemical reactions of N‐propargyl pyrroles 1 a – c , containing aldehyde, keto, and ester groups on the pyrrole ring, with [Ru]?Cl ([Ru]=Cp(PPh₃)₂Ru; Cp=C₅H₅), an aldehyde group in the pyrrole ring is found to play a crucial role in stimulating the cyclization reaction. The reaction of 1 a , containing an aldehyde group, with [Ru]?Cl in the presence of NH₄PF₆ yields the vinylidene complex 2 a , which further reacts with allyl amine to give the carbene complex 6 a with a pyrrolizine group. However, if 1 a is first reacted with allyl amine to yield the iminenyne 8 a , then the reaction of 8 a with [Ru]?Cl in the presence of NH₄PF₆ yields the ruthenium complex 9 a , containing a cationic pyrrolopyrazinium group, which has been fully characterized by XRD analysis. These results can be adequately explained by coordination of the triple bond of the propargyl group to the ruthenium metal center first, followed by two processes, that is, formation of a vinylidene intermediate or direct nucleophilic attack. Additionally, the deprotonation of 2 a by R₄NOH yields the neutral acetylide complex 3 a . In the presence of NH₄PF₆, the attempted alkylation of 3 a resulted in the formation the Fischer‐type amino–carbene complex 5 a as a result of the presence of NH₃, which served as a nucleophile. With KPF₆, the alkylation of 3 a with ethyl and benzyl bromoacetates afforded the disubstituted vinylidene complexes 10 a and 11 a , containing ester groups, which underwent deprotonation reactions to give the furyl complexes 12 a and 13 a , respectively. For 13 a , containing an O‐benzyl group, subsequent 1,3‐migration of the benzyl group was observed to yield product 14 a with a lactone unit. Similar reactivity was not observed for the corresponding N‐propargyl pyrroles 1 b and 1 c , which contained keto and ester groups, respectively, on the pyrrole ring.     

Annelated Pyridines as Highly Nucleophilic and Lewis Basic Catalysts for Acylation Reactions

New heterocyclic derivatives of 9‐azajulolidine have been synthesized and characterized with respect to their nucleophilicity and Lewis basicity. The Lewis basicity of these bases as quantified through their theoretically calculated methyl‐cation affinities correlate well with the experimentally measured reaction rates for addition to benzhydryl cations. All newly synthesized pyridines show exceptional catalytic activities in benchmark acylation reactions, which correlate only poorly with Lewis basicity or nucleophilicity parameters. A combination of Lewis basicity with charge and geometric parameters in the framework of a three‐component quantitative structure–activity relationship (QSAR) model is, however, highly predictive.     

Energetic 4,4′‐Oxybis[3,3′‐(1‐hydroxytetrazolyl)]furazan and Its Salts

Energetic compounds that incorporate multiple nitrogen‐rich heterocycles are of great interest for high‐density energetic materials. A facile synthetic strategy to combine an oxy bridge and furazan groups, as well as tetrazole‐ols, into a molecule ( 5 ) was found. Some energetic salts based on 5 were prepared by neutralization. All of the compounds were fully characterized. Additionally, the structure of 7 has been elucidated by single‐crystal XRD analysis. Physicochemical and energetic properties were also studied; these show that these newly designed energetic salts exhibit good thermal stabilities. Hydroxylammonium salt ( 6 ) has a detonation performance and sensitivities comparable with those of 1,3,5‐trinitroperhydro‐1,3,5‐triazine (RDX).     

Exploration of the Synthetic Potential of Electrophilic Trifluoromethylthiolating and Difluoromethylthiolating Reagents

The electrophilicity parameters (E) of some trifluoromethylthiolating and difluoromethylthiolating reagents were determined by following the kinetics of their reactions with a series of enamines and carbanions with known nucleophilicity parameters (N, s_N), using the linear free‐energy relationship log k₂=s_N(N+E). The electrophilic reactivities of these reagents cover a range of 17 orders of magnitude, with Shen and Lu's reagent 1 a being the most reactive and Billard's reagent 1 h being the least reactive electrophile. While the observed electrophilic reactivities (E) of the amido‐derived trifluoromethylthiolating reagents correlate well with the calculated Gibbs energies for heterolytic cleavage of the X?SCF₃ bonds (Tt⁺DA), the cumol‐derived reagents 1 f and 1 g are more reactive than expected from the thermodynamics of the O?S cleavage. The E parameters of the tri/difluoromethylthiolating reagents derived in this work provide an ordering principle for their use in synthesis.     

Probing the Bioactive Conformation of an Archetypal Natural Product HDAC Inhibitor with Conformationally Homogeneous Triazole‐Modified Cyclic Tetrapeptides

Fooling enzymes with mock amides : Analogues of apicidin, a cyclic‐tetrapeptide inhibitor of histone deacetylase (HDAC), were designed with a 1,4‐ or 1,5‐disubstituted 1,2,3‐triazole in place of a backbone amide bond to fix the bond in question in either a trans‐like or a cis‐like configuration. Thus, the binding affinity of distinct peptide conformations (see picture) could be probed. One analogue proved in some cases to be superior to apicidin as an HDAC inhibitor.

     

Tuning the Electronic Properties and Acid‐Response Behavior of N‐Heteroacene‐Based π‐Conjugated Liquids by Changing the Number of π‐Conjugated Substituents

We have designed and synthesized two room‐temperature‐fluorescent π‐conjugated liquids based on the N‐heteroacene framework ( 1 and 2 ). These two π‐conjugated liquids, which contained one and two thiophene rings, respectively, exhibited different electronic properties and rheology behaviors. Single‐crystal X‐ray analysis of dithiophene‐appended compound 4 revealed that two thiophene rings hindered the interactions of the imino N atoms with acids through the formation of interactions between the S atoms of the thiophene rings and the imino N atoms of the pyrazine group. On the other hand, monothiophene‐appended molecules 1 and 3 each contained an unhindered imino N atom on the opposite site to the thiophene ring. Upon dissolving various acids with different pK_a values in compounds 1 and 2 , these slight structural differences gave rise to marked differences in their acid‐response behaviors, thereby resulting in the emission of variously colored fluorescence in the liquid state. Furthermore, when acids with lower pK_a values was dissolved in compounds 1 and 2 , phase transition occurred from an isotropic liquid state to a self‐organized liquid‐crystalline phase.     

Fabrication of Efficient Hydrogenation Nanoreactors by Modifying the Freedom of Ultrasmall Platinum Nanoparticles within Yolk–Shell Nanospheres

The synthesis of silica‐based yolk–shell nanospheres confined with ultrasmall platinum nanoparticles (Pt NPs) stabilized with poly(amidoamine), in which the interaction strength between Pt NPs and the support could be facilely tuned, is reported. By ingenious utilization of silica cores with different surface wettability (hydrophilic vs. ‐phobic) as the adsorbent, Pt NPs could be confined in different locations of the yolk–shell nanoreactor (core vs. hollow shell), and thus, exhibit different interaction strengths with the nanoreactor (strong vs. weak). It is interesting to find that the adsorbed Pt NPs are released from the core to the hollow interiors of the yolk–shell nanospheres when a superhydrophobic inner core material (SiO₂?Ph) is employed, which results in the preparation of an immobilized catalyst (Pt@SiO₂?Ph); this possesses the weakest interaction strength with the support and shows the highest catalytic activity (88 500 and 7080 h^?1 for the hydrogenation of cyclohexene and nitrobenzene, respectively), due to its unaffected freedom of Pt NPs for retention of the intrinsic properties.     

Drug Design Inspired by Nature: Crystallographic Detection of an Auto‐Tailored Protease Inhibitor Template

De novo drug discovery is still a challenge in the search for potent and selective modulators of therapeutically relevant target proteins. Here, we disclose the unexpected discovery of a peptidic ligand 1 by X‐ray crystallography, which was auto‐tailored by the therapeutic target MMP‐13 through partial self‐degradation and subsequent structure‐based optimization to a highly potent and selective β‐sheet peptidomimetic inhibitor derived from the endogenous tissue inhibitors of metalloproteinases (TIMPs). The incorporation of non‐proteinogenic amino acids in combination with a cyclization strategy proved to be key for the de novo design of TIMP peptidomimetics. The optimized cyclic peptide 4 (ZHAWOC7726) is membrane permeable with an IC₅₀ of 21 nm for MMP‐13 and an attractive selectivity profile with respect to a polypharmacology approach including the anticancer targets MMP‐2 (IC₅₀: 170 nm ) and MMP‐9 (IC₅₀: 140 nm ).     

Hydrolysis of Organophosphate Esters: Phosphotriesterase Activity of Metallo‐β‐lactamase and Its Functional Mimics

The phosphotriesterase (PTE) activity of a series of binuclear and mononuclear zinc(II) complexes and metallo‐β‐lactamase (mβl) from Bacillus cereus was studied. The binuclear complex 1 , which exhibits good mβl activity, shows poor PTE activity. In contrast, complex 2 , a poor mimic of mβl, exhibits much higher activity than 1 . The replacement of Cl^? ligands by OH^? is important for the high PTE activity of complex 2 because this complex does not show any catalytic activity in methanol. The natural enzyme mβl from B. cereus is also found to be an inefficient catalyst in the hydrolysis of phosphotriesters. These observations indicate that the binding of β‐lactam substrates at the binuclear zinc(II) center is different from that of phosphotriesters. Furthermore, phosphodiesters, the products from the hydrolysis of triesters, significantly inhibit the PTE activity of mβl and its functional mimics. Although the mononuclear complexes 3 and 4 exhibited significant mβl activity, these complexes are found to be almost inactive in the hydrolysis of phosphotriesters. These observations indicate that the elimination of phosphodiesters from the reaction site is important for the PTE activity of zinc(II) complexes.     

Bi‐anchoring Organic Dyes that Contain Benzimidazole Branches for Dye‐Sensitized Solar Cells: Effects of π Spacer and Peripheral Donor Groups

Benzimidazole‐branched bi‐anchoring organic dyes that contained triphenylamine/phenothiazine donors, 2‐cyanoacrylic acid acceptors, and various π linkers were synthesized and examined as sensitizers for dye‐sensitized solar cells. The structure–activity relationships in these dyes were systematically investigated by using absorption spectroscopy, cyclic voltammetry, and density functional theory calculations. The wavelength of the absorption peak was more‐heavily influenced by the nature of the π linker than by the nature of the donor. For a given donor, the absorption maximum (λ_max) was red‐shifted on changing the π linker from phenyl to 2,2′‐bithiophene, whilst the dyes that contained triphenylamine units displayed higher molar extinction coefficients (?) than their analogous phenothiazine‐based triphenylamine dyes, which led to good light‐harvesting properties in the triphenylamine‐based dyes. Electrochemical data for the dyes indicated that the triphenylamine‐based dyes possessed relatively low‐lying HOMOs, which could be beneficial for suppressing back electron transfer from the conduction band of TiO₂ to the oxidized dyes, owing to facile regeneration of the oxidized dye by the electrolyte. The best performance in the DSSCs was observed for a dye that possessed a triphenylamine donor and 2,2′‐bithiophene π linkers. Electron impedance spectroscopy (EIS) studies revealed that the use of triphenylamine as the donor and phenyl or 2,2′‐bithiophene as the π linkers was beneficial for disrupting the dark current and charge‐recombination kinetics, which led to a long electron lifetime of the injected electrons in the conduction band of TiO₂.     

Reduction of NO by CO on Unsupported Ir: Bridging the Materials Gap

Temperature programmed desorption (TPD) and density functional theory (DFT) are used to investigate adsorption sites and reaction of coadsorbed NO and CO on planar Ir(210) and faceted Ir(210) with tailored sizes of three‐sided nanopyramids exposing (311), (31${\bar 1}$ ) and (110) faces. Both planar and faceted Ir(210) are highly active for reduction of NO by CO with high selectivity to N₂, which is accompanied by simultaneous oxidation of CO. Evidence is found for structure sensitivity in adsorption sites and reaction of coadsorbed NO and CO on faceted Ir(210) versus planar Ir(210). Strong interaction between NO and CO at high NO exposure and one‐monolayer CO pre‐coverage results in “explosive” evolution of N₂ and CO₂ on planar Ir(210) and size effects in reduction of NO by CO on faceted Ir(210) for average facet size ranging from 5 to 14 nm without change in facet structure.     

Template‐Free Preparation of Volvox‐like CdxZn1−xS Nanospheres with Cubic Phase for Efficient Photocatalytic Hydrogen Production

Volvox‐like Cd_xZn_1?xS solid solutions with a cubic zinc blend structure were synthesized through a template‐free ethylene glycol process. Cd(Ac)₂ ? 2 H₂O, Zn(Ac)₂ ? 2 H₂O, and thiourea are used as the starting materials and dissolved in ethylene glycol. These reaction precursors and solvent not only contributed to control over the formation of the volvox‐like spherical geometry, but also exerted vigorous domination for existence of cubic‐phase Cd_xZn_1?xS nanostructures. As‐prepared volvox‐like Cd_xZn_1?xS nanospheres have a diameter of around 100 nm with extensional shells. These samples show excellent photocatalytic H₂ evolution activity from water splitting under visible‐light irradiation without any cocatalyst or scaffolding, owing to their tunable band gap, cubic zinc blend structure, and unique hierarchical porous structure with a high surface area (as high as 95.2 m² g^?1).     

Replacement of an Indole Scaffold Targeting Human 15‐Lipoxygenase‐1 Using Combinatorial Chemistry

Human 15‐lipoxygenase‐1 (15‐LOX‐1) belongs to the class of lipoxygenases, which catalyze oxygenation of polyunsaturated fatty acids, such as arachidonic and linoleic acid. Recent studies have shown that 15‐LOX‐1 plays an important role in physiological processes linked to several diseases such as airway inflammation disease, coronary artery disease, and several types of cancer such as rectal, colon, breast and prostate cancer. In this study, we aimed to extend the structural diversity of 15‐LOX‐1 inhibitors, starting from the recently identified indolyl core. In order to find new scaffolds, we employed a combinatorial approach using various aromatic aldehydes and an aliphatic hydrazide tail. This scaffold‐hopping study resulted in the identification of the 3‐pyridylring as a suitable replacement of the indolyl core with an inhibitory activity in the micromolar range (IC₅₀=16±6 μm ) and a rapid and efficient structure–activity relationship investigation.