Characterization of the FKBP.rapamycin.FRB ternary complex

Rapamycin is an important immunosuppressant, a possible anticancer therapeutic, and a widely used research tool. Essential to its various functions is its ability to bind simultaneously to two different proteins, FKBP and mTOR. Despite its widespread use, a thorough analysis of the interactions between FKBP, rapamycin, and the rapamycin-binding domain of mTOR, FRB, is lacking. To probe the affinities involved in the formation of the FKBP.rapamycin.FRB complex, we used fluorescence polarization, surface plasmon resonance, and NMR spectroscopy. Analysis of the data shows that rapamycin binds to FRB with moderate affinity (K(d) = 26 +/- 0.8 microM). The FKBP12.rapamycin complex, however, binds to FRB 2000-fold more tightly (K(d) = 12 +/- 0.8 nM) than rapamycin alone. No interaction between FKBP and FRB was detected in the absence of rapamycin. These studies suggest that rapamycin's ability to bind to FRB, and by extension to mTOR, in the absence of FKBP is of little consequence under physiological conditions. Furthermore, protein-protein interactions at the FKBP12-FRB interface play a role in the stability of the ternary complex.     

Rh(i)-catalyzed dimerization of ene-vinylidenecyclopropanes for the construction of spiro[4,5]decanes and mechanistic studies

Rh(i) complex catalyzed dimerization of ene-vinylidenecyclopropanes took place smoothly to construct a series of products containing spiro[4,5]decane skeletons featuring a simple operation procedure, mild reaction conditions, and good functional group tolerance. In this paper, the combination of experimental and computational studies reveals a counterion-assisted Rh(i)–Rh(iii)–Rh(v)–Rh(iii)–Rh(i) catalytic cycle involving tandem oxidative cyclometallation/reductive elimination/selective oxidative addition/selective reductive elimination/reductive elimination steps; in addition, a pentavalent spiro-rhodium intermediate is identified as the key intermediate in this dimerization reaction upon DFT calculation.

Rh(i) complex catalyzed dimerization of ene-vinylidenecyclopropanes has been demonstrated, and its reaction mechanism is revealed based on a series of mechanistic studies.     

Luminescent monomeric and dimeric Ru(ii) acyclic carbene complexes as selective sensors for NH3/amine vapor and humidity

A new class of luminescent bis(bipyridyl) Ru(ii) pyridyl acyclic carbene complexes with environmentally-sensitive dimerization equilibrium have been developed. Owing to the involvement of the orbitals of the diaminocarbene ligand in the emissive excited state, the phosphorescence properties of these complexes are strongly affected by H-bonding interactions with various H-bonding donor/acceptor molecules. With the remarkable differences in the emission properties of the monomer, dimer, and H-bonded amine adducts together with the change of the dimerization equilibrium, these complexes can be used as luminescent gas sensors for humidity, ammonia, and amine vapors. With the responses to amines and humidity and the corresponding change in the luminescence properties, a proof-of-principle for binary optical data storage with a reversible concealment process has been described.

A new class of selective ammonia/amine vapor and humidity sensors have been developed from the luminescent bis(bipyridyl) Ru(ii) pyridyl acyclic carbene complexes with environmentally-sensitive dimerization equilibrium.     

Picomolar FKBP inhibitors enabled by a single water-displacing methyl group in bicyclic [4.3.1] aza-amides

Methyl groups can have profound effects in drug discovery but the underlying mechanisms are diverse and incompletely understood. Here we report the stereospecific effect of a single, solvent-exposed methyl group in bicyclic [4.3.1] aza-amides, robustly leading to a 2 to 10-fold increase in binding affinity for FK506-binding proteins (FKBPs). This resulted in the most potent and efficient FKBP ligands known to date. By a combination of co-crystal structures, isothermal titration calorimetry (ITC), density-functional theory (DFT), and 3D reference interaction site model (3D-RISM) calculations we elucidated the origin of the observed affinity boost, which was purely entropically driven and relied on the displacement of a water molecule at the protein–ligand–bulk solvent interface. The best compounds potently occupied FKBPs in cells and enhanced bone morphogenic protein (BMP) signaling. Our results show how subtle manipulation of the solvent network can be used to design atom-efficient ligands for difficult, solvent-exposed binding pockets.

Enhancement by displacement. A single methyl group displaces a water molecule from the binding site of FKBPs, resulting in the most potent binders known, outperforming the natural products FK506 and rapamycin in biochemical and cellular assays.     

Efficient construction of the hexacyclic ring core of palau'amine: the pKa concept for proceeding with unfavorable equilibrium reactions

Palau''amine has received a great deal of attention as an attractive synthetic target due to its intriguing molecular architecture and significant immunosuppressive activity, and we achieved its total synthesis in 2015. However, the synthesized palau''amine has not been readily applicable to the mechanistic study of immunosuppressive activity, because it requires 45 longest linear steps from a commercially available compound. Here, we report the short-step construction of the ABCDEF hexacyclic ring core of palau''amine. The construction of the CDE tricyclic ring core in a single step is achieved by our pK_a concept for proceeding with unfavorable equilibrium reactions, and a palau''amine analog without the aminomethyl and chloride groups is synthesized in 20 longest linear steps from the same starting material. The palau''amine analog is confirmed to retain the immunosuppressive activity. The present synthetic approach for a palau''amine analog has the potential for use in the development of palau''amine probes for mechanistic elucidation.

A palau''amine analog (2) was synthesized from 2-cyclopentenone in 20 steps. The construction of the CDE tricyclic ring core in a single step is achieved by our pK_a concept for proceeding with the unfavorable equilibrium reactions.     

Synthesis and characterisation of the ternary intermetalloid clusters {M@[As8(ZnMes)4]}3− (M = Nb,Ta) from binary [M@As8]3− precursors

The development of rational synthetic routes to inorganic arsenide compounds is an important goal because these materials are finding applications in many areas of materials science. In this paper, we show that the binary crown clusters [M@As₈]³⁻ (M = Nb, Ta) can be used as synthetic precursors which, when combined with ZnMes₂, generate ternary intermetalloid clusters with 12-vertex cages, {M@[As₈(ZnMes)₄]}³⁻ (M = Nb, Ta). Structural studies are complemented by mass spectrometry and an analysis of the electronic structure using DFT. The synthesis of these clusters presents new opportunities for the construction of As-based nanomaterials.

Two ternary intermetalloid clusters were constructed through binary intermetalloid clusters with a low valent group 12 metal salt. These clusters represent the first example of the structural transformation for intermetalloid clusters.     

Controlling cyclization pathways in palladium(ii)-catalyzed intramolecular alkene hydro-functionalization via substrate directivity

We report a series of palladium(ii)-catalyzed, intramolecular alkene hydrofunctionalization reactions with carbon, nitrogen, and oxygen nucleophiles to form five- and six-membered carbo- and heterocycles. In these reactions, the presence of a proximal bidentate directing group controls the cyclization pathway, dictating the ring size that is generated, even in cases that are disfavored based on Baldwin''s rules and in cases where there is an inherent preference for an alternative pathway. DFT studies shed light on the origins of pathway selectivity in these processes.

We report a series of palladium(ii)-catalyzed, intramolecular alkene hydrofunctionalization reactions with carbon, nitrogen, and oxygen nucleophiles to form five- and six-membered carbo- and heterocycles.     

Oxygen harvesting from carbon dioxide: simultaneous epoxidation and CO formation

Due to increasing concentrations in the atmosphere, carbon dioxide has, in recent times, been targeted for utilisation (Carbon Capture Utilisation and Storage, CCUS). In particular, the production of CO from CO₂ has been an area of intense interest, particularly since the CO can be utilized in Fischer–Tropsch synthesis. Herein we report that CO₂ can also be used as a source of atomic oxygen that is efficiently harvested and used as a waste-free terminal oxidant for the oxidation of alkenes to epoxides. Simultaneously, the process yields CO. Utilization of the atomic oxygen does not only generate a valuable product, but also prevents the recombination of O and CO, thus increasing the yield of CO for possible application in the synthesis of higher-order hydrocarbons.

Selective formation of atomic oxygen to form epoxides in a waste free process is reported. Simultaneously generating carbon monoxide from carbon dioxide for further use.     

Oxa-spirocycles: synthesis,properties and applications

A general approach to a new generation of spirocyclic molecules – oxa-spirocycles – was developed. The key synthetic step was iodocyclization. More than 150 oxa-spirocyclic compounds were prepared. Incorporation of an oxygen atom into the spirocyclic unit dramatically improved water solubility (by up to 40 times) and lowered lipophilicity. More potent oxa-spirocyclic analogues of antihypertensive drug terazosin were synthesized and studied in vivo.

A general practical approach to a new generation of spirocyclic molecules – oxa-spirocycles – is developed.     

Functionalised nanopores: chemical and biological modifications

Nanopore technology has established itself as a powerful tool for single-molecule studies. By analysing changes in the ion current flowing through a single transmembrane channel, a wealth of molecular information can be elucidated. Early studies utilised nanopore technology for sensing applications, and subsequent developments have diversified its remit. Nanopores can be synthetic, solid-state, or biological in origin, but recent work has seen these boundaries blurred as hybrid functionalised pores emerge. The modification of existing pores and the construction of novel synthetic pores has been an enticing goal for creating systems with tailored properties and functionality. Here, we explore chemically functionalised biological pores and the bio-inspired functionalisation of solid-state pores, highlighting how the convergence of these domains provides enhanced functionality.

The convergence of chemistry, biology, and solid-state approaches enables the construction hybrid nanopores with enhanced single-molecule applications.     

Ferroptosis promotes sonodynamic therapy: a platinum(ii)–indocyanine sonosensitizer

Sonodynamic therapy (SDT) has unique advantages in deep tumour ablation due to its deep penetration depth, showing great preclinical and clinical potential. Herein, a platinum(ii)–cyanine complex has been designed to investigate its potential as a SDT anticancer agent. It generates singlet oxygen (¹O₂) under ultrasound (US) irradiation or light irradiation, and exhibits US-cytotoxicity in breast cancer 4T1 cells but with negligible dark-cytotoxicity. Mechanistic investigations reveal that Pt-Cy reduces the cellular GSH and GPX4, and triggers cancer cell ferroptosis under US irradiation. The metabolomics analysis illustrates that Pt-Cy upon US treatment significantly dysregulates glutathione metabolism, and finally induces ferroptosis. In vivo studies further demonstrate that Pt-Cy inhibits tumor growth under US irradiation and its efficiency for SDT is better than that for PDT in vivo. This is the first example of platinum(ii) complexes for sonodynamic therapy. This work extends the biological applications of metal complexes from PDT to SDT.

A novel platinum(ii)–cyanine complex showed a greater excellent sonodynamic therapeutic effect than photodynamic therapy in vivo. This work expands the biological applications of metal complexes from traditional photodynamic therapy to sonodynamic therapy.     

The mechanism of Raf activation through dimerization

Raf, a threonine/serine kinase in the Raf/MEK/ERK pathway, regulates cell proliferation. Raf''s full activation requires dimerization. Aberrant activation through dimerization is an important therapeutic target. Despite its clinical importance, fundamental questions, such as how the side-to-side dimerization promotes the OFF-to-ON transition of Raf''s kinase domain and how the fully activated ON-state kinase domain is stabilized in the dimer for Raf signaling, remain unanswered. Herein, we decipher an atomic-level mechanism of Raf activation through dimerization, clarifying this enigma. The mechanism reveals that the replacement of intramolecular π–π stacking by intermolecular π–π stacking at the dimer interface releases the structural constraint of the αC-helix, promoting the OFF-to-ON transition. During the transition, the inhibitory hydrophobic interactions were disrupted, making the phosphorylation sites in A-loop approach the HRD motif for cis-autophosphorylation. Once fully activated, the ON-state kinase domain can be stabilized by a newly identified functional N-terminal basic (NtB) motif in the dimer for Raf signaling. This work provides atomic level insight into critical steps in Raf activation and outlines a new venue for drug discovery against Raf dimerization.

We decipher an atomic-level mechanism of Raf activation through dimerization, revealing that the disruption of intramolecular π–π stacking at the dimer interface promotes the OFF-to-ON transition.     

Ternary hybrid CuO-PMA-Ag sub-1 nm nanosheet heterostructures

Multi-component two-dimensional (2D) hybrid sub-1 nm heterostructures could potentially possess many novel properties. Controlling the site-selective distribution of nanoparticles (NPs) at the edge of 2D hybrid nanomaterial substrates is desirable but it remains a great challenge. Herein, we realized for the first time the preparation of ternary hybrid CuO-phosphomolybdic acid-Ag sub-1 nm nanosheet heterostructures (CuO-PMA-Ag THSNHs), where the Ag NPs selectively distributed at the edge of 2D hybrid CuO-PMA sub-1 nm nanosheets (SNSs). And the obtained CuO-PMA-Ag THSNHs as the catalyst exhibited excellent catalytic activity in alkene epoxidation. Furthermore, molecular dynamics (MD) simulations demonstrated that the SNSs interact with Ag NPs to form stable nanoheterostructures. This work would pave the way for the synthesis and broader applications of multi-component 2D hybrid sub-1 nm heterostructures.

Ag nanoparticles selectively distributed at the edge of CuO-PMA sub-1 nm nanosheets to form ternary hybrid CuO-PMA-Ag sub-1 nm nanosheet heterostructures, which as the catalyst exhibited excellent catalytic activity in alkene epoxidation.     

Albumin-mediated “Unlocking” of supramolecular prodrug-like nanozymes toward selective imaging-guided phototherapy

Construction of an activatable photosensitizer and integration into an adaptive nanozyme during phototherapy without producing off-target toxicity remains a challenge. Herein, we have fabricated a prodrug-like supramolecular nanozyme based on a metallic-curcumin and cyanine co-assembly. The albumin-mediated phenol AOH group transformation of nanozyme changes its adjustable oxygen stress from negative superoxide dismutase-like activity of ROS-scavenging to positive photo oxidase activity with an ROS-amplifying capacity. It further increases the depth penetration of a nanozyme in a tumor spheroid, selectively targeting tumorous phototherapy. It also triggers a signal in targeted tumor cells and helps increase cancer cell ablation. This work suggests new options for development of activatable supramolecular nanozymes and provides a synergetic prodrug-like nanozyme strategy for early diagnosis and preclinical phototherapeutics.

An adaptive nanozyme without producing off-target toxicity has been successfully applied in phototherapy.     

Phenylene segments of zigzag carbon nanotubes synthesized by metal-mediated dimerization

Well-studied cycloparaphenylenes (CPPs) correspond to the simplest segments of armchair CNTs, whereas the corresponding macrocyclic oligophenylene strip of zigzag CNTs is still missing. Herein, we present two series of conjugated macrocycles (CM2PP and CN2PP) containing two meta-phenylene or 2,7-naphthylene units facing each other in the strip. CM2PP and CN2PP can be regarded as the shortest cyclic primitive segments of zigzag CNTs. They were synthesized by gold-mediated dimerization and unambiguously characterized. They adopted the tubular structures and can further pack into one-dimensional supramolecular nanotubes. In particular, the supramolecular nanotube of CM2P4P mimics the CNT(9, 0) structure. Structural analysis and theoretical calculation accounted for the reduced ring strain in CM2PPs and CN2PPs. CM2PPs and CN2PPs exhibited a large optical extinction coefficient and high photoluminescence quantum yield. CN2P8P can accommodate fullerene C₆₀, forming a Saturn-like C₆₀@CN2P8P complex, a mimic structure of zigzag CNT peapods.

Two types of macrocycles were synthesized by gold-mediated dimerization, representing the phenylene cutouts of zigzag carbon nanotubes. These macrocycles showed intriguing optical and supramolecular assembly properties.     

Front Cover: Exploring Helical Folding in Oligomers of Cyclopentane‐Based ϵ‐Amino Acids: A Computational Study (ChemistryOpen 3/2022)

The Front Cover shows the preferred conformation of oligomers of the aminoacid Amc₅a. The backbone sequences were investigated using DFT methods in solution. More information can be found in the Research Article by Hae Sook Park et al.     

Front Cover: Enhancement of Chiroptical Responses of trans‐Bis[(β‐iminomethyl)naphthoxy]platinum(II) Complexes with Distorted Square Planar Coordination Geometry (ChemistryOpen 4/2022)

The Front Cover shows the comparison of circularly polarized luminescence (CPL) properties of square planar platinum(II) complexes with different coordination geometries. Computational studies have revealed that the distortion of the coordination geometry is key to enhancement of the chiroptical responses of these compounds. More information can be found in the Research Article by Masahiro Ikeshita et al.     

Silicon functionalization expands the repertoire of Si-rhodamine fluorescent probes

Fluorescent dyes such as rhodamines are widely used to assay the activity and image the location of otherwise invisible molecules. Si-rhodamines, in which the bridging oxygen of rhodamines is replaced with a dimethyl silyl group, are increasingly the dye scaffold of choice for biological applications, as fluorescence is shifted into the near-infrared while maintaining high brightness. Despite intense interest in Si-rhodamines, there has been no exploration of the scope of silicon functionalization in these dyes, a potential site of modification that does not exist in conventional rhodamines. Here we report a broad range of silyl modifications that enable brighter dyes, further red-shifting, new ways to modulate fluorescence, and the introduction of handles for dye attachment, including fluorogenic labeling agents for nuclear DNA, SNAP-tag and HaloTag labeling. Modifications to the bridging silicon are therefore of broad utility to improve and expand the applications of all Si-dyes.

Functionalization of the bridging silicon atom of Si-rhodamine dyes allows tuning of dye performance, the attachment of sensors, and the addition of biomolecular targeting ligands useful for the construction of live cell imaging probes.     

Electrooxidative dearomatization of biaryls: synthesis of tri- and difluoromethylated spiro[5.5]trienones

Radical spirocyclization via dearomatization has emerged as an attractive strategy for the rapid synthesis of structurally diverse spiro molecules. We report the use of electrochemistry to perform an oxidative dearomatization of biaryls leading to tri- and difluoromethylated spiro[5.5]trienones in a user friendly undivided cell set-up and a constant current mode. The catalyst- and chemical oxidant-free dearomatization procedure features ample scope, and employs electricity as the green and sole oxidant.

Radical spirocyclization via dearomatization has emerged as an attractive strategy for the rapid synthesis of structurally diverse spiro molecules.     

CO reductive oligomerization by a divalent thulium complex and CO2-induced functionalization

The divalent thulium complex [Tm(Cp^ttt)₂] (Cp^ttt = 1,2,4-tris(tert-butyl)cyclopentadienyl) reacts with CO to afford selective CO reductive dimerization and trimerization into ethynediolate (C₂) and ketenecarboxylate (C₃) complexes, respectively. DFT calculations were performed to shed light on the elementary steps of CO homologation and support a stepwise chain growth. The attempted decoordination of the ethynediolate fragment by treatment with Me₃SiI led to dimerization and rearrangement into a 3,4-dihydroxyfuran-2-one complex. Investigation of the reactivity of the C₂ and C₃ complexes towards other electrophiles led to unusual functionalization reactions: while the reaction of the ketenecarboxylate C₃ complex with electrophiles yielded new multicarbon oxygenated complexes, the addition of CO₂ to the ethynediolate C₂ complex resulted in the formation of a very reactive intermediate, allowing C–H activation of aromatic solvents. This original intermolecular reactivity corresponds to an unprecedented functionalization of CO-derived ligands, which is induced by CO₂.

The divalent thulium complex [Tm(Cp^ttt)₂] activates CO to form reductive CO dimerization or trimerization products. These complexes further react with electrophiles, including CO₂, yielding multicarbon oxygenates and original C–H activation products.