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Protein unfolding and refolding processes were analyzed by confinement in a metallo-cage that prevented the undesirable aggregation of its unfolding structures. The NMR observation revealed the hysteresis behavior of protein unfolding/refolding.

The patient is a 60-year-old female with a history of multiple times of recurrences of an esophageal diverticulum. She was referred for a diagnosis of persistent dysphagia and vomiting. Balloon dilation did not improve the symptoms; thus, she was referred for surgery. Esophageal fluoroscopy revealed a 5 cm diverticulum. There was no significant change in the size before and after dilation. Gastrointestinal endoscopy revealed a diverticulum in the lower esophagus, with a residue accumulation. The esophagus directly below the diverticulum was narrowed. The patient was diagnosed with recurrent lower esophageal diverticulum and underwent surgery. The operative findings showed poor coloration of the gastric fundus surrounding operated before by Nissen’s method, so the patient underwent lower esophagogastric resection and interstitial jejunal reconstruction. The postoperative course was uneventful and discharged on the 19th day. She is 6 years postoperatively and gained six kg compared to her preoperative weight. She has remained in excellent health.

Theoretical analysis revealed the mechanism that accelerates base-catalyzed amide hydrolysis inside the octahedral coordination cage via mechanical bond twisting as demonstrated in recent experiments.

Superb control over the helical chirality of highly-entangled (M3L2)n polyhedra (M = Cu(i), Ag(i); n = 2,4,8) was achieved via multiplication of weak chiral inductions by side chains accumulated on the huge polyhedral surfaces.

In the crystalline sponge method, the crucial step for ordering the absorbed guest is soaking of the guest into the pores of the crystalline sponge. Here, we find that the choice of solvent is particularly important for smooth guest soaking and ordering. Moderately polar solvents, such as ketones and esters, which we have previously avoided for the guest-soaking process, efficiently promote diffusion and guest ordering by filling the gaps in the pores through co-crystallization with the guests. Using this modified protocol, we successfully demonstrate the structural analysis of various steroids.

When substrates are confined in an isolated cavity, they experience circumstances that are distinctly different from those in a bulk solution. Molecular self-assembly has widened the potential of m...

Despite the frequent occurrence of knotted frameworks in protein structures, the latent potential of peptide strands to form entangled structures is rarely discussed in peptide chemistry. Here we report the construction of highly entangled molecular topologies from Ag(I) ions and tripeptide ligands. The efficient entanglement of metal-peptide strands and the wide scope for design of the amino acid side chains in these ligands enabled the construction of metal-peptide 91 torus knots and 1012 torus links. Moreover, steric control of the peptide side chain induced ring opening and twisting of the torus framework, which resulted in an infinite toroidal supercoil nanostructure.

Summary Spatial isolation of molecules is often a powerful strategy for regulating their molecular behavior. Biological systems employ such mechanisms well; however, scientists have yet to rival nature, particularly for macromolecular substrates. We demonstrated that the encapsulation of a protein in a molecular cage with an open framework stabilizes the tertiary structure of the protein and improves its enzymatic activity. Particularly, when the three-dimensionally confined enzyme was exposed to an organic solvent, its half-life was prolonged 1,000-fold. Kinetic and spectroscopic analysis of the enzymatic reaction revealed that the key to this stability is the isolated space; this is reminiscent of chaperonins, which use their large internal cavities to assist the folding of client proteins. The single-molecule protein caging affords a new type of protein-based nanobiotechnology that accelerates molecular biology research as well as industrial applications.

This Review discusses, along with the historical background, the principles as well as proof-of-concept studies of the crystalline sponge (CS) method, a new single-crystal X-ray diffraction (SCXRD) method for the analysis of the structures of small molecules without sample crystallization. The method uses single-crystalline porous coordination networks (crystalline sponges) that can absorb small guest molecules within their pores. The absorbed guest molecules are ordered in the pores through molecular recognition and become observable by conventional SCXRD analysis. The complex {[(ZnI2 )3 (tpt)2 ]⋅x(solvent)}n (tpt=tris(4-pyridyl)-1,3,5-triazine) was first proposed as a crystalline sponge and has been most generally used. Crystalline sponges developed later are also discussed here. The principle of the CS method can be described as "post-crystallization" of the absorbed guest, whose ordering is templated by the pre-latticed cavities. The method has been widely applied to synthetic chemistry as well as natural product studies, for which proof-of-concept examples will be shown here.

When chiral compounds with low enantiomeric excess (ee, R:S=m:n) were absorbed into the void of the crystalline sponge (CS), enantiomerically pure [(R)m(S)n] chiral composites were formed, changing the centrosymmetric space group into non-centrosymmetric one. The absolute configuration of the analyte compounds was elucidated with a reasonable Flack (Parsons) parameter value. This phenomenon is characteristic to the “post-crystallization” in the pre-determined CS crystalline lattice, seldom found in common crystallization where the crystalline lattice is defined by an analyte itself. The results highlight the potential of the CS method for absolute configuration determination of low ee samples, an often encountered situation in asymmetric synthesis studies.

The properties of rare-earth-metal ions in aqueous media often depend on their various hydration modes, which allow them to exist as monomeric or oligomeric species with different coordination numbers. Capturing rare-earth-metal ions in a confined cavity can fix their hydration modes and thus enable their intrinsic properties to be distinguished. However, the isolation of ionic species from bulk aqueous media is not an easy task due to competitive interaction with bulk water. Here, we report the encapsulation of hydrated rare-earth-metal ions in a hydrophobic cavity of a synthetic cage. Cap-like counter anions located at the cage's portals play an important role in capturing the rare-earth metals at a fixed position via electrostatic interactions. Preferential encapsulation of early lanthanoid (III) ions was observed even though all the rare-earth metals have the same hydration number and geometry, as visualized by the competitive inclusion of a dye molecule. Accordingly, the early lanthanoid ion was selectively extracted from a mixture of two rare-earth-metal ions.

The patient is a 58-year-old woman. She was referred to our hospital following a computed tomography scan that revealed a 2-cm tumor-like lesion in the pancreatic body. Endoscopic ultrasound fine-needle aspiration examination revealed a suspected undifferentiated carcinoma with pleomorphic type. The patient was diagnosed with anaplastic carcinoma of the pancreas (ACP) and underwent distal pancreatectomy with lymph nodes dissection. The resected body and tail of the pancreas had a nodular tumor measuring 30 mm in diameter. Histologically, the main lesion of the tumor showed well-differentiated adenocarcinoma, and diffuse proliferation of atypical short spindle cells and round cells accompanied by multinucleated giant cells aggregation was observed around the tubular structure; hence, it was diagnosed with ACP. The postoperative course was uneventful, and the patient was discharged 14 days after the operation. It has already been about 5 years since the surgery, and although the tumor has recurred, the patient is still alive and undergoing chemotherapy.

The ability of a cationic coordination cage to encapsulate molecular guests is enhanced by non-covalent capping of the cage portals with tripodal anions. The capped cage provides new cation binding sites at the portals, which enable accommodation of cationic substrates within the cationic cage. In addition, non-covalent capping allows neutral guests in the cage to be exchanged for cationic ones on demand.

3-(3-Hydroxy-2-(hydroxymethyl)phenyl)propanoic acid, 2-hydroxymethyl-3-hydroxy-(E)-cinnamic acid, and colletofurans A–E were isolated from Colletotrichum boninense AM-12–2. Colletofurans A–E are th...

We synthesized a double-walled knotted cage from a flexible tripodal ligand. The characteristic double-walled structure provided a unique adaptive behavior of the cavity upon inclusion of organic molecules, which was evidenced by NMR and X-ray measurements. The semiflexible host framework, restricted by the knotted topology, enabled kinetic molecular recognition revealing the sequential binding of two different guests from their mixture.

Rectal duplication cysts are extremely rare and account for only 4% of all gastrointestinal duplication cysts. They may become difficult for removal in the case of a large tumor in a narrow pelvis. Herein, we report a case of rectal duplication cysts excision via robotic-assisted laparoscopic surgery and its utility.

A molecular host with photosensitizing centers provides photo-responsive host-guest properties based on its molecular recognition ability. Here, we construct a self-assembled photoactive Ir(

Trans-iso-α-acid is one of the main contributors to the bitter taste of fresh beer and is known to transform into various derivatives during beer aging. However, structural characterization of the derivatives has been a challenging task because of the formation of too many components. Herein, we report that most of the transformation products of trans-iso-α-acid, isolated in this study in only small quantities by HPLC, can be structurally analyzed with the crystalline sponge method. Thirteen compounds, including eight that were previously unreported, have been successfully isolated and analyzed with complete assignment of their absolute configuration. This provides an improved understanding of the chemical transformations that occur during beer aging.

A rare case of bleeding from the duodenal mucosa due to arteriovenous malformation of the pancreatic head is reported. Caution needs to be observed, then excision may be necessary since noninvasive treatment such as coil embolization is not enough for complete hemostasis when patient suddenly decompensates.

A molecular host with photosensitizing centers provides photo-responsive host–guest properties based on its molecular recognition ability. Here, we construct a self-assembled photoactive Ir(iii) cage-shaped complex that contains anion binding pockets on its rim. The anion recognition ability of the complex enables efficient catalysis of the visible-light-induced E–Z isomerization of an anionic styrene derivative.

Mechanically interlocked host frameworks are expected to show dynamic guest inclusion/release without disruption of their inherent structures. Here, we synthesized a double-walled knotted cage from...

C-S bond formation reactions are widely distributed in the biosynthesis of biologically active molecules, and thus have received much attention over the past decades. Herein, we report intramolecular C-S bond formation by a P450 monooxygenase, TleB, which normally catalyzes a C-N bond formation in teleocidin biosynthesis. Based on the proposed reaction mechanism of TleB, a thiol-substituted substrate analogue was synthesized and tested in the enzyme reaction, which afforded the unprecedented sulfur-containing thio-indolactam V, in addition to an unusual indole-fused 6/5/8-tricyclic product whose structure was determined by the crystalline sponge method. Interestingly, conformational analysis revealed that the SOFA conformation is stable in thio-indolactam V, in sharp contrast to the major TWIST form in indolactam V, resulting in differences in their biological activities.

Summary Entanglements of strings are regularly encountered on the macroscale yet rarely utilized in nanoscale construction. Here, we report highly entangled peptide-mimic structures created through folding and assembly of silver(I) ions and a triglycine ligand (L). The highly flexible triglycine strand assembled into a septafoil knot ([Ag⋅L]7) and its eight-crossing link analog ([Ag⋅L]8), both of which were formed for the first time by chemical synthesis. The two structures result from circular oligomerization of the same 1-crossing Ag⋅L motif. We also obtained poly[n]catenane [Ag⋅L]n from a topologically isomeric 2-crossing motif. Our observations reveal that dynamic linkages of short peptides enable easy access to knotted structures, which are restricted in protein structures because of the entropic (and/or kinetic) disadvantage of self-threading processes in long peptide chains, with remarkable stereoselectivity in the self-assembly process.

Discrete (M3L2) n cages assembled from a tripodal ligand (L) and metal ions (M: Cu(i) or Ag(i)) are embedded in networked coordination hosts formed by partial dissociation of the same discrete cages during the crystallization process. The resulting "eggs-in-an-egg-carton" structures provide unique examples of the co-crystallization of discrete and infinite coordination frameworks.

Cavity creation is a key to the origin of biological functions. Small cavities such as enzyme pockets are created simply through liner peptide folding. Nature can create much larger cavities by threading and entangling large peptide rings, as learned from gigantic virus capsids, where not only chemical structures but the topology of threaded rings must be controlled. Although interlocked molecules are a topic of current interest, they have for decades been explored merely as elements of molecular machines, or as a synthetic challenge. No research has specifically targeted them for, and succesfully achieved, cavity creation. Here we report the emergence of a huge capsular framework via multiple threading of metal–peptide rings. Six equivalent C4-propeller-shaped rings, each consisting of four oligopeptides and Ag+, are threaded by each other a total of twelve times (crossing number: 24) to assemble into a well-defined 4 nm-sized sphere, which acts as a huge molecular capsule., Constructing molecular cages from entangled molecules is a complex task requiring precise topological control. Here, the authors thread together six metal-peptide rings into a giant cubic molecular capsule with a defined cavity and 24 crossover points.

A biomimetic route to farnesyl pyrophosphate and dimethyl orsellinic acid (DMOA)-derived meroterpenoid scaffolds has yet to be reported despite great interest from the chemistry and biomedical research communities. A concise synthetic route with the potential to access DMOA-derived meroterpenoids is highly desirable to create a library of related compounds. Herein, we report novel dearomatization methodology followed by polyene cyclization to access DMOA-derived meroterpenoid frameworks in six steps from commercially available starting materials. Furthermore, several farnesyl alkene substrates were used to generate structurally novel, DMOA-derived meroterpenoid derivatives. DFT calculations combined with experimentation provided a rationale for the observed thermodynamic distribution of polycyclization products. published

Tenebrathin (1), a new C-5-substituted γ-pyrone with a nitroaryl side chain, was isolated from the rare actinomycete Streptoalloteichus tenebrarius NBRC 16177. The chemical structure of 1 was elucidated by a spectroscopic analysis using the crystalline sponge method of crystallization-free X-ray crystallography. The biosynthetic origin of the unusual C-5-substituted γ-pyrone in 1 was revealed by a 13C-labeling experiment. Compound 1 exhibited moderate cytotoxicity against several cancer cell lines and likely targets some protein kinases.

Even flexible linear substrates are conformationally fixed within the hydrophobic confined cavities of enzymes. This enables preorganization of the substrates and their positioning in close proximity to the active center to facilitate stereo- and site-selective reactions. Here, we demonstrate the site-selective electrophilic addition of linear diterpenoids within a self-assembled coordination cage. The reactions proceed through folding of the linear substrates into a U-shaped conformation, which results in noncovalent protection of internal C═C bonds to enhance the site selectivity.

Construction of entangled nanostructures from molecular rings or strands has long attracted chemists, yet synthetic approaches for highly entangled nanostructures remain unexplored to date. Here, w...

The cooperation of weak acetylene π-coordination and relatively strong metal-heteroatom coordination has emerged as a promising strategy for the construction of highly complex but well-ordered nanostructures. Here, we report the formation of an (M