Diosgenin is a spiroketal steroidal natural product extracted from plants and used as the single most important precursor for the world steroid hormone industry. The sporadic occurrences of diosgenin ...in distantly related plants imply possible independent biosynthetic origins. The characteristic 5,6-spiroketal moiety in diosgenin is reminiscent of the spiroketal moiety present in anthelmintic avermectins isolated from actinomycete bacteria. How plants gained the ability to biosynthesize spiroketal natural products is unknown. Here, we report the diosgenin-biosynthetic pathways in himalayan paris (Paris polyphylla), a monocot medicinal plant with hemostatic and antibacterial properties, and fenugreek (Trigonella foenum-graecum), an eudicot culinary herb plant commonly used as a galactagogue. Both plants have independently recruited pairs of cytochromes P450 that catalyze oxidative 5,6-spiroketalization of cholesterol to produce diosgenin, with evolutionary progenitors traced to conserved phytohormone metabolism. This study paves the way for engineering the production of diosgenin and derived analogs in heterologous hosts.
Cycloelatanene A and B are marine natural products first reported a few years ago. Their relative structures had been elucidated by an extensive NMR study and found to be epimers. However, their ...absolute configurations had not been established because they were isolated in only minute quantities as oily compounds. In this study, the complete structures of cycloelatanene A and B, including absolute configurations, were determined by the crystalline sponge method. The structure analysis confirmed the unique tricyclic structure involving a spiro5.5undecene skeleton. One stereogenic centre at C4 was revised as a result of this analysis. Since it only took 1-2 weeks to complete the experiments using the crystalline sponge method (guest-soaking followed by crystallographic analysis), this method is now highly recommended as a first port of call to achieve complete natural product structure elucidation.
An overcrowded alkene with an anti-folded conformation was converted to its twisted conformer, accompanied by a dramatic color change from yellow to deep purple, by inclusion in a self-assembled T d ...-symmetric coordination cage. The shape of the caged cavity was suitable and desirable for trapping of the twisted conformer. The twisted conformation was temporarily memorized in the alkene even after guest ejection. Permanent trapping of the twisted conformation was achieved by bromination of the twisted conformer formed in situ in the cage.
Folding and assembly are intra- and inter-molecular processes, respectively, for spontaneously generating predetermined, well-defined molecular structures. Though the cooperative processes of these ...mechanisms have been studied in coiled coils and β-sheets, they have been seldom utilized simultaneously in the synthetic fields. We have been developing a new folding-and-assembly (F&A) strategy, in which the folding and metal-directed self-assembly of a short peptide fragment occur simultaneously by helping and inducing the processes of each other. Depending on the sequence design, each short peptide ligand exhibits a specific conformation during metal coordination and simultaneously assembles into an advanced nanostructure, which has been hardly achieved by known synthetic strategies. The concepts, examples of the F&A strategy, the function of the obtained structures as well as future directions are disclosed in this perspective.
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Challenges and Opportunities•Bottom-up construction of over 10-nm-sized, well-defined molecular frameworks (artificial virus capsid)•Realization of supramolecular catalysis (artificial enzymes)•Collaboration of self-folding and self-assembly techniques
To date, a variety of well-defined molecular structures have been constructed in both self-folding and self-assembly fields. To bring breakthroughs in both fields, we have been developing a new folding-and-assembly strategy, in which both folding and self-assembly processes work in concert. Here, we summarize our recent examples of advanced nanostructures of metal-linked peptidic chains and give perspective viewpoints of this strategy.
One-step quantitative self-assembly of aromatic towers consisting of seven to nine discretely stacked aromatic rings is achieved from 25−27 multicomponents via the interpenetration of two identical ...coordination cages.
Cavity control: A highly selective 1,4‐addition reaction of a toluene derivative to o‐quinones proceeds efficiently within a self‐assembled coordination cage (see scheme). The cage accelerates the ...formation of the 1,4‐adduct but suppresses all other reaction pathways that are normally favorable in the absence of the cage.
Kinetic studies on the ligand exchange of self-assembled M12L24 spherical complexes demonstrate that the multicomponent self-assembly roughly undergoes three stages. Initially, (i) there are very ...rapid equilibrations (ms−1) among the many components; (ii) as more stable structures are formed, the system equilibrates quickly (s−1 to min−1) among the completed and uncompleted self-assemblies; misassembled structures are presumably corrected at this stage; and finally (iii) very slow equilibration (hours to days) at the final stage after the self-assembly completes, producing the kinetic stability of the whole. The half-lives of the ligand exchange processes in the M12L24 complexes are much longer than those for comparable monodentate Pd(II)−pyridine complexes by a factor of ∼105, suggesting that, once formed, the 36-component molecular spheres behave like covalent componds.
A dinuclear ruthenium complex, (η5-indenyl)Ru(CO)22, was noncovalently enclathrated within a self-assembled coordination cage. In the cavity, rapid cis–trans isomerization and ligand exchange between ...the terminal and bridging carbonyls were suppressed, and only the carbonyl-bridged cis configuration was observed by X-ray crystallographic analysis.
“Molecular flasks” are well-defined supramolecular cages that can encapsulate one or more molecular guests within their cavities and, in so doing, change the physical properties and reactivities of ...the guests. Although molecular flasks are powerful tools for manipulating matter on the nanoscale, most of them are limited in their scope because of size restrictions. Recently, however, increasingly large and diverse supramolecular cages have become available with enough space in their cavities for larger chemical systems such as polymers, nanoparticles, and biomolecules. Here we report how a class of metallosupramolecular cages known as M12L24 polyhedra have been adapted to serve as nanometer-scale containers for solutions of a pseudorotaxane host–guest complex based on a tetracationic cyclophane host, cyclobis(paraquat-p-phenylene) (CBPQT4+), and a 1,5-dioxynaphthalene (DNP) guest. Remarkably, the hierarchical integration of pseudorotaxanes and M12L24 superhosts causes the system to express stimulus-responsive behavior, a property which can be described as emergent because neither the DNP⊂CBPQT4+ nor the M12L24 assemblies exhibit this behavior independently. The DNP-containing M12L24 molecular flasks are effectively “sealed off” to CBPQT4+ until ions are added as a stimulus to “open” them. The electrolyte stimulus reduces the electrostatic screening distance in solution, allowing favorable DNP⊂CBPQT4+ host–guest interactions to overcome repulsive Coulombic interactions between the cationic M12L24 cages and CBPQT4+ rings. This unusual example of ion-gated transport into chemical nanocontainers is reminiscent of transmembrane ion channels which act as gates to the cell, with the important difference that this system is reversible and operates at equilibrium.
Aim: Adiponectin (APN) exhibits different atheroprotective effects, and we have previously reported that APN function is modulated by its binding proteins, E-selectin ligand 1, Mac-2 binding protein, ...and cystatin C. In the present study, we aimed to identify a novel atheroprotective mechanism of APN via C–C motif chemokine 2 (CCL2). Methods: We conducted iMAP®-intravascular ultrasound (IVUS) in 111 Japanese male patients with stable angina. The plaque characteristics were determined where “plaque burden” (EEM CSA − lumen CSA)/(EEM CSA)×100 (%) ＞50%, and their correlation with serum CCL2 and APN levels was analyzed. Using western blot analysis, the effects of APN on the biological effects of CCL2 were examined in their mutual binding by co-immunoprecipitation assay, the monocyte migration, and the phosphorylation of MAP kinases. Results: In a clinical study, we found that the percentage of plaque in the culprit lesion was correlated positively with serum CCL2 and negatively with serum APN levels, with significance. We identified CCL2 as a novel APN-binding serum protein using immunoprecipitation and western blot analysis. CCL2-induced phosphorylation of MAP kinases and monocyte migration was significantly attenuated by APN in vitro. Conclusion: The opposite association of APN and CCL2 on the percentage of coronary plaque might be caused by their direct interaction and competitive functions on monocyte migration.
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