Pillar[5]arene-Derived endo-Functionalized Molecular Tube for Mimicking Protein-Ligand Interactions.

Artificial tubular molecular pockets bearing polar functionalities on their inner surface are useful model systems for understanding the mechanisms of protein-ligand interactions in living systems. We herein report a pillar[5]arene-derived molecular tube, [P4-(OH)BPO], whose endo conformational isomer endo-[P4-(OH)BPO] possesses an inwardly pointing hydrogen-bond (H-bond) donor (OH) in its deep cavity and a strong H-bond acceptor (C═O) on its predominantly hydrophobic inner surface, rendering it a perfect protein binding pocket mimetic. A fragment-based drug design model was established using endo-[P4-(OH)BPO] and a library of various shape-complementary fragment ligands (1-38). On the basis of the binding affinity data for "fragment-pocket" complexes G⊂endo-[P4-(OH)BPO] (G = 1-38), two rationally designed "lead molecules" (39 and 40) were identified as being able to enhance binding affinity significantly by forming H-bonds with both the donor and acceptor of endo-[P4-(OH)BPO]. The described work opens new avenues for developing pillar[n]arene-derived protein binding pocket-mimetic systems for studies of protein-ligand interactions and mechanisms of enzymatic reactions.

Thiazolo[5,4-d]thiazole-Based Donor-Acceptor Covalent Organic Framework for Sunlight-Driven Hydrogen Evolution.

2D covalent organic frameworks (COFs) could have well-defined arrangements of photo- and electro-active units that serve as electron or hole transport channels for solar energy harvesting and conversion, but their insufficient charge transfer and rapid charge recombination impede the sunlight-driven photocatalytic performance. We report a new donor-acceptor (D-A) system, PyTz-COF that was constructed from the electron-rich pyrene (Py) and electron-deficient thiazolo[5,4-d]thiazole (Tz). With its bicontinuous heterojunction, PyTz-COF demonstrated exceptional optoelectronic properties, photocatalytic ability in superoxide anion radical-mediated coupling of (arylmethyl)amines and photoelectrochemical activity in sunlight-driven hydrogen evolution. Remarkably, PyTz-COF exhibited a photocurrent up to 100 µA cm-2 at 0.2 V vs. RHE and could reach a hydrogen evolution rate of 2072.4 µmol g-1 h-1 . This work is paving the way for reticular design of highly efficient and highly active D-A systems for solar energy harvesting and conversion.

A Triazine-Based Analogue of Graphyne: Scalable Synthesis and Applications in Photocatalytic Dye Degradation and Bacterial Inactivation.

Graphyne, a theorized carbon allotrope possessing only sp- and sp2 -hybridized carbon atoms, holds great potentials in many fields, especially in catalysis and energy-transfer/storage devices. Using a bottom-up strategy, we synthesized a new N-doped graphyne analogue, triazine- and 1,4-diethynylbenzene-based graphyne TA-BGY, in solution in gram-scale. The unique sp/sp2 carbon-conjugated TA-BGY possesses an extended porous network structure with a BET surface area of approximately 300 m2 g-1 . Owing to its low optical band gap (1.44 eV), TA-BGY was expected to have many applications, which were exemplified by the photodegradation of methyl orange and photocatalytic bacterial inactivation.

A Diaminopillar[5]arene-Based Macrobicyclic Molecule: Synthesis, Characterization and A Lock-Key Story.

A new macrobicyclic molecule (BC-DAP5), consisting of a diaminopillar[5]arene cavity and a fused ring, was successfully constructed using a Grubbs metathesis reaction. Further studies indicated that BC-DAP5 possessed a unique molecular behavior, showing a response to acid/base stimuli. In BC-DAP5, protons (acid) acted as a lock, locking the fused ring out of the cavity (pillar[5]arene), and a base served as the key, making the fused ring switch in or out freely. Reversible control of the molecular behavior was achieved simply by adding acid and base alternately.

Unidirectional complexation of pillar[4]arene[1]benzoquinoneoxime with alkyl alcohols.

Despite progress in the unidirectional complexation of cyclodextrins and calixarenes with nonsymmetric guests, unidirectional complexation using pillararenes as hosts remains scarcely explored. In this report, we describe the formation of unidirectional [2]pseudorotaxane-like complexes which were realized using n-alkyl alcohol guests and pillar[4]arene[1]benzoquinoneoxime made from pillar[4]arene[1]quinone in a selective monofunctionalizing manner.

Guest-regulated chirality switching of planar chiral pseudo[1]catenanes.

pseudo[1]Catenane 3 is in a self-included conformation in chloroform, but in dichloromethane, it exists in an equilibrium between the self-included conformational state and a de-threading one. The planar chirality inversion of 3 can be triggered by the host-guest complexation of 3 with adiponitrile G, but the extent of such chiral switching depends on the length of self-included bis(pyrazin-2-yloxy)alkane chains in 3 - longer chains are more favored than shorter ones in the inversion.

Correction: Guest-regulated chirality switching of planar chiral pseudo[1]catenanes.

Correction for 'Guest-regulated chirality switching of planar chiral pseudo[1]catenanes' by Ya-Fen Yang et al., Org. Biomol. Chem., 2018, DOI: 10.1039/c8ob00156a.

Total Synthesis of (±)-Minfiensine via a Formal [3+2] Cycloaddition.

(±)-Minfiensine (1) was synthesized in 10 steps in 26% overall yield with the 1,2,3,4-tetrahydro-9a,4a-iminoethanocarbazole core constructed through a [3+2] cycloaddition reaction between indole and an azaoxyallylic cation.

Bis- and mono(m-benzoic acid)-functionalized pillar[5]arenes.

Installation of m-benzoic acid functionalities on pillar[5]arene rims resulted in bis- and mono(m-benzoic acid)-functionalized pillar[5]arenes 1 and 2. Bis(m-benzoic acid)-functionalized pillar[5]arene 1 was able to self-assemble to form one-dimensional channels with DMF molecules residing in pillar[5]arene cavities. Esterification of two carboxylic acids in 1 with decane-1,10-diol did not afford a [1]catenane, but a bicyclic compound. Although 1-decanol esterification of mono(m-benzoic acid)-functionalized pillar[5]arene 2 did not form a self-included [1]pseudorotaxane-like structure, a mono(decyl m-benzoate)-functionalized pillar[5]arene bearing an ethyl acetate chain was found to form a self-included complex with the ethyl acetate moiety residing inside the pillar[5]arene cavity.

Tetranitro-oxacalix[4]crown-Based Host-Guest Recognition Motif and a Related [2]Rotaxane-Based Molecular Switch.

Different from so far reported oxacalix[4]crown-based host-guest motifs in which oxacalix[4]crowns act only as hydrogen bond acceptors, a [2]pseudorotaxane-type tetranitro-oxacalix[4]crown/urea host-guest recognition motif was developed in which tetranitro-oxacalix[4]crown played a role as both a hydrogen bond donor and an acceptor to stabilize the resulting supramolecular complex. Furthermore, on the basis of a [2]pseudorotaxane complex formed from a tetranitro-oxacalix[4]crown and an axle containing a secondary ammonium ion and a urea group, a [2]rotaxane-based molecular switch was created, in which the oxacalix[4]crown wheel was able to reversibly translocate between the secondary ammonium binding site and the urea binding site of the axle under acid-base stimulation.

A Shape-Persistent Cryptand for Capturing Polycyclic Aromatic Hydrocarbons.

A shape-persistent cryptand 1, containing two face-to-face oriented electron-deficient 2,4,6-triphenyl-1,3,5-triazine units separated by approximately 7 Å, and bridged by two rigid 1,8-naphthyridine linkers and a pentaethylene oxide loop, is created for capturing polycyclic aromatic hydrocarbons. Cryptand 1 formed 1:1 complexes with PAH guest molecules, such as phenanthrene (6), anthracene (7), pyrene (8), triphenylene (9), and tetraphene (10). The single-crystal structure of complex 6⊂1 revealed that 6 was included in the cavity of 1 via face-to-face π···π stacking interactions. Soaking crystalline 1 in a toluene solution of anthracene resulted in anthracene from the toluene solution being picked up by the crystalline solid of 1.

A1/A2-Diamino-Substituted Pillar[5]arene-Based Acid-Base-Responsive Host-Guest System.

An acid-base-responsive supramolecular host-guest system based on a planarly chiral A1/A2-diamino-substituted pillar[5]arene (1)/imidazolium ion recognition motif was created. The pillar[4]arene[1]diaminobenzene 1 can bring an electron-deficient imidazolium cation into its cylindrically shaped cavity under neutral or basic conditions and release it under acidic conditions.

Transition-Metal-Free Synthesis of N-Hydroxy Oxindoles by an Aza-Nazarov-Type Reaction Involving Azaoxyallyl Cations.

A novel transition-metal-free method to construct N-hydroxy oxindoles by an aza-Nazarov-type reaction involving azaoxyallyl cation intermediates is described. A variety of functional groups were tolerated under the weak basic reaction conditions and at room temperature. A one-pot process was also developed to make the reaction even more practical. This method provides alternative access to oxindoles and their biologically active derivatives.

Selectivity and Cooperativity in the Binding of Multiple Guests to a Pillar[5]arene-Crown Ether Fused Tricyclic Host.

A novel tricylic host molecule 1 that consists of two pillar[5]arene units and a crown ether ring was found to selectively bind two kinds of guest molecules with different shapes, sizes, and electronic constitutions, namely 1,4-dicyanobutane G1 and paraquat G2, with its two macrocyclic subunits, to form a four-component complex 2G1⊂1⊃G2. An (1)H NMR study of stepwise bindings of G1 and G2 to host 1 in CDCl3/DMSO-d6 revealed that the strength of the association between complex 2G1⊂1 and guest G2 was only one-fourth of that between free 1 and G2, demonstrating a negative heterotropic cooperativity of G1 in the binding of G2 to host 1.

A trigonal prismatic ligand in the metal-mediated self-assembly of one- and two-dimensional metallosupramolecular polymers.

A novel trispyrazine-pillared prismatic bicycooxacalixaromatic ligand L is synthesized, and its application in metal-mediated self-assembly is described. Under self-assembly conditions, single chain, double-stranded cross-linked coordination polymer and two-dimensional (2D) coordination polymeric networks were formed via M-L (Ag(+), Cu(2+), and Zn(2+)) coordinative interactions. Structural analyses revealed that the antiparallelly arranged one-dimensional coordination polymers (Cu(2+) and Zn(2+)) are arranged to generate well-defined voids to host aromatic guests (benzene) via C-H···π and π···π interactions, while the double-stranded cross-linked coordination polymer (Ag(+)) contains a rhomboidal [Ag2(L(3))2] (L(3): tridentate ligand) cage motif to include a benzene guest; the "thicker" (thickness: ac 5 Å) 2D coordination polymeric networks (Ag(+), Cu(2+), and Zn(2+)), however, are all formed by connection of one or two kinds of topologically different metallomacrocyclic cage units. These unique metallomacrocyclic cage units in the 2D coordination polymeric networks are capable of hosting different guest species. For instance, the rhomboidal [M2(L(3))2] (M = Ag(+), Cu(2+)) cage units were found to host a benzene or a nitrate anion; a hexahedral [M3(L(3))3] (M = Ag(+)) cage was found to host a ligand L or a DMF molecule; the hexahedral [M4(L(3))4] (M = Cu(2+)) cage was found to host four solvent molecules of benzene; and the rectangular [M3(L(3))3] (M = Cu(2+), Zn(2+)) cage units, however, were found to host two THF molecules. The results highlight the potential of ligand L for applications in the construction of "thicker" 2D coordination polymeric networks with well-defined metallomacrocyclic cage units capable of hosting various guest species.

ortho-Functionalization of Pillar[5]arene: An Approach to Mono-ortho-Alkyl/Aryl-Substituted A1/A2-Dihydroxypillar[5]arene.

Despite the fact that the rim and lateral functionalizations of pillar[n]arenes have been well explored, ortho-functionalization has rarely been realized. In this work, we report a facile method of introducing a single functionality ortho to the hydroxyl group in A1/A2-dihydroxypillar[5]arene via a Grignard addition to pillar[4]arene[1]quinone followed by a dienone-phenol rearrangement. The described ortho-alkylation/arylation method allowed formation of various mono ortho-alkyl/aryl-substituted A1/A2-dihydroxypillar[5]arenes previously difficult to obtain.

s-Tetrazine-Bridged Photochromic Aromatic Framework Material.

Integrating fluorescent chromophores in aromatic frameworks could not only prevent aggregation-induced quenching caused by the π-π stacking interaction between the chromophore components but also confer new fluorescence properties. Herein, we report the fabrication of s-tetrazine-bridged aromatic frameworks TzAF by the incorporation of the smallest aromatic fluorophore, s-tetrazine (Tz), into the skeleton of a tetrahedrally connected lattice of aromatic frameworks. The thin films of TzAF coated on silica gel plates were found to exhibit reversible photoswitching fluorescence characteristics under alternate UV and visible-light irradiations with excellent fluorescence stability and high on/off contrast. The repeatable "on/off"fluorescence photoswitchability of the TzAF thin films was mechanistically attributed to light-induced reversible transformation between TzAF's neutral and radical states.

Highly Branched Pillar[5]arene-Derived Porous Aromatic Frameworks (PAFs) for Removal of Organic Pollutants from Water.

The adsorption process is widely used for the treatment of wastewater containing organic pollutants. We fabricated highly branched pillar[5]arene-based porous aromatic frameworks (PAFs), PAF-P5, for the adsorption and removal of organic pollutants (short-chain alkyl derivatives 1-3 and pesticide molecules 4-6) from water with high removal efficiency (RE). However, PAF-P5 was incapable of adsorbing aromatic organic dyes 7-9. Adsorption kinetic studies indicated that the adsorption is mainly driven by strong host-guest interactions between 1-3 and the pillar[5]arene units in PAF-P5, while 4-6 only weakly interacted with the pillar[5]arene units in PAF-P5. Moreover, chemically breaking down the pillar[5]arene rings in PAF-P5 caused changes in the pore size, the microenvironment inside of the pores, and the frame morphology, and the resultant frameworks, PAF-DeP5, exhibited poor adsorption toward 1-6 but adsorbed 7-9 possibly through physical adsorption as implied by fitting the experimental data into the adsorption kinetic models.

A Dual Inhibitor of DYRK1A and GSK3ß for ß-Cell Proliferation: Aminopyrazine Derivative GNF4877.

Loss of ß-cell mass and function can lead to insufficient insulin levels and ultimately to hyperglycemia and diabetes mellitus. The mainstream treatment approach involves regulation of insulin levels; however, approaches intended to increase ß-cell mass are less developed. Promoting ß-cell proliferation with low-molecular-weight inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) offers the potential to treat diabetes with oral therapies by restoring ß-cell mass, insulin content and glycemic control. GNF4877, a potent dual inhibitor of DYRK1A and glycogen synthase kinase 3ß (GSK3ß) was previously reported to induce primary human ß-cell proliferation in vitro and in vivo. Herein, we describe the lead optimization that lead to the identification of GNF4877 from an aminopyrazine hit identified in a phenotypic high-throughput screening campaign measuring ß-cell proliferation.

Selective DYRK1A Inhibitor for the Treatment of Type 1 Diabetes: Discovery of 6-Azaindole Derivative GNF2133.

Autoimmune deficiency and destruction in either ß-cell mass or function can cause insufficient insulin levels and, as a result, hyperglycemia and diabetes. Thus, promoting ß-cell proliferation could be one approach toward diabetes intervention. In this report we describe the discovery of a potent and selective DYRK1A inhibitor GNF2133, which was identified through optimization of a 6-azaindole screening hit. In vitro, GNF2133 is able to proliferate both rodent and human ß-cells. In vivo, GNF2133 demonstrated significant dose-dependent glucose disposal capacity and insulin secretion in response to glucose-potentiated arginine-induced insulin secretion (GPAIS) challenge in rat insulin promoter and diphtheria toxin A (RIP-DTA) mice. The work described here provides new avenues to disease altering therapeutic interventions in the treatment of type 1 diabetes (T1D).