Search

1,5,9-Tribromo-2,3,6,7,10,11-hexamethoxy-4b1-methyltribenzo-triquinacene, a C3-symmetric TBTQ derivative, can be prepared conveniently and with high regioselectivity from readily available starting materials. It is a versatile key compound for the synthesis of other chiral 1,5,9-trifunctionalized TBTQ derivatives and pi-extended congeners in which the bays of the TBTQ skeleton are bridged by vinylene units and 1,2-arylene units. X-ray crystal structure analysis and UV-vis spectroscopy show that vinylene bay-bridging enables better pi-conjugation with the arene rings of the TBTQ core than 1,2-arylene bay-bridging does. © 2023 Wiley-VCH GmbH.

Two pi-extended bay-bridged tribenzotriquinacenes ("TBTQ wizard hats") 12 and 16 bearing three mutually conjugated, alternating veratrole-type and ortho-benzoquinone units were synthesized. The electronic properties of these complementarily arranged, nonplanar push-pull systems are affected by the fusion with the rigid, C3-symmetric TBTQ core to a different extent, as revealed by X-ray structural analysis, UV-vis spectroscopy and cyclovoltammetry. The combination of three quinone units within the original TBTQ core and three veratrole-type bay bridging units in 12 gives rise to a more efficiently pi-conjugated chromophore, as reflected by the shallower shape of wizard hat and its absorption in the visible up to 750 nm in comparison to 16. Congener 12 contains an aromatic 18-pi electron system in contrast to the cross-conjugated analog 16. X-ray structure analysis of the precursor dodecaether 15 revealed the formation of a cage-like supramolecular dimer, in which the peripheral dioxane-type ether groups interlace by twelve noncovalent C-H..O bonds. © 2022 Wiley-VCH GmbH.

A helically twisted ribbon-shaped nanographene 3 containing four pentagons, eighteen hexagons and four heptagons was synthesized by a cascade of classical Scholl and non-classical Scholl-type cycloheptatriene formation reactions. In the pivotal step of the synthesis, ten carbon-carbon bonds and four cycloheptatriene rings were formed in one single operation in 11% yield. In this way, the fenestrindane core 1 was annelated with two m-quaterphenyl units 4 at opposite rims, generating a unique helically twisted structure 3 with D-2-symmetry. X-ray crystallography confirmed this [5.5.5.5]fenestrane-based molecular topology and revealed the aggregation of a pair of antipodal enantiomers, (M)-3 and (P)-3, in the solid state. The torsion angles, planarity of hexagons in the two tribenzo[fg,ij,rst]pentaphene substructures and the local aromaticity of the hexagons were studied based on the crystal data. The optical and electronic properties of compound 3 were investigated by UV/Vis and fluorescence spectroscopy and cyclic voltammetry. Based on the reactions of several partially cyclized intermediates and DFT calculations, a mechanistic sequence of the reaction pathways towards the formation of the nanographene 3 is proposed. In particular, factors that affect the relative ease and the role of hydride abstraction from one of the sp(3)-hybridized benzhydrylic bridgeheads, giving rise to cycloheptatrien-7-ol side products, are unfolded in this study. It is demonstrated that this side track occurs exclusively at the most highly conjugated pi-electron system formed and efficiently competes with the classical and non-classical Scholl cyclodehydrogenation reactions in the last stage of the reaction sequence.

Two isomeric polyacylhydrazones P-1 and P-2 were prepared by dynamic covalent chemistry. Due to the presence of aromatic moieties and intramolecular hydrogen bonds in the backbone, both polymers ex...

A pair of enantiomerically pure metallodimers containing two deeply concave tribenzotriquinacene (TBTQ) units linked by a platinum-diacetylene unit were synthesized. Such linear metal-centered TBTQ dimers are considered as edges of metallosquares and metallocubes that bear four or eight mutually syn -oriented TBTQ bowls at their tips, respectively. The structures of the metallodimers were characterized by (1) H, (13) C and (31) P NMR spectroscopy, ESI mass spectrometry, and circular dichroism. The single X-ray crystal structure of (+)-enantiomer confirmed the absolute configuration of the metallodimers and revealed an edge (tip-to-tip) length of 18.456 angstrom and an approximated syn -orientation of the two TBTQ bowls in the solid state.

Isomeric 2,5- and 2,6-bis(iodoethynyl)pyrazine have been employed to assemble single-component polygonal molecular tessellations and intertwined double helices via intermolecular ethynyl C—I⋯N halogen bonding. X-ray crystallography elucidated the 3D supramolecular architectures of five ditopic heteroaromatic polymorphs obtainable via crystallization in various organic solvents.

The successful enlargement of the curved pi-electron periphery of the wizard hat-shaped polycyclic aromatic compound 1 is described. The target structure 2 features an m,m,p,m,m,p,m,m,p-nonaphenylene belt fused to a central tribenzotriquinacene unit. The synthesis involves a multiple regioconvergent Scholl-type dehydrocyclization as the key step. Spectroscopic, structural, and electronic properties of the title compound 2 are reported.

The synthesis of the enantiomerically pure

Starting from a hitherto unknown 2-aminotribenzo-triquinacene, several 2-amino-3-X-substituted TBTQ derivatives, all bearing a single ortho-difunctionalized indane wing, were synthesized as rigid and chiral building blocks for the potential construction of complex supramolecular architectures. Efficient access to two pairs of enantiomeric TBTQ derivatives, namely, the peripheral ortho-nitroaniline (X = NO2) and the related anthranilic acid (X = CO2H), was developed using chiral auxiliaries as the resolving reagents. The structure of the intermediate diastereomers was confirmed by H-1 and C-13 NMR spectroscopy, high-resolution mass spectroscopy (HRMS), and polarimetry. The absolute configuration of the optically active derivatives was confirmed by quantum chemical time-dependent density functional theory (TD-DFT) calculations of the theoretical electronic circular dichroism (ECD) spectra and by single-crystal X-ray structure analysis of a synthesis intermediate.

Porous curved polycyclic aromatic compounds 6 and 14 bearing a tribenzotriquinacene (TBTQ) core encircled by an m,p,p,m,m,p,p,m,m,p,p,m-cyclododecaphenylene belt were synthesized and characterized by NMR spectroscopy and mass spectrometry. These trefoil hydrocarbon macrocycles were constructed in high yield using an intramolecular threefold Scholl macrocyclization. X-ray crystal analysis of 14 demonstrated a large wizard-hat-shaped structure with three pores (radii 2.9-3.0 angstrom). The pi-stacking aggregation of the hexa-n-dodecyloxy derivative 6a and the chloride anion binding properties of 14 were studied by NMR spectroscopy. Such stacking and anion binding properties were much weaker in the singly 11 and doubly macrocyclized products 12.

A new chiral tribenzotriquinacene bearing an ortho-bromoaniline nucleus was synthesized and optically resolved. The individual enantiomers, the absolute configuration of which was confirmed by single-crystal X-ray structure analysis, were stereoselectively converted into the same pyrazine-fused syn-bis-TBTQ derivative by chirality-assisted Buchwald-Hartwig amination. The corresponding diastereomeric anti-dimer was obtained alongside the syn-dimer from the racemic sample under similar reaction conditions. X-ray structure analysis of the dimers confirmed the mutual biconcave and convex-concave configuration of their TBTQ moieties and the preservation of the orthogonal orientation of the indane wings within each of them.

A triazole-containing branched bis(dipeptidomimetic) 2 using l-lysine as a flexible branching unit was synthesized and characterized. The compound was found to form weak dimers (K dim = 19 M–1) in chloroform as shown by vapor pressure osmometry (VPO) and concentration-dependent 1H NMR studies. On the other hand, the compound was capable of binding chloride and monobasic diethyl phosphate (DEP) in chloroform. Job plot analysis, MALDI-TOF mass spectrometry, and NMR titration studies revealed a 1:1 binding stoichiometry with good binding affinities (K a ≈ 640–780 M–1). Structural studies using ­ROESY NMR spectroscopy and molecular modelling on the 2–DEP complex indicated the adoption of a helix-like conformation by the host with the guest situated near the branching juncture.

A series of di-(dithienylethene) (DTE) tetraamides 4 diDTE-X-NHR was synthesized and characterized. Their organogelation property could be rationally optimized by controlling the extent of intramolecular vs. intermolecular hydrogen bonding and also by tuning the extent of side chain interdigitation. Among these compounds, diDTE-Dec-NHDodec4e showed excellent gelation properties with minimum gelation concentration (MGC) values ≤10 mg mL−1 in a wide variety of aromatic solvents. Upon UV (313 nm) irradiation, 32% of the DTE functionality in 4e underwent photocyclization accompanied with a photochromic change and a substantial weakening of the gel network structure. The pure doubly-cyclized isomer 4e-cc was separated and found to be a very weak organogelator (MGC ∼25 mg mL−1) in a limited number of aromatic solvents. More interestingly, self-sorting of 4e and 4e-cc was observed in a 1 : 1 mixture of 4e and 4e-cc freeze-dried gel sample, indicating a high degree of non-self discrimination was present in the mixed gel of these two structurally similar isomers. The results demonstrated that such di-DTE derivatives are photochromic materials with interesting organogelating and self-sorting properties.

Depending on the length (n) and the nature of the end group (X), structurally flexible oligoamides OAT and OATe were found to be good organogelators and their mixtures showed narcissistic self-sorting in both the xerogel and wet gel states., Several series of structurally flexible, non-preorganized oligoamides with carboxylic acid, hydride, N-propargyl amide and N-propyl amide end groups were synthesized and characterized. They were found to be strong organogelators for aromatic solvents. Both the number and density of the amide units, and the nature of the end group were found to influence the gel strength as well as the kinetics of gel formation. Oligomers with a higher number and density of amide units were found to form stronger gels. Rather unexpectedly, a slight change of the end group could significantly affect the enthalpy and entropy of formation of the resulting self-assembly. Oligomers with the N-propargyl amide end group were found to be kinetically trapped in the melted state, which devoid them of forming crystalline zone upon cooling. On the other hand, the corresponding saturated N-propyl amide analog did not show the same effect. Upon mixing of these oligomers, narcissistic self-sorting could be observed in both the wet gel and xerogel states if (i) the difference in the number of amide units is greater than one or (ii) the amide unit densities are different. A semi-quantitative assessment of the extent of self-sorting could be achieved by constructing the corresponding phase diagram of the mixed gel systems. It is concluded that narcissistic self-sorting does not just prevail in mixtures making up of structurally different molecules, but appears to be fairly general even in mixtures of structurally similar molecular homologs.

The Scholl-type cyclodehydrogenation generating up to four cycloheptatriene rings around a fenestrindane core leads to novel, saddle-shaped polyaromatic hydrocarbon derivatives. In this article, we present the results of in-depth experimental and computational works on the oxidative cyclization of various 1,4,9,12-tetraarylfenestrindanes. In particular, the kinetic control of the four-step cyclization of the electronically activated tetrakis(3,4-dimethoxyphenyl) derivative is elucidated. The reasons for the exclusive emergence of one single among the three possible doubly cyclized intermediates and for the nonappearance of the singly and triply cyclized intermediates are clarified. In addition, the origin of the concomitant bridgehead hydroxylation is studied. The reactivity of a set of fifteen symmetrically and unsymmetrically substituted 1,4,9,12-tetraarylfenestrindanes towards Scholl-type cyclodehydrogenation is presented, pinpointing the structural factors that underlie this reaction and demonstrating the potential and limitations of this synthetic approach. A particularly surprising finding of this study is that the electronically nonactivated 1,4,9,12-tetraphenylfenestrindane can also undergo the fourfold Scholl-type cyclization process and can be transformed to the parent saddle hydrocarbon. © 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The synthesis of enantiomerically pure, configurationally stable fenestrindane-based polyaromatic compounds with saddle-like structures is reported. Seven racemic fenestrane synthetic precursors were first screened by chiral HPLC for resolvability into enantiomers. Among the three resolvable precursors, a tribenzofenestrene derivative was resolved on a semipreparative scale, and the absolute configuration of the more slowly eluting enantiomer was established by X-ray crystallography. The enantiopure tribenzofenestrenes were then separately converted, in six steps, to the saddle-shaped fenestrindane derivatives in optically pure form. The two enantiomeric pairs of saddles were characterized by H-1 and C-13 NMR spectroscopy, mass spectrometry, and circular dichroism spectroscopy. All new compounds reported herein represent the first enantiopure non-natural carbocyclic fenestranes isolated to date.

A nonplanar polycyclic aromatic compound 6 bearing a tribenzotriquinacene (TBTQ) core merged with an o,p,o,p,o,p-hexaphenylene belt was prepared and characterized by NMR spectroscopy and X-ray crystallography. The key synthesis step involves three Scholl-type cycloheptatriene ring formation steps of the 1,4,8-tris(3',4'-dimethoxyphenyl)-TBTQ derivative 5. The bridging of each of the three TBTQ bays by 1,2-phenylene units in compound 6 gives rise to an unusual wizard hat shaped structure, which represents a promising key intermediate for the construction of nonplanar nanographene molecules bearing a TBTQ core.

Our recent research efforts on the synthesis of nonplariar nanographenes bearing tribeivotriquinacene or fenestrindane skeleton are stiirirnarizedWizard hat-shaped or saddle-shaped nanographenes could be prepared using a non-classical Scholl-type cycloheptatriene formation or 19-membered ring macrocyclization, The key to the success of these transformation relies on the proper installation of the electron rich aryl functional groups in the bay areas of these molecular motifs, The three-dimensional structures of some of the nanographenes were determined by X-ray cryistallography. Furthermore, these carbon-rich n-conjugated molecules are also showed to have interesting photophysical, self-assoication and host-guest complexation properties.

Construction of single-component supramolecular triangle and unprecedented spontaneous resolution of pairs of intertwined supramolecular 31 - and 32 -double helices by the self-assembly of achiral 2-(iodoethynyl)pyridine and its derivatives have been achieved through intermolecular ethynyl C-I⋅⋅⋅⋅N halogen bonds in the crystalline state. Fine-tuning of the molecular structure of the achiral monomer and choice of solvents for crystallization have a dominant effect on the resultant supramolecular architectures.

A new C 3v -symmetrical tribenzotriquinacene (TBTQ) derivative bearing six 8-quinolinyloxymethyl units at the rim of the bowl-shaped molecular framework is synthesized in a single-step by six-fold etherification of the corresponding hexakis(chloromethyl)-TBTQ precursor with 8-hydroxyquinoline. The resulting compound acts as a fluorescence chemosensor, producing a ‘turn-off’ fluorescent quenching response in the presence of Ag+ ions, and is highly selective toward Ag+ over other cations, such as Al3+, Ca2+, Cd2+, Co2+, Cr3+, Cu2+, Fe3+, Ga3+, Hg2+, In3+, K+, Mg2+, Mn2+, Na+, Ni2+, Pb2+, Pd2+, and Zn2+. The fluorescence intensity change of the chemosensor solution can be clearly observed by the naked eye upon addition of silver salts.

A pair of enantiomerically pure metallosquares based on linear platinum-diacetylene edges and tribenzotriquinacene corner units was synthesized. Their structures were characterized by (1) H-, (13) C- and (31) P NMR spectroscopy as well as MALDI-TOF mass spectrometry and circular dichroism. Based on DFT calculation, the optimized geometry possesses a distorted square conformation in which the four edges are not sitting on the same plane. The molecular square further self-assembled in the solid state to afford microspheres with diameter of approximately 300 nm, as determined by scanning electron microscopy.

A number of three-fold C3v -symmetrical tribenzotriquinacene (TBTQ) cavitands were synthesized by a "metamorphosis-to-half" strategy, employing six-fold etherification reactions between the hexakis(chloromethyl)-TBTQ intermediate 2 a and various 5-functionalized resorcinols. X-ray structure analyses of single crystals of the cavitands revealed limited rotational flexibility of the resorcinol bridging units, which enables an apical, nearly co-axial orientation of the three functional groups and, as a consequence, the construction of nanoscale cage-like molecules via covalent or coordination bonding. On this basis, two TBTQ-based hemicryptophanes were prepared from the TBTQ cavitands via covalent bond formation in good yields. A dumbbell-shaped TBTQ-based metallo-cryptophane was also synthesized in 34 % yield by a solvothermal reaction between cadmium nitrate and two equivalents of the TBTQ-cavitand triacid, as confirmed by single-crystal X-ray diffraction and MALDI-ToF mass spectrometry.

Systematic studies on the role of substituents in the bay-bridging cycloheptatriene ring formation around the tribenzotriquinacene (TBTQ) core via the non-typical Scholl reaction were carried out. The electronic effect of the substituents was found to be the predominant factor that controls the ease of the cyclization reaction, while the steric effect of methoxy groups in the bay regions of the TBTQ core appears to be also significant but less important. In several cases with insufficient electronic activation and/or unfavorable steric restriction, single bay-bridging occurred with or without concomitant bridgehead hydroxylation. Alternatively, an unprecedented ring opening/closure of the TBTQ skeleton by electrophilic ipso-attack was found to intervene in other cases. Starting from the electronically and sterically most favorable precursor, a 1,4,8-tris-(2,3,4-trimethoxyphenyl)-TBTQ derivative, a new wizard-hat-shaped, three-fold bay-bridged TBTQ nanographene core bearing nine methoxy groups at the molecular periphery was synthesized with high efficiency.

Two saddle-shaped polycyclic aromatic compounds (8a and 8b) bearing an all-cis-[5.5.5.5]fenestrane core surrounded by an o,p,o,p,o,p,o,p-cyclooctaphenylene belt were synthesized and characterized by NMR spectroscopy and mass spectrometry. The key step of this synthesis involves the formation of four cycloheptatriene rings from the corresponding electron-rich 1,4,9,12-tetraarylfenestrindane derivatives 7a and 7b in Scholl-type cyclizations. The structural details of the D-2d-symmetric saddle compound 8a were determined by X-ray crystallography, and the properties of 8a and 8b were studied by UV/Vis and fluorescence spectroscopy and cyclic voltammetry.

Hydrogen-bond-assisted host guest complexation of a tris(catechol)-functionalized tribenzotriquinacene with various tetraalkylammonium halides yielded diversified supramolecular architectures ranging from octameric C-3-symmetric cages and C-2- and C-4-symmetric channels to corrugated layers, depending on both the anionic and cationic components of the guest species. Single crystal X-ray analyses of this series of complexes revealed intricate anionic host networks formed by intermolecular O-H center dot center dot center dot O and O-H center dot center dot center dot X hydrogen-bonds involving catechol host molecules and halides, which accommodate the bulky quaternary ammonium guest ions in cavities, channels, or between corrugated sheets. With fine-tuning of the symmetry and size of the hydrophobic cationic guest and accompanying halide species, this simple "Mix and Match" of host and guest components provides an efficient route to the assembly of supramolecular architectures.

This account summarizes our ongoing studies on the synthesis and properties of oligo- and poly(amide-triazole)s. Various structural factors, such as dipole–dipole interactions, polymer side-chain effects and zip-templating effects that can influence the supramolecular self-assembly process are revealed. The unique attributes of these multifunctional compounds as gelating and chemosensing materials are discussed. 1 Background 2 Linear Oligo(amide-triazole) Compounds Derived from Oligopeptides 3 Linear Oligo(amide-triazole) Compounds Derived from Oligo- and Polyamides 4 Conclusions and Outlook

Tributylphosphine-catalyzed regioselective [3+2] cycloadditions between ethyl 5,5-diarylpenta2,3,4-trienoate 1 and various aromatic aldehydes 2 to produce a wide variety of polysubstituted 2,5-dihydrofurans 3, and between 1 and beta-unsubstituted alpha,beta-unsaturated carbonyl compounds 5 to give polysubstituted cyclopentenes 6 with a quaternary carbon center, are reported. In both cases the reaction partners approach each other via the sterically less hindered orientation to afford the target products in excellent regioselectivity. The reaction mechanism involved first the generation of a zwitterionic intermediate between the butatriene 1 and PBu3. For the formation of 2,5-dihydrofurans 3, the preferred cyclization mode encompassed the nucleophilic attack of the a-position of butatriene to the aldehydic carbon of 2, followed by the ring closure between the aldehydic oxygen of 2 and the gamma-position of butatriene, which is the first report of a normal [3+2] cycloaddition between cumulenes and aldehydes. For the formation of cyclopentenes 6, the reaction involved attack of the gamma-position of the butatriene to the electron-deficient beta-position of the alpha,beta-unsaturated carbonyl compounds 5, followed by the ring closure between the alpha-position of 5 and the a-position of butatriene, which shows a different regioselectivity to the previously reported [3+2] cycloadditions between butatriene and olefins.

Two isomeric bottlebrush polyamides P-1 and A-1, with the same repeating monomer dipole units aligned along the polymer backbone in pseudo-parallel and pseudo-antiparallel fashion, respectively, were synthesized and characterized. Both polymers can form thermoreversible gels with aromatic solvents but P-1 was found to show inferior gelation strength compared with that of A-1. Furthermore, despite their close structural resemblance, a 1:1 mixture of the P-1 and A-1 polymers was shown to exhibit self-sorting in the gel state. Gel formation was found to be a kinetically trapped process through hydrogen bonding, π-π stacking interactions, and side chain interdigitation. The different gelation and self-sorting properties can be explained by the local dipole-dipole interactions originating from the different modes of backbone dipole alignment. In single gel systems, the antiparallel-aligned dipoles in A-1 facilitated a more compact molecular packing owing to the enthalpically more favorable polymer chain association. On the other hand, the parallel-aligned dipoles in P-1 gave rise to a less stable head-to-head packing, which had difficulties to convert to the more stable head-to-tail packing in a kinetically trapped environment. In the mixed gel system, it is the unfavorable hetero-polymer mismatch dipole-dipole interaction that inhibited the mixing of the A-1 and P-1 polymers and led to self-sorting.

Two tribenzotriquinacene-based crown ethers, TBTQdibenio-24-crown-8 5 and-TBTQbenzo-21-crOwn-7 6, were prepared from the key TBTQ intermediate, 2,3-dihydroxy-4b,8b,12b,12d-tetramethyltribenzotriquinacene (13), which in turn was synthesized in six steps using two variants of our cyclodehydration method on a multigrarri scale. The host-guest complexation properties of the TBTQbased crown ethers 5 and 6 With a pataquat derivative, 16, and two secondary ammonium salts, 17 and 18, were studied by H-1 NMR spectroscopy and mass spectrometry. It was found that host 5 binds to the paraquat deriVative 16 as a 1:1 complex in CDCl3/CD3CN solution with an association constant K-a = (9.2 +/- 1.8) X 10(2) M-1, whereas no complexation was found for 17 and 18. In contrast, the TBTQcrown ether 6 assembles selectively with dibutylammonium hexafluorophosphate 18 as a 1:1 complex in CDCl3/CD3COCD3 [K-a = (5.0 +/- 1.4) X 10(2) M-1]; for which a threaded [2]pseudorotaxane structure is assumed.

A series of platinum(II) terpyridine complexes with L-valine-modified alkynyl ligands has been synthesized. A complex with an unsubstituted terpyridine and one valine unit on the alkynyl is shown to be capable of gel formation, which is in sharp contrast to the gelation properties of the corresponding organic counterparts. Upon sol-gel transition, a drastic color change from yellow to red is observed, which is indicative of the involvement of Pt⋅⋅⋅Pt interactions. Through the concentration- and temperature-dependent UV/Vis absorption, emission, circular dichroism, and (1) H NMR studies, the contribution of hydrogen bonding, Pt⋅⋅⋅Pt and π-π stacking interactions as driving forces for gelation have been established, and the importance of maintaining a delicate balance between different intermolecular forces has also been illustrated.

A series of main-chain poly(amide-triazole)s were prepared by copper(I)-catalyzed alkyne-azide AABB-type copolymerizatons between five structurally similar diacetylenes 1-5 with the same diazide 6. The acetylene units in monomers 1-5 possessed different degrees of conformational flexibility due to the different number of intramolecular hydrogen bonds built inside the monomer architecture. Our study showed that the conformational freedom of the monomer had a profound effect on the polymerization efficiency and the thermoreversible gelation properties of the resulting copolymers. Among all five diacetylene monomers, only the one, that is, 1-Py(NH)(2) which possesses the pyridine-2,6-dicarboxamide unit with two built-in intramolecular H bonds could produce the corresponding poly(amide-triazole) Poly-(PyNH)(2) with a significantly higher degree of polymerization (DP) than other monomers with a lesser number of intramolecular H bonds. In addition, it was found that only this polymer exhibited excellent thermoreversible gelation ability in aromatic solvents. A self-assembling model of the organogelating polymer Poly-(PyNH)(2) was proposed based on FTIR spectroscopy, XRD, and SEM analyses, in which H bonding, π-π aromatic stacking, hydrophobic interactions, and the structural rigidity of the polymer backbone were identified as the main driving forces for the polymer self-assembly process.

Coronaviral infection is associated with up to 5% of respiratory tract diseases. The 3C-like protease (3CLpro) of coronaviruses is required for proteolytic processing of polyproteins and viral replication, and is a promising target for the development of drugs against coronaviral infection. We designed and synthesized four nitrile-based peptidomimetic inhibitors with different N-terminal protective groups and different peptide length, and examined their inhibitory effect on the in-vitro enzymatic activity of 3CLpro of severe-acute-respiratory-syndrome-coronavirus. The IC50 values of the inhibitors were in the range of 4.6–49 μM, demonstrating that the nitrile warhead can effectively inactivate the 3CLpro autocleavage process. The best inhibitor, Cbz-AVLQ-CN with an N-terminal carbobenzyloxy group, was ∼10x more potent than the other inhibitors tested. Crystal structures of the enzyme–inhibitor complexes showed that the nitrile warhead inhibits 3CLpro by forming a covalent bond with the catalytic Cys145 residue, while the AVLQ peptide forms a number of favourable interactions with the S1–S4 substrate-binding pockets. We have further showed that the peptidomimetic inhibitor, Cbz-AVLQ-CN, has broad-spectrum inhibition against 3CLpro from human coronavirus strains 229E, NL63, OC43, HKU1, and infectious bronchitis virus, with IC50 values ranging from 1.3 to 3.7 μM, but no detectable inhibition against caspase-3. In summary, we have shown that the nitrile-based peptidomimetic inhibitors are effective against 3CLpro, and they inhibit 3CLpro from a broad range of coronaviruses. Our results provide further insights into the future design of drugs that could serve as a first line defence against coronaviral infection., Graphical abstract Highlights ► Four nitrile-based peptidomimetic inhibitors were synthesized and characterized. ► Crystal structures of 3C-like protease in complex with inhibitors were determined. ► The structures justified why the best inhibitor, Cbz-AVLQ-CN, was more potent. ► The peptidomimetic inhibited a broad-spectrum of coronaviral 3C-like proteases.

A series of amphiphilic oligo(glycerol-aliphatic) layer-blocked dendrons with different hydrophilic-lipophilic balance values (3.5–15.0) was prepared for use in controlled drug delivery and self-assembly studies. The synthetic strategies involved first a convergent growth of the inner hydrophobic sector followed by a divergent growth of the outer hydrophilic sector.

Influenza A virus is the major cause of epidemics and pandemics worldwide. In this study, virtual screening was used to identify compounds interacting with influenza A polymerase PB2 cap-binding domain (CBD). With a database of 21,351 small molecules, 28 candidate compounds were tested and one compound (225) was identified as hit compound. Compound 225 and three of its analogs (225D1, 426 and 426Br) were found to bind directly to PB2 CBD by surface plasmon resonance (SPR). The evaluation of compounds 426Br and 225 indicated that they could bind to PB2 CBD and inhibit influenza virus at low micromolar concentration. They were predicted to bind the cap binding site of the protein by molecular modeling and were confirmed by SPR assay using PB2 CBD mutants. These two compounds have novel scaffolds and could be further developed into lead compound for influenza virus inhibition.

barcis -1-Amino-3-hydroxymethyl-cyclobutane-1-carboxylic Acid (1) has been isolated from Atelia herbert-smithii Pittier (Leguminosae) and its structure determined by spectroscopic and X-ray crystallographic methods. By a study of the 1H NMR spectrum of the crude extract, the relative amount of (I) to that of methanoproline in the plant was shown to be 1 to 1.15.

Through a surprisingly nonregioselective oxidation process, the reaction of two analogous 2-hydroxy-substituted tribenzotriquinacenes (TBTQs) 8a/8b by o-iodoxybenzoic acid was found to afford the corresponding C-s- and C-1-symmetrical TBTQ-o-quinones 6a/6b and 7a/7b, respectively, in 1:1 ratio and excellent combined yields. This finding represents the first example of direct introduction of a functional group into a sterically hindered, inner bay-positions of a parent TBTQ skeleton. In contrast, the analogous reaction with 1-hydroxy-TBTQ 15 failed to produce the desired o-quinone 7a. After reduction of the quinones 6a and 7a to the corresponding catechols 17 and 23, electrophilic aromatic substitution could also be realized at the activated inner bay-position(s) to afford several tri- and tetrafunctionalized TBTQ compounds 18, 21, and 25. The C-s-symmetrical o-quinone 6a was converted into further single-wing extended derivatives such as TBTQ-based phenazines 27a-f, through condensation reactions, and to benzodioxine derivative 32 by Diels-Alder reaction with tetracyclone. The novel TBTQ: quinones and the corresponding TBTQ-catechols offer a variety of new accesses to single-wing-extended and functionalized TBTQ derivatives.

The successful merging of two multiply tert-butylated hexa-peri-hexabenzocoronene (HBC) units with all-cis-tetrabenzo[5.5.5.5]-fenestrane (fenestrindane) at two opposite aromatic rings was described. Due to steric inhibition of the tert-butyl substituents near the merging region with the fenestrindane core, attempts to construct a highly warped but fully conjugated polycyclic aromatic hydrocarbon that contains two cycloheptatriene rings failed to materialize.

Nine dendronized poly(amide-triazole)s 2-Gm Gn (m=1-3, n=1-3), were prepared by the 1:1 copolymerization between AA-type dendritic diazides 4-Gm (m=1-3) and BB-type dendritic diacetylenes 5-Gn (n=1-3) under the copper(I)-mediated click coupling conditions. The degree of polymerization value of the polymers was found to range from 15-50, and decreased with increasing size of the dendron, suggesting steric hindrance had a retardation role on the copolymerization efficiency. Based on FT-IR and (1)H NMR studies, it was found that significantly strong, interchain hydrogen bonding between the amide units was present in the solution state after copolymerization, whereas the monomers 4-Gm and 5-Gn were devoid of any intermolecular hydrogen-bonding interaction. Hence a positive allosteric hydrogen-bonding effect was observed after polymerization, and could be rationalized by the zip effect. The strength of the interchain association in polymers 2-Gm Gn was found to decrease with increasing size of the dendron (i.e., 2-G1 G1>2-G1 G2>2-G2 G1≈2-G2 G2>2-G1 G3≈2-G3 G1>2-G2 G3≈2-G3 G2>2-G3 G3). Among the nine polymers, only 2-G1 G2 and 2-G2 G1 were good organogelators for aromatic solvents, while the 2-G2 G2 polymer, bearing the closest structural resemblance to the previously reported organogelator 1-G2 prepared from the polymerization of AB-type monomers, was devoid of gelating power. Careful analysis of structures of the present polymer series 2-Gm Gn and the previously reported series 1-Gn suggested that the polymer backbone symmetry played a subtle role in controlling their self-assembling and gelating properties.

This paper develops a structure−activity relationship understanding of the way in which surfactant-like dendrons with hydrophilic spermine surface groups and a variety of lipophilic units at their focal points can self-assemble and subsequently bind to DNA with high affinity. The choice of functional group at the focal point of the dendron and the high tunability of the molecular structure have a very significant impact on DNA binding. Mesoscale modeling of the mode of dendron self-assembly provides a direct insight into how the mode of self-assembly exerts its effect on the DNA binding process. In particular, the hydrophobic unit controls the number of dendrons in the self-assembled micellar structures, and hence their diameters and surface charge density. The DNA binding affinity correlates with the surface charge density of the dendron aggregates. Furthermore, these structure−activity effects can also be extended to cellular gene delivery, as surface charge density plays a role in controlling the extent of endosomal escape. It is reported that higher generation dendrons, although binding DNA less strongly than the self-assembling lower generation dendrons, are more effective for transfection. The impact of the lipophilic group at the focal point is less significant for the DNA binding ability of these larger dendrons, which is predominantly controlled by the spermine surface groups, but it does modify the levels of gene transfection. Significant synergistic effects on gene delivery were observed when employing combinations of the dendrons and polyethyleneimine (PEI, 25 kDa), with transfection becoming possible at low loading levels where the two components would not transfect individually, giving practically useful levels of gene delivery.

A self-assembled poly(amide-triazole) physical gel (1) was found to show responsive behaviour towards halide anions, while the corresponding monomeric (2) and dimeric homologues (3) were non-gelating. In the presence of halide anions, polymer gel 1 collapsed to become a solution, but could be restored back to the gel state after addition of a AgNO3 salt.