Synthesis and Acidity of 5-(m-Terphenyl-2'-yl)-1H-tetrazoles: Evidence for an Enhanced Polar-π Effect Compared to Carboxylic Acids.

The polar-π effect on tetrazoles, medicinal chemistry isosteres of carboxylate, is tested by a Hammett pKa (microtitration) analysis over a series of 5-(m-terphenyl-2'-yl)-1H-tetrazoles. A comparison with m-terphenyl-2'-yl-carboxylic acids supports the isostere analogy also in response to environmental changes. Computational (B97D/def2TZVPPD) extension of the series plus a scan of solvents (vacuum to water) demonstrates the trend with the dielectric constant. The effect is energetically small but may make statistically significant contributions to the tetrazole pharmacological profile.

Catalytic Dynamic Kinetic Resolutions in Tandem to Construct Two-Axis Terphenyl Atropisomers.

The defined structure of molecules bearing multiple stereogenic axes is of increasing relevance to materials science, pharmaceuticals, and catalysis. However, catalytic enantioselective approaches to control multiple stereogenic axes remain synthetically challenging. We report the catalytic synthesis of two-axis terphenyl atropisomers, with complementary strategies to both chlorinated and brominated variants, formed with high diastereo- and enantioselectivity. The chemistry proceeds through a sequence of two distinct dynamic kinetic resolutions: first, an atroposelective ring opening of Bringmann-type lactones produces a product with one established axis of chirality, and second, a stereoselective arene halogenation delivers the product with the second axis of chirality established. In order to achieve these results, a class of Brønsted basic guanidinylated peptides, which catalyze an efficient atroposelective chlorination, is reported for the first time. In addition, a complementary bromination is reported, which also establishes the second stereogenic axis. These bromo-terphenyls are accessible following the discovery that chiral anion phase transfer catalysis by C2-symmetric phosphoric acids allows catalyst control in the second stereochemistry-determining event. Accordingly, we established the fully catalyst-controlled stereodivergent synthesis of all possible chlorinated stereoisomers while also demonstrating diastereodivergence in the brominated variants, with significant levels of enantioselectivity in all cases.

Structure-Activity Relationships and Potent Cytotoxic Activities of Terphenyllin Derivatives from a Small Compound Library.

A small library of 120 compounds was established with seventy new alkylated derivatives of the natural product terphenyllin, together with 45 previous reported derivatives and four natural p-terphenyl analogs. The 70 new derivatives were semi-synthesized and evaluated for cytotoxic activities against four cancer cell lines. Interestingly, 2',4''-diethoxyterphenyllin, 2',4,4''-triisopropoxyterphenyllin, and 2',4''-bis(cyclopentyloxy)terphenyllin showed potent activities with IC50 values in a range from 0.13 to 5.51 µM, which were similar to those of the positive control, adriamycin. The preliminary structure-activity relationships indicated that the introduction of alkyl substituents including ethyl, allyl, propargyl, isopropyl, bromopropyl, isopentenyl, cyclopropylmethyl, and cyclopentylmethyl are important for improving the cytotoxicity.

Three-Component Synthesis of a Library of m-Terphenyl Derivatives with Embedded ß-Aminoester Moieties.

The three-component reaction between alkyl- or arylamines, ß-ketoesters and chalcones in refluxing ethanol containing a catalytic amount of Ce(IV) ammonium nitrate allowed the construction of a large library of highly substituted dihydro- m-terphenyl derivatives containing ß-alkylamino- or ß-arylamino ester moieties. This process generates three new bonds and one ring and proceeds in high atom economy, having two molecules of water as the only side product. Another domino process, in which the original MCR was telescoped with a subsequent aza Michael/retro-aza Michael sequence, allowed the one-pot preparation of a library of compounds with a N-unsubstituted ß-aminoester fragment. Finally, to extend the structural diversity of these libraries, we also examined the aromatization of the central ring of our compounds in the presence of dichlorodicyanoquinone. This reaction sequence did not affect the integrity of a stereogenic center belonging to the amino component.

Total Synthesis of Boletopsin 11 Enabled by Directed ortho-C(sp2)-H Arylation.

A nine-step synthesis of boletopsin 11 (1), a bioactive fungal natural product, is disclosed. Key features include a one-pot [O]-oxa-Michael cascade to establish the polyoxygenated dibenzofuran core followed by a Pd-catalyzed directed ortho-C(sp2)-H arylation to complete the fully functionalized carbon skeleton. Exploration of the latter transformation led to the discovery of an unexpected tandem ortho-C(sp2)-H arylation event, and the scope of the directed ortho-C(sp2)-H reaction was further investigated with coupling partners varying in stereoelectronic properties.

Design, semisynthesis, α-glucosidase inhibitory, cytotoxic, and antibacterial activities of p-terphenyl derivatives.

Terphenyllin (1), a naturally abundant p-terphenyl metabolite, was isolated from the coral derived fungus Aspergillus candidus together with four natural analogues 2-5. To evaluate their potency and selectivity, a series of new derivatives of 1 were designed and semisynthesized. They were evaluated for their α-glucosidase inhibitory, cytotoxic, and antibacterial activities. Compounds 1, 3, 4, 7, 8, 10, 11, 14, 15, 21, 23, 24, 29, 39, and 40 showed significant α-glucosidase inhibitory activity with IC50 values of 4.79-15 µM, which were stronger than that of the positive controls, 1-deoxynojirimycin (IC50 = 192.0 µM) and acarbose (IC50 = 707.9 µM). Compounds 7 and 10 have relatively higher therapeutic indices (CC50/IC50 = 17 and 10, respectively), representing potential promising leads. The enzyme kinetic studies of compounds 1 and 24 showed a non-competitive inhibition on α-glucosidase with Ki values of 1.50 and 3.45 µM, respectively. Additionally, compounds 14, 21, 26, 29, 32, 35, and 37 were found to exhibit strong cytotoxicity against three tumor cell lines A549 (lung adenocarcinoma epithelial), HeLa (cervical carcinoma), and HepG2 (hepatocellular liver carcinoma) with IC50 values ranging from 0.15 to 5.26 µM. Further study indicated that 32 could induce S-phase arrest in the cell cycle progression.

Development of terphenyl-2-methyloxazol-5(4H)-one derivatives as selective reversible MAGL inhibitors.

Monoacylglycerol lipase is a serine hydrolase that plays a major role in the degradation of the endocannabinoid neurotransmitter 2-arachidonoylglycerol. A wide number of MAGL inhibitors are reported in literature; however, many of them are characterised by an irreversible mechanism of action and this behavior determines an unwanted chronic MAGL inactivation, which acquires a functional antagonism of the endocannabinoid system. The possible use of reversible MAGL inhibitors has only recently been explored, due to the lack of known compounds possessing efficient reversible inhibitory activities. In this work, we report a new series of terphenyl-2-methyloxazol-5(4H)-one derivatives characterised by a reversible MAGL-inhibition mechanism. Among them, compound 20b showed to be a potent MAGL reversible inhibitor (IC50 = 348 nM) with a good MAGL/FAAH selectivity. Furthermore, this compound showed antiproliferative activities against two different cancer cell lines that overexpress MAGL.

Total Synthesis of Kehokorins A-E, Cytotoxic p-Terphenyls.

This paper describes a general method for the synthesis of kehokorins A-E, novel cytotoxic p-terphenyls. 2,4,6-Trihydroxybenzaldehyde served as a common building block for preparation of the central aromatic ring. Construction of their p-terphenyl skeletons was achieved by a stepwise Suzuki-Miyaura coupling, whereas the phenyldibenzofuran moiety was built up by an intramolecular Ullmann reaction. Introduction of an l-rhamnose residue into partly protected kehokorin B was performed by the trichloroacetimidate method.

One-pot Synthesis and Antitumor Activity of Unsymmetrical Terphenyls.

In this paper a simple and efficient method for the unsymmetrical terphenyls via sequential one-pot Suzuki coupling reactions using Pd(OAc)2 without isolation of the intermediate is described. The prepared terphenyls were found to possess potent anticancer properties against a panel of cancer cells which includes A549, HeLa, MCF7, DU145, HT29 and BxPC-3. Structural similarity with combretastatin A4, these terphenyls disrupted the tubulin polymerization in vitro and destabilized the microtubules in cells. Flow cytometry studies indicated growth arrest of cells in the G2/M phase of the cell cycle corresponding to antimitotic action. Furthermore, compound 4c showed potent anti-mitotic activity even in zebrafish model and could likely be a potential therapeutic compound as it is active both in in vitro and in vivo.

In Vitro and In Vivo Trypanosomicidal Action of Novel Arylimidamides against Trypanosoma cruzi.

Arylimidamides (AIAs) have been shown to have considerable biological activity against intracellular pathogens, includingTrypanosoma cruzi, which causes Chagas disease. In the present study, the activities of 12 novel bis-AIAs and 2 mono-AIAs against different strains ofT. cruziin vitroandin vivowere analyzed. The most active wasm-terphenyl bis-AIA (35DAP073), which had a 50% effective concentration (EC50) of 0.5 µM for trypomastigotes (Y strain), which made it 26-fold more effective than benznidazole (Bz; 13 µM). It was also active against the Colombiana strain (EC50= 3.8 µM). Analysis of the activity against intracellular forms of the Tulahuen strain showed that this bis-AIA (EC50= 0.04 µM) was about 100-fold more active than Bz (2 µM). The trypanocidal effect was dissociated from the ability to trigger intracellular lipid bodies within host cells, detected by oil red labeling. Both an active compound (35DAP073) and an inactive compound (26SMB060) displayed similar activation profiles. Due to their high selectivity indexes, two AIAs (35DAP073 and 35DAP081) were moved toin vivostudies, but because of the results of acute toxicity assays, 35DAP081 was excluded from the subsequent tests. The findings obtained with 35DAP073 treatment of infections caused by the Y strain revealed that 2 days of therapy induced a dose-dependent action, leading to 96 to 46% reductions in the level of parasitemia. However, the administration of 10 daily doses in animals infected with the Colombiana strain resulted in toxicity, preventing longer periods of treatment. The activity of the combination of 0.5 mg/kg of body weight/day 35DAP073 with 100 mg/kg/day Bz for 10 consecutive days was then assayed. Treatment with the combination resulted in the suppression of parasitemia, the elimination of neurological toxic effects, and survival of 100% of the animals. Quantitative PCR showed a considerable reduction in the parasite load (60%) compared to that achieved with Bz or the amidine alone. Our results support further investigations of this class with the aim of developing novel alternatives for the treatment of Chagas disease.

Site-specific incorporation of a fluorescent terphenyl unnatural amino acid.

The site-specific incorporation of unnatural amino acids into proteins has a wide range of biological implications. Of particular interest is the incorporation of fluorescent probes as a mechanism to track protein function, transport, and folding. Thus, the development of a novel system for the incorporation of new fluorescent unnatural amino acids has significant utility. Specifically, we have elucidated an aminoacyl-tRNA synthetase capable of recognizing a terphenyl UAA derivative, and charging a cognate tRNA with this amino acid for protein incorporation. Moreover, we have successfully incorporated this fluorescent UAA into GFP at several key residues, demonstrating a novel means to modulate fluorescence within the protein.

Discovery and Synthesis of Boletopsins 13 and 14, Brominated Fungal Metabolites of Terrestrial Origin.

Here we report the discovery and synthesis of complex polybrominated p-terphenyl ethers isolated from a mushroom (Boletopsis sp.) used as a traditional medicine by the Kiovi people in the highlands of Papua New Guinea. Boletopsins 13 and 14 represent the first report of polybrominated fungal metabolites to be produced by a terrestrial fungus. The synthetic method employs 2,4,4,6-tetrabromo-2,5-cyclohexadienone to achieve selective polybromination of the extended aromatic system in a selective and sequential manner.

6,7-Bismethoxy-2,11-dihydroxytetraphenylene Derived Macrocycles: Synthesis, Structures, and Complexation with Fullerenes.

6,7-Bismethoxy-2,11-dihydroxytetraphenylene (1), a novel building block of tetraphenylene-derived macrocycles, was synthesized via palladium-catalyzed cross-coupling reactions and characterized by X-ray diffraction. The relevant macrocyclic hosts derived from 1 have well-defined structures with fixed conformations both in solution and solid state. They showed efficient and unique properties toward complexation with fullerenes C60 and C70 in toluene.

Fluorescence Turn-on Enantioselective Recognition of both Chiral Acidic Compounds and α-Amino Acids by a Chiral Tetraphenylethylene Macrocycle Amine.

New chiral tetraphenylethylene (TPE) macrocycles bearing optically pure amine groups were synthesized and found to have a discriminating ability between the two enantiomers of not only chiral acidic compounds but also α-amino acids by enantioselective aggregation and aggregation-induced emission (AIE) effects. NMR spectra, including 2D-NOESY, disclosed that the host-guest interaction of the macrocycle receptor played a key role in addition to the acid-base interactions.

Self-templated chemically stable hollow spherical covalent organic framework.

Covalent organic frameworks are a family of crystalline porous materials with promising applications. Although active research on the design and synthesis of covalent organic frameworks has been ongoing for almost a decade, the mechanisms of formation of covalent organic frameworks crystallites remain poorly understood. Here we report the synthesis of a hollow spherical covalent organic framework with mesoporous walls in a single-step template-free method. A detailed time-dependent study of hollow sphere formation reveals that an inside-out Ostwald ripening process is responsible for the hollow sphere formation. The synthesized covalent organic framework hollow spheres are highly porous (surface area ∼1,500 m(2 )g(-1)), crystalline and chemically stable, due to the presence of strong intramolecular hydrogen bonding. These mesoporous hollow sphere covalent organic frameworks are used for a trypsin immobilization study, which shows an uptake of 15.5 µmol g(-1) of trypsin.

Synthesis, biological evaluation and modeling studies of terphenyl topoisomerase IIα inhibitors as anticancer agents.

We report the synthesis and evaluation of a series of novel terphenyls. Compound 17 had the most potent anticancer activity, indicating that the phenolic hydroxyl was a key group. A DNA relaxation test showed that compound 17 had a strong inhibitory effect on TOP2α, but not on TOP1, which was consistent with the docking analysis results. We performed a 3D-QSAR study using CoMFA and CoMSIA to determine, for the first time, the chemical-biological relationship in the inhibition of TOP by terphenyls. The CoMFA and CoMSIA model had good modeling statistics: leave-one-out q(2) of 0.605 and 0.622, r(2) of 0.998 and 0.994, and r(2)pred (test set) of 0.742 and 0.660. These results suggest that the ortho-phenolic hydroxyl on ring A is important for producing terphenyls with more efficacious activity.

Optically active helical vinylterphenyl polymers: chiral teleinduction in radical polymerization and tunable stereomutation.

Helical vinyl aromatic polymers are emerging as interesting chiral materials due to their dynamic tailorability, synthetic simplicity, and outstanding chemical and physical stabilities. This Personal Account discusses long-range chirality transfer in the radical polymerization of vinylterphenyl monomers and tunable stereomutation of the resultant polymers. It begins with a general introduction to the design, synthesis, and characterization of helical poly{(+)-2,5-bis[4'-((S)-2-methylbutyloxy)phenyl]styrene}, the first one of this series of polymers. Then, long-range chirality transfer during radical polymerization of terphenyl-based vinyl monomers is explained. After that, the chiroptical property control of the resultant polymers by means of the transition from kinetically controlled conformation to thermodynamically controlled conformation and external stimulus is described. This Personal Account concludes by discussing the advantages and disadvantages of the strategy of using vinylterphenyls to obtain optically active helical polymers and providing a short outlook, especially emphasizing the importance of tacticity on the chiroptical properties of polymers.

Heteroatom-bridged tetraphenylenes: synthesis, structures, and properties.

Novel oxygen-, nitrogen-, sulfur-, and selenium-bridged tetraphenylenes were prepared from known tetraphenylene derivatives. Structures of these compounds were unambiguously confirmed by X-ray crystallographic analyses. Photophysical and electrochemical investigations of these heteroatom-bridged tetraphenylenes suggested their potential applications as electronic materials.

Novel triphenylantimony(V) and triphenylbismuth(V) complexes with benzoic acid derivatives: structural characterization, in vitro antileishmanial and antibacterial activities and cytotoxicity against macrophages.

Two novel organoantimony(V) and two organobismuth(V) complexes of the type ML2 were synthesized, with L = acetylsalicylic acid (HL1) or 3-acetoxybenzoic acid (HL2) and M = triphenylantimony(V) (M1) or triphenylbismuth(V) (M2). Complexes, [M1(L1)2] (1), [M1(L2)2]∙CHCl3 (2), [M2(L1)2], (3) and [M2(L2)2] (4), were characterized by elemental analysis, IR and NMR. Crystal structures of triphenylantimony(V) dicarboxylate complexes 1 and 2 were determined by single crystal X-ray diffraction. Structural analyses revealed that 1 and 2 adopt five-coordinated extremely distorted trigonal bipyramidal geometries, binding with three phenyl groups in the equatorial position and two deprotonated organic ligands (L) in the axial sites. The metal complexes, their metal salts and ligands were evaluated in vitro for their activities against Leishmania infantum and amazonensis promastigotes and Staphylococcus aureus and Pseudomonas aeruginosa bacteria. Both the metal complexes showed antileishmanial and antibacterial activities but the bismuth complexes were the most active. Intriguingly, complexation of organobismuth(V) salt reduced its activity against Leishmania, but increased it against bacteria. In vitro cytotoxic test of these complexes against murine macrophages showed that antimony(V) complexes were the least toxic. Considering the selectivity indexes, organoantimony(V) complexes emerge as the most promising antileishmanial agents and organobismuth(V) complex 3 as the best antibacterial agent.

Synthesis and photophysical properties of biphenyl and terphenyl arylene-ethynylene macrocycles.

A series of single-walled carbon nanotube precursors, C3h-symmetric cyclotri(ethynylene)(biphenyl-2,4'-diyl) and cyclotri(ethynylene)(p-terphenyl-2,4″-diyl), have been prepared by a linear stepwise oligomerization-cyclization route and by statistical intermolecular cyclooligomerization. In addition to producing these members of a novel class of arylene ethynylene macrocycles, 1 and 2, the latter statistical process produces the smaller cyclic dimer, cyclodi(ethynylene)(p-terphenyl-2,4″-diyl) and the larger cyclic tetramer cyclotetra(ethynylene)(biphenyl-2,4'-diyl). These macrocycles display large Stokes shifts in their fluorescence spectra. Their biphenyl or terphenyl connectivity prevents these macrocycles from achieving full planarity in the ground state, and the ethynylene moieties could provide synthetic access to cyclic arylene oligomers and discrete carbon nanotube segments.