Non-cyclic Analogues Research Articles

Synthesis and antiarrhythmic activity of a new benzodioxolsubstituted 4-spirocycloalkan(tetrahydropyran)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines

By the reaction of 1-(3,4-dimethoxy)phenylcycloalkanmethan- and 4-(3,4-dimethoxyphenyl)tetrahydropyran-4-methanamines with benzo[ d ][1,3]dioxol-5-carbonyl chloride corresponding N -substituted benzo[ d ][1,3]dioxol-5-carboxamides were synthesized. Cyclization of the latter with phosphorus oxychloride gave dihydroisoquinolines reduced with sodium borohydride to the corresponding spiro-substituted tetrahydroisoquinolines, whose methylation according to Eschweiler-Clark reaction gave N -methyl derivatives. By condensation abovementioned amines with benzo[ d ][1,3]dioxol-5-carbaldehyde Schiff bases were synthesized. The reduction of the latter with sodium borohydride gave the corresponding secondary amines - non-cyclic analogues of tetrahydroisoquinolines, which undergo cyclization under the conditions of the Eschweiler-Clark reaction to form N -benzodioxolmethyl-substituted tetrahydroisoquinolines.

The Synthesis of a Multiple D-A Conjugated Macrocycle and Its Application in Organic Photovoltaic.

As a novel class of materials, D-A conjugated macrocycles hold significant promise for chemical science. However, their potential in photovoltaic remains largely untapped due to the complexity of introducing multiple donor and acceptor moieties into the design and synthesis of cyclic π-conjugated molecules. Here, we report a multiple D-A ring-like conjugated molecule (RCM) via the coupling of dimer molecule DBTP-C3 as a template and thiophenes in high yields. RCM exhibits a narrow optical gap (1.33 eV) and excellent thermal stability, and shows a remarkable photoluminescence yield (ΦPL ) of 11.1 % in solution, much higher than non-cyclic analogues. Organic solar cell (OSC) constructed with RCM as electron acceptor shows efficient charge separation at donor-acceptor band offsets and achieves a power conversion efficiency (PCE) of 14.2 %-approximately fourfold higher than macrocycle-based OSCs reported so far. This is partly due to low non-radiative voltage loss down to 0.20 eV and a high electroluminescence yield (ΦEL ) of 4×10-4 . Our findings emphasize the potential of D-A cyclic conjugated molecules in advancing organic photovoltaic technology.

Alkaline aerobic oxidation of native softwood lignin in the presence of Na+-cyclic polyether complexes

Alkaline aerobic oxidation is a promising way to convert lignin to low molecular weight phenols, especially 4-hydroxybenzaldehydes. Our previous studies reported that oxidation of softwood lignin samples with a bulky cation, Bu4N+, facilitates selective production of vanillin (4-hydroxy-3-methoxybenzaldehyde). This study presents vanillin production from native softwood lignin in Japanese cedar (Cryptomeria japonica) in NaOH aq. in the presence of cyclic polyethers, with our expectation that Na+-polyether complexes exhibit effects similar to those of Bu4N+. Oxidation of wood flour (10 mg) in 4.0 M NaOH aq. (2.0 mL) at 120 °C under air gave vanillin with 6.2 wt% lignin-based yield, which was raised to 15.2 wt% by the addition of 15-crown-5 (1,4,7,10,13-pentaoxacyclopentadecane). On the other hand, such effect was not observed with the addition of tetraethylene glycol dimethyl ether, a non-cyclic analog of 15-crown-5. Mechanistic study with a lignin model compound revealed that stabilization of a vanillin precursor by the complex cation was a reason for the increased vanillin yield exhibited by the crown ether. This is similar to the influence of Bu4N+ reported previously, suggesting effective control of aerobic oxidation by large size cationic species.

Modelling the binding mode of macrocycles: Docking and conformational sampling

Drug discovery is increasingly tackling challenging protein binding sites regarding molecular recognition and druggability, including shallow and solvent-exposed protein-protein interaction interfaces. Macrocycles are emerging as promising chemotypes to modulate such sites. Despite their chemical complexity, macrocycles comprise important drugs and offer advantages compared to non-cyclic analogs, hence the recent impetus in the medicinal chemistry of macrocycles. Elaboration of macrocycles, or constituent fragments, can strongly benefit from knowledge of their binding mode to a target. When such information from X-ray crystallography is elusive, computational docking can provide working models. However, few studies have explored docking protocols for macrocycles, since conventional docking methods struggle with the conformational complexity of macrocycles, and also potentially with the shallower topology of their binding sites. Indeed, macrocycle binding mode prediction with the mainstream docking software GOLD has hardly been explored. Here, we present an in-depth study of macrocycle docking with GOLD and the ChemPLP scores. First, we summarize the thorough curation of a test set of 41 protein-macrocycle X-ray structures, raising the issue of lattice contacts with such systems. Rigid docking of the known bioactive conformers was successful (three top ranked poses) for 92.7% of the systems, in absence of crystallographic waters. Thus, without conformational search issues, scoring performed well. However, docking success dropped to 29.3% with the GOLD built-in conformational search. Yet, the success rate doubled to 58.5% when GOLD was supplied with extensive conformer ensembles docked rigidly. The reasons for failure, sampling or scoring, were analyzed, exemplified with particular cases. Overall, binding mode prediction of macrocycles remains challenging, but can be much improved with tailored protocols. The analysis of the interplay between conformational sampling and docking will be relevant to the prospective modelling of macrocycles in general.

Development of novel macrocyclic small molecules that target CTG trinucleotide repeats

We describe the molecular design, synthesis, and investigation of a series of acridine-triaminotriazine macrocycles that selectively bind to CTG trinucleotide repeats in DNA with minimal nonspecific binding. The limited conformational flexibility enforces the stacking of the triaminotriazine and acridine units. Isothermal titration calorimetry studies and Job plot analyses revealed that the ligands bound to d(CTG) mismatched sites. The acridine and triaminotriazine units were shown to intramolecularly π-stack in aqueous solutions. Compared to a noncyclic analog, the macrocycles showed an almost 10-fold lower cytotoxicity in HeLa cells and up to 4-fold higher transcription inhibition of d(CTG·CAG)74.

Selective binding of potassium and calcium ions to novel cyclic proanthocyanidins in wine by HPLC-HRMS.

Cyclic B-type (referred also as crown) proanthocyanidins were recently identified in wines. An HPLC-HRMS/MS method was applied to study the binding of cyclic and non-cyclic PAC to potassium and calcium ions, which affect the chemico-physical stability of wines. Different binding affinities suggest that cyclic and non-cyclic analogues, despite the equal number of monomer units, influence the colloidal stability of wine and are related to the grape variety or winemaking conditions. Nineteen red and white wines were analysed by HPLC high resolution tandem mass spectrometry with positive electrospray ionization to investigate the distribution of novel cyclic proanthocyanidins and their calcium, potassium and sodium adducts. Principal Component Analysis was used to study the distribution of the wines and the relationships among proanthocyanidins with and without cation complexes. A dependence on specific isomers (and conformations) was found for the non-cyclic procyanidin (PC) trimer whereas the cyclic tetrameric PAC were shown to bind better to potassium than their non-cyclic analogues. The binding to these metals appeared to be influenced not only be the number of monomer units but also by the conformation assumed by the molecules. Statistical analysis evidenced that the adducts distribution in different wines is less influenced by the grape variety used for winemaking than their associated [M+H]+ species studied earlier. Wines from 19 grape varieties were investigated in order to identify potassium and calcium complexes of non- and cyclic B-type proanthocyanidins that were recently discovered. The results showed a dependence of the distribution of metal complexes according to the cyclic or non cyclic geometry of proanthocyanidins. The multivariate analysis of the mass spectrometric results showed a relationship with the grape variety, however not so straightforward as evidenced for the non-complexed species.

Disulfide-Linked/Peptide-Incorporated Macrocycles: Unique Redox-Responsiveness and Application for Intracellular Cargo-Delivery

The use of disulfide-linked macrocycles for biomedicine applications was not explored, which is, at least partially, due to the lack of a straightforward strategy to incorporate a cell-surface binding ligand into the macrocycles for facilitating cellular uptake. Herein, we discover that twin disulfides consisting of a flexible peptide and a structurally rigid organic molecule can be transformed into stable and trimeric macrocycles upon triggering with thiols. The disulfide linked/peptide incorporated macrocycles are substantially more stable in weakly reducing environments compared to their non-cyclic analogues due to the cooperativity of the three interlinked disulfide bonds. We further demonstrated that the trimeric macrocycles can be a promising scaffold for the development of intracellular cargo-delivery systems by incorporating a cell-penetrating peptide into the macrocycles.

Structural reevaluation of the electrophilic hypervalent iodine reagent for trifluoromethylthiolation supported by the crystalline sponge method for X-ray analysis.

Hypervalent iodine λ3-benziodoxoles are common electrophilic transfer reagents known for their enhanced stability compared to their non-cyclic analogues. Herein we present data showing that chlorobenziodoxole reacts with two different thiolate nucleophiles (thiocyanate and trifluoromethylthiolate), resulting in the formation of stable thioperoxy complexes rather than the expected benziodoxole derivatives. We further report a revised structure for the earlier described electrophilic trifluoromethylthiolation reagent (1), which was previously believed to contain the benziodoxole framework. Our findings, which are based on a combination of analytical techniques, including the recently introduced crystalline sponge method for X-ray analysis, unambiguously demonstrate that 1 is a thioperoxy compound both in solution and the solid state.

The synthesis of new calix[n]arene quaternary ammonium salts and investigation of their catalytic affinities for three component Mannich-type reactions in water

Two new calix[n]arenes and a non-cyclic analogue substituted with 1-(2-furoyl)piperazine have been synthesized.

Catalytic properties of micellar systems based on 4-aza-1-alkyl-1-azoniabicyclo[2.2.2]octane bromides

The catalytic effect of micellar systems based on alkylated 1,4-diazabicyclo[2.2.2]octanes on the alkaline hydrolysis of butyl chloromethyl 4-nitrophenyl phosphonate is reported. The catalytic effect is due to the reactants concentrating in the micellar phase. It increases with an increase in the hydrophobicity of the surfactant. The bicyclic surfactant manifests the higher efficiency than its cyclic and noncyclic analogues. The micellization properties of alkylated 1,4-diazabicyclo[2.2.2]octanes in aqueous solutions have been investigated by the NMR method. An increase in the hydrophobicity of the surfactant decreases the critical micelle concentration and increases the hydrodynamic radius and aggregation numbers of the micelles.

ChemInform Abstract: “pKa” of Calixarenes and Analogs in Nonaqueous Solvents

The acid dissociation constants (Kapp) of p-t-butylcalix[n]arenes (1n: n=4, 6, and 8), O-methylated p-t-butylcalix[4]arene (2Men), and their noncyclic analogs (3n) were estimated in THF at 25°C. As pH indicators, Et4N+ salts of p-nitrophenolate, 2,4-dinitrophenolate, and picrate were employed. The pKapp values for 1n were lowered by at least four pK units from that of p-t-butylphenol because of strong intramolecular hydrogen-bonding interactions. Compounds 2n involved both the strong and weak hydrogen bonds: the proton in the strong hydrogen bond showed the acidity comparable with that of 1n whereas that in the weak hydrogen bond showed the relatively high pKapp. These properties were discussed in relation to δOH (chemical shift in 1HNMR) and νOH(OH vibration band in IR). This is the first systematic discussion on “pKa” of p-t-butylcalix[n]arenes.

Surprisingly stable ammonium ion complex of a non-cyclic crown-type polyether: solid and solution studies

The first crystal structure of an NH4+ ion complex with 1,13-bis(8-quinolyl)-1,4,7,10,13-pentaoxatridecane (L), a representative non-cyclic analogue of 18-crown-6, is reported along with the characteristics of the complex’s solution; very interestingly, L forms a more stable complex with the NH4+ ion than does 18-crown-6 by the formation of unique recognition tetrahedral-type hydrogen bonds.

Macrocyclic inhibitors for the serine protease plasmin

Macrocyclic inhibitors for the serine protease plasmin were synthesized and evaluated. The inhibitors were constructed starting from a cyclohexanone core. This core was linked to either the C- or N-terminus of a peptide so that the inhibitors were designed to interact with the non-primed or primed binding sites of the protease. Macrocycles were prepared by connecting the side chain of Tyr or Trp, via a short linker, to one end of the peptide. The activities of the macrocyclic inhibitors, while modest, were up to 10-fold more potent than a related non-cyclic analog.

Synthesis and spectral properties of cyanine dyes—Derivatives of 10,10-dimethyl-7,8,9,10-tetrahydro-6 H-pyrido[1,2- a]indolium

The electronic absorption spectra of merocyanines and symmetric cationic polymethine dyes based on 10,10-dimethyl-7,8,9,10-tetrahydro-6 H-pyrido[1,2- a]indolium have been investigated in a wide range of solvent polarity. An important feature of these compounds is a cyclic group connecting the nitrogen atom of indole nucleus with the polymethine chain. The explored cationic cyanine dyes, in comparison with the derivatives of 3 H-indole, are characterized by less bond order and charge alternation in their chromophore in the ground state. It causes a decrease of both vibronic and intermolecular solute–solvent interactions and, consequently, a decrease of their solvatochromic range, a long-wavelength shift, a narrowing, and an increase of the peak intensity of their spectral bands. The synthesized merocyanines get the greater dipolarity of the ground state, as compared to their non-cyclic analogues. It leads to a color deepening and an increase of the absorption band intensity. Besides, it was revealed that the reversion of solvatochromism for merocyanines with N, N-diethylthiobarbituric moiety containing a cyclic group takes place. The listed regularities fail for the short-chain polymethine dyes. Presumably, it is caused by steric hindrances resulting in non-planarity of their molecules.

The Glutamate Uptake System in Presynaptic Vesicles: Further Characterization of Structural Requirements for Inhibitors and Substrates

Noncyclic fluorine-substituted and cyclic analogs of glutamic acid were tested for their ability to inhibit glutamate uptake in isolated bovine presynaptic vesicles, in order to assess the specific structural requirements of the glutamate translocation system in the vesicle membrane. Cyclic analogs that permitted close interaction between the positive and negative charges of the glutamate molecule were effective inhibitors; maximum inhibitory potency was observed with L-trans-1-aminocyclopentane-1,3-dicarboxylic acid (L-t-ACPD), while D-t-ACPD was less active. Analogs with a larger or smaller ring (as in trans-1-aminocyclohexane-1,3-dicarboxylic acid or trans-1-aminocyclobutane-1,3-dicarboxylic acid) were also inhibitory, but somewhat less so. trans-ACPD was also taken up by the vesicles with a time course and ATP dependence similar to uptake of glutamate, and this uptake was inhibited by glutamate. The K(m) value for t-ACPD uptake was similar to its K(i) for inhibition of glutamate uptake, while its rate of uptake was lower than that of glutamate. Fluorine-substituted noncyclic analogs with substitutions at the 4-carbon were less effective than glutamic acid itself, although 4,4-difluoroglutamic acid was equal in activity to the unsubstituted compound. Inhibition by these derivatives appeared to be competitive in nature, and they probably were also transported by the vesicle uptake system.

Selective angiotensin II AT 2 receptor agonists devoid of the imidazole ring system

A versatile parallel synthetic method to obtain three series of non-cyclic analogues of the first drug-like selective angiotensin II AT 2 receptor agonist ( 1) has been developed. In analogy with the transformation of losartan to valsartan it was demonstrated that a non-cyclic moiety could be employed as an imidazole replacement to obtain AT 2 selective compounds. In all the three series, AT 2 receptor ligands with affinities in the lower nanomolar range were found. None of the analogues exhibited any affinity for the AT 1 receptor. Four compounds, 17, 22, 39 and 51, were examined in a neurite outgrowth cell assay. All four compounds were found to exert a high agonistic effect as deduced from their capacity to induce neurite elongation in neuronal cells, as does angiotensin II.

Biochemical and functional characterization of high‐affinity urotensin II receptors in rat cortical astrocytes

The urotensin II (UII) gene is primarily expressed in the central nervous system, but the functions of UII in the brain remain elusive. Here, we show that cultured rat astrocytes constitutively express the UII receptor (UT). Saturation and competition experiments performed with iodinated rat UII ([(125)I]rUII) revealed the presence of high- and low-affinity binding sites on astrocytes. Human UII (hUII) and the two highly active agonists hUII(4-11) and [3-iodo-Tyr9]hUII(4-11) were also very potent in displacing [(125)I]rUII from its binding sites, whereas the non-cyclic analogue [Ser5,10]hUII(4-11) and somatostatin-14 could only displace [(125)I]rUII binding at micromolar concentrations. Reciprocally, rUII failed to compete with [(125)I-Tyr0,D-Trp8]somatostatin-14 binding on astrocytes. Exposure of cultured astrocytes to rUII stimulated [(3)H]inositol incorporation and increased intracellular Ca(2+) concentration in a dose-dependent manner. The stimulatory effect of rUII on polyphosphoinositide turnover was abolished by the phospholipase C inhibitor U73122, but only reduced by 56% by pertussis toxin. The GTP analogue Gpp(NH)p caused its own biphasic displacement of [(125)I]rUII binding and provoked an affinity shift of the competition curve of rUII. Pertussis toxin shifted the competition curve towards a single lower affinity state. Taken together, these data demonstrate that rat astrocytes express high- and low-affinity UII binding sites coupled to G proteins, the high-affinity receptor exhibiting the same pharmacological and functional characteristics as UT.

Design and Ionophore Properties of Some Macrocyclic Calixarene-Based Ligands

Some new classes of complexones based on functionalized thiacalix[4]arenes, calix[4]resorcin- and pyrogallolarenes were synthesized and their ionophore properties were studied toward alkali and some d and f metal cations. Calixarenes, unlike their noncyclic analogs, were shown to exhibit cooperataive effect of different noncovalent interactions due to preorganization of donor groups on calixarene matrix.

Oxymethylcrowned chromene: photoswitchable stoichiometry of metal ion complex and ion-responsive photochromism

Chromene derivatives bearing oxymethyl-12-crown-4 ( 1 ), -15-crown-5 ( 2 ), -18-crown-6 ( 3 ) ether moieties, and non-cyclic analogue ( 4 ) were synthesized, and their metal ion binding properties and photochromism were examined. NMR titration with alkali metal ions revealed that 1 formed a 1:2 complex (metal ion: ligand) with Na +, while Li + afforded a 1:1 complex of 1 . In cases of K + and Rb +, the complexes were a mixture of 1:1 and 1:2 complexes, but the formation of 1:1 complex was observed again with Cs +. Under UV irradiation, however, the complex stoichiometry of 1 with all alkali metal ions was 1:1. As a comparison of NMR spectra between the Li + and Na + complexes of 1 indicated considerable upfield shift for the chromene moiety of the Na + complex, π–π stacking of the chromene moiety seems to induce formation of the 1:2 complex. These results indicate that the chromene moiety is not only to show photochromism but also to induce aggregation to form the 1:2 complex resulted in switching of the complex stoichiometry by UV irradiation. The formation of 1:2 complex appeared only with 1 because flexibility of the crown moieties for 2 and 3 interfered the formation of 1:2 complex. Studies on photochromism in the presence of a metal ion demonstrated that the chromene derivatives bearing crown ether moieties show ion-responsive photochromism depending on the metal ion binding ability of their crown ether moieties.

Synthesis and Photochromism of Novel Chromene Derivatives Bearing a Monoazacrown Ether Moiety

AbstractCrowned chromenes − four novel naphthopyrans (chromenes) bearing monoaza‐12‐crown‐4, ‐15‐crown‐5, ‐18‐crown‐6, and a noncyclic analogue at the 5‐position − were synthesized, and their photochromism in acetonitrile was examined in the presence of alkali and alkaline‐earth metal ions. Incorporation of crown ether units to chromene moieties facilitated to a great extent both the thermal isomerization and photoisomerization of the chromene moiety, reflecting the metal‐ion‐binding ability of the crown ether moiety. Comparison of the crowned chromenes with the corresponding crowned spirobenzopyrans reveals that photochromism of the crowned chromene reflects an interaction between the metal ion and the crown ether moiety that is stronger than that of the crowned spirobenzopyran, and shows only positive photochromism with significant red‐shifts in the UV/Vis absorption spectra, in contrast to the crowned spirobenzopyrans reported previously. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)