Bulky Aromatic Groups Research Articles

BODIPY dyes in bio environment: Spectral characteristics and possibilities for practical application

Abstract Boron dipyrrin (BODIPY) dyes serve as perspective fluorescent sensors and probes in a vast range of biochemical and medical applications. Thus, mechanisms of interaction with biomolecules and accompanying spectral behavior of BODIPY are of major interest for fundamental science and practical applications. 8-aryl BODIPY derivatives were found to have high fluorescent respond upon the protein addition. Investigation of the interaction between the series of BODIPY complexes and Bovine Serum Albumin (BSA) using ultraviolet-visible (UV-vis) absorption, fluorescence spectroscopy under simulated physiological conditions (pH 7.4) and molecular docking methods was performed. The results of fluorescence spectroscopy indicated that the fluorescence of hydrophobic BODIPY dyes substantially increases in the presence of BSA. The prospected reason is binding of the dye to the BSA hydrophobic cavities in the subdomain IIA. Aromatic moiety size increase causes shifting of the interaction driving force from mostly non-specific to the π-stacking. Among all probes, the 8-phenyl substituted dye showed the highest sensitivity and the quantitative fluorescent response for BSA in aqueous solution. BODIPY with 8-phenyl substituent or analogs therefore could be used as protein surface polarity sensors, at the same time all of the investigated dyes with bulky aromatic groups could be used as hydrophobic molecule tags and markers for bioimaging tasks.

Molecularly Engineered Azobenzene Derivatives for High Energy Density Solid-State Solar Thermal Fuels.

Solar thermal fuels (STFs) harvest and store solar energy in a closed cycle system through conformational change of molecules and can release the energy in the form of heat on demand. With the aim of developing tunable and optimized STFs for solid-state applications, we designed three azobenzene derivatives functionalized with bulky aromatic groups (phenyl, biphenyl, and tert-butyl phenyl groups). In contrast to pristine azobenzene, which crystallizes and makes nonuniform films, the bulky azobenzene derivatives formed uniform amorphous films that can be charged and discharged with light and heat for many cycles. Thermal stability of the films, a critical metric for thermally triggerable STFs, was greatly increased by the bulky functionalization (up to 180 °C), and we were able to achieve record high energy density of 135 J/g for solid-state STFs, over a 30% improvement compared to previous solid-state reports. Furthermore, the chargeability in the solid state was improved, up to 80% charged from 40% charged in previous solid-state reports. Our results point toward molecular engineering as an effective method to increase energy storage in STFs, improve chargeability, and improve the thermal stability of the thin film.

3D-QSAR Studies of Isatin Derivatives with Anti-Cancer In Vitro: Advanced CoMFA, CoMSIA and Docking Methods

Three-dimensional quantitative structure–activity relationship (3D-QSAR) and docking methods were performed to study 47 tubulin inhibitors, isatin derivatives with anticancer activity against human monocyte-like histiocytic lymphoma human U937 cells. The established 3D-QSAR model from Comparative Molecular Field Analysis (CoMFA), Comparative Molecular Similarity Index Analysis (CoMSIA) approaches show a significant statistical quality and a satisfying predictive ability, with high correlation coefficient value (R2=0.936, R2=0.970) and cross-validation coefficient value (Q2=0.821, Q2=0.884) of CoMFA and CoMSIA, respectively. The predictive ability of the CoMFA (R2 test=0.607) and CoMSIA (R2 test=0.650) model was confirmed by a test set. The CoMFA, CoMSIA contour maps and docking analyses indicate that the substituent R1 should be oxygen which better than azotes to forms a more potent inhibitor against tubulin enzyme and R2, R3, R4 and R5 substituents should be higher electronegative but R6 should be a bulky aromatic group like a methylnaphthol monosubstituted or disubstitued by OCH3. The interaction information between target and ligand was presented such the useful theoretical references for analyzing to understand the action mechanism, designing new more potent inhibitors and optimizing their activities prior to synthesis.

Polyurea microcapsules from isocyanatoethyl methacrylate copolymers

ABSTRACTThe synthesis of two types of isocyanate side chain containing copolymers, poly(methyl methacrylate‐co‐isocyanatoethyl methacrylate) (P(MMA‐co‐IEM)) and poly(benzyl methacrylate‐co‐isocyanatoethyl methacrylate) (P(BnMA‐co‐IEM)), which were synthesized by Cu(0)‐mediated radical polymerization, is reported. Polymerization proceeded to high conversion giving polymers of relatively narrow molar mass distributions. The incorporation of the bulky aromatic groups in the latter copolymer rendered it sufficiently stable toward hydrolysis and enabled the isolation of the product and its characterization by 1H and 13C NMR, and FTIR spectroscopy and SEC. Both P(MMA‐co‐IEM) and P(BnMA‐co‐IEM) were functionalized with dibutylamine, octylamine, and (R)‐(+)‐α‐methylbenzyl‐amine, which further proved the successful incorporation of the isocyanate groups. Furthermore, P(BnMA‐co‐IEM) was used for the fabrication of liquid core microcapsules via oil‐in‐water interfacial polymerization with diethylenetriamine as crosslinker. The particles obtained were in the size range of 10–90 µm in diameter independent of the composition of copolymer. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016, 54, 2698–2705

Synthesis and emission properties of poly(diphenylacetylene)s having various aromatic rings

Diphenylacetylenes possessing both an n-octyloxy group and a substituent groups (H: 1a, phenyl: 1b, naphthyl: 1c, anthryl: 1d, biphenyl: 1e) were polymerized using TaCl5/n-Bu4Sn. Diarylacetylenes having bulky aromatic groups such as α-naphthyl and 9-anthryl cannot afford high-molecular-weight polymer, but the present monomers polymerized to afford relatively high-molecular-weight polymers (Mn = 222,000–596,000) because they have a phenyl spacer between bulky aromatic group and reactive part of C≡C. The solubility of 2a-c and 2e exhibited good solubility in relatively low polar solvents because of long alkyl groups. The emission maxima of 2b-e were all 512 nm, which was longer than that of 2a. No difference of emission maximum among 2b-e were observed in solution. However, the emission maxima in film of 2b, 2c, 2d, and 2e were 530, 526, 524, and 542 nm, respectively. Compared to the emission in solution, that of 2b and 2e in film exhibited large shifts while that of 2c and 2d exhibited smaller shifts. This is because the bulky aromatic groups of naphthyl and anthryl hardly took coplanar structures owing to the steric hindrance.

Isolation and Structures of 1,2,3‐Triazole‐Derived Mesoionic Biscarb­enes with Bulky Aromatic Groups

Abstract1,2,3‐Triazole‐derived mesoionic biscarbenes bridged by a pyridylene group were synthesized and their structures were determined. Bulky substituents on the carbene rings stabilized the carbenes, which enabled their crystal structures to be determined. As implied by DFT calculations and the experimental results, the carbenes are partly reduced to anionic radical species in the presence of strong bases. This suggests that the pyridylene and triazolylidene moieties endow molecules with both electron‐acceptor and ‐donor properties. A rare example of an iron complex with a pincer carbene was synthesized.

Synthesis and Structure-Activity Relationships of Substituted Urea Derivatives on Mouse Melanocortin Receptors.

The melanocortin system is involved in the regulation of several complex physiological functions. In particular, the melanocortin-3 and -4 receptors (MC3R/MC4R) have been demonstrated to regulate body weight, energy homeostasis, and feeding behavior. Synthetic and endogenous melanocortin agonists have been shown to be anorexigenic in rodent models. Herein, we report synthesis and structure-activity relationship (SAR) studies of 27 nonpeptide small molecule ligands based on an unsymmetrical substituted urea core. Three templates containing key residues from the lead compounds, showing diversity at three positions (R(1), R(2), R(3)), were designed and synthesized. The syntheses were optimized for efficient microwave-assisted chemistry that significantly reduced total syntheses time compared to a previously reported room temperature method. The pharmacological characterization of the compounds on the mouse melanocortin receptors identified compounds 1 and 12 with full agonist activity at the mMC4R, but no activity was observed at the mMC3R when tested up to 100 μM concentrations. The SAR identified compounds possessing aliphatic or saturated cyclic amines at the R(1) position, bulky aromatic groups at the R(2) position, and benzyl group at the R(3) position resulted in mMC4R selectivity over the mMC3R. The small molecule template and SAR knowledge from this series may be helpful in further design of MC3R/MC4R selective small molecule ligands.

Synthesis of New Chloroquine Derivatives as Antimalarial Agents

A series of hybrid molecules referred to as “reversed chloroquines” (RCQs) were designed, synthesized, and tested against chloroquine resistant strains of Plasmodium falciparum. The designed compounds contain bulky aromatic groups and chloroquine like nucleus linked with each other via two or three carbon alkyl linkers. Five compounds were designed based on the structure – activity relationship. These five compounds have been successfully synthesized, of which three compounds show significant antimalarial activity in vitro. A modification of the reversal agent (RA) like moiety was designed using substituted biphenyl groups. The aminoalkyl substitution of the heterocycle and tertiary aliphatic aminoalkyl nitrogen atom with two- or three-carbon bridges to the heteroaromatic nitrogen is required for potential “resistance reversal activity”. The synthesized compounds were screened for their in vitro antimalarial activity as characterized by the 50% inhibitory concentration (IC50), cytotoxic concentration (CC50), and selectivity index (SI). These compounds did not show any cytotoxic effect. One of these compounds (5), which contains two-carbon linker chain, unsaturation at position 2, and chlorine substituted biphenyls in RA-like moiety, was found to possess appreciable and promising in vitro antimalarial activity against the chloroquine sensitive 3D7 strain of P. falciparum.

Self-assembling of tapered benzenesulfonate-based dendrons with bulky aromatic focal groups

Comparative analysis of the structure and phase behavior of the synthesized compounds on the basis of symmetrically and asymmetrically substituted benzenesulfonic acids with bulky aromatic focal groups revealed that their phase behavior is determined equally by the shape of the mesogenic groups as well as by specific interactions at the focal points of the monodendrons.

NIS/PhI(OAc)2-mediated diamination/oxidation of N-alkenyl formamidines: facile synthesis of fused tricyclic ureas.

Facile synthesis of bicyclic ureas by NIS/PhI(OAc)2-mediated diamination/oxidation of N-alkenyl formamidines is reported. Bulky aromatic groups such as 2,6-diisopropylphenyl and mesityl and alkyl groups were tolerated towards the process. Several control experiments have been performed, and the reaction outcomes indicate that the oxidation process is probably concerted with the diamination cyclization, and succinimide generated from NIS-mediated aminoamidiniumation step promoted the PhI(OAc)2-mediated oxidation step. The new methodology provides an efficient method for the synthesis of fused tricyclic ureas.

Design and synthesis of potent and selective P2X3 receptor antagonists derived from PPADS as potential pain modulators

Pyridoxalphosphate-6-azophenyl-2′,4′-disulfonate (7a, PPADS), a nonselective P2X receptor antagonist, was extensively modified to develop more stable, potent, and selective P2X3 receptor antagonists as potential antinociceptive agents. Based on the results of our previous report, all strong anionic groups in PPADS including phosphate and sulfonate groups were changed to carboxylic acids or deleted. The unstable azo (–NN–) linkage of 7a was transformed to more stable carbon-carbon, ether or amide linkages through the synthesis of the 5-hydroxyl-pyridine moieties with substituents at 2 position via a Diels-Alder reaction. This resulted in the retention of antagonistic activity (IC50 = 400 ∼ 700 nM) at the hP2X3 receptor in the two-electrode voltage clamp (TEVC) assay system on the Xenopus oocytes. Introduction of bulky aromatic groups at the carbon linker, as in compounds 13h–n, dramatically improved the selectivity profiles of hP2X3 when compared with mP2X1 and hP2X7 receptors. Among the substituents tested at the 2-position, the m-phenoxybenzyl group showed optimum selectivity and potency at the hP2X3 receptor. In searching for effective substituents at the 4- and 3-positions, we found that compound 36j, with 4-carboxaldehyde, 3-propenoic acid and 2-(m-phenoxy)benzyl groups, was the most potent and selective hP2X3 receptor antagonist with an IC50 of 60 nM at hP2X3 and marginal antagonistic activities of 10 μM at mP2X1 and hP2X7. Furthermore, using an ex-vivo assay system, we found that compound 36j potently inhibited pain signaling in the rat dorsal horn with 20 μM 36j displaying 65% inhibition while 20 μM pregabalin, a clinically available drug, showed only 31% inhibition.

Preparation and characterization of lignin based macromonomer and its copolymers with butyl methacrylate

Copolymerization of butyl methacrylate (BMA) with biobutanol lignin (BBL) was achieved by free-radical polymerization (FRP) using a lignin-based macromonomer. The lignin-based macromonomer containing acrylic groups was prepared by reacting acryloyl chloride with biobutanol lignin using triethylamine (TEA) as absorb acid agentin. From the results of elemental analysis and GPC, the average degree of polymerization (DP) of BBL was estimated to be five. A detailed molecular characterization has been performed, including techniques such as 1H NMR, 13C NMR and UV–vis spectroscopies, which provided quantitative information about the composition of the copolymers. The changes in the solubility of lignin-g-poly(BMA) copolymers in ethyl ether were dependent on the length of poly(BMA) side chain. TGA analysis indicated that the lignin-containing poly(BMA) graft copolymers exhibited high thermal stability. The bulky aromatic group of lignin increased the glass-transition temperature of poly(BMA). In order to confirm the main structure of copolymer, (AC-g-BBL)-co-BMA copolymer was also synthesized by atom transfer radical polymerization (ATRP), and the results revealed that the copolymer prepared by ATRP had the same solution behavior as that prepared by FRP, and the lignin-based macromonomer showed no homopolymerizability due to the steric hindrance. In addition, the lignin-co-BMA copolymer had a surprisingly higher molecular weight than poly(BMA) under the same reaction condition, suggesting that a branched lignin based polymer could be formed.

Synthesis and characterization of some new aromatic polytriazoles as proton conductive membranes

A series of new poly(1,2,4-triazole)s (PTAs) containing pyridine heterocyclic ring, bearing bulky aromatic pendent groups, were synthesized from the reaction of the corresponding polyhydrazides with aniline or 4-aminobenzenesulfonic acid in polyphosphoric acid (PPA) at 175 °C. The non-sulfonated PTAs showed glass transition temperatures (T gs) of 220–250 °C and inherent viscosities (η inh) equal to 0.48–0.78 dL/g, and the sulfonated poly(1,2,4-triazole)s (S-PTAs) exhibited T gs of 235–265 °C and inherent viscosities equal to 0.50–0.83 dL/g. The former polymers were soluble in conc. H2SO4 and partially soluble in hot N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethylacetamide (DMAc), and 1-methyl-2-pyrrolidone (NMP), and the latter were soluble in DMF, NMP, DMSO and DMAc at room temperature. All polymers had useful levels of thermal stability and were stable up to 450 °C in nitrogen. The proton conductivities of undoped sulfonated polytriazole membranes and the acid-doped sulfonated polytriazole membranes lie in the range of 5 × 10−4–8.1 × 10−3 and 5 × 10−3–2.3 × 10−2 S/cm, respectively, at 90 °C and 100 % relative humidity.

Synthesis and Evaluation of Biphenyl Compounds as Kinesin Spindle Protein Inhibitors

Kinesin spindle protein (KSP), an ATP-dependent motor protein, plays an essential role in bipolar spindle formation during the mitotic phase (M phase) of the normal cell cycle. KSP has emerged as a novel target for antimitotic anticancer drug development. In this work, we synthesized a range of new biphenyl compounds and investigated their properties in vitro as potential antimitotic agents targeting KSP expression. Antiproliferation (MTT (=3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide)) assays, combined with fluorescence-assisted cell sorting (FACS) and Western blot studies analyzing cell-cycle arrest confirmed the mechanism and potency of these biphenyl compounds in a range of human cancer cell lines. Structural variants revealed that functionalization of biphenyl compounds with bulky aliphatic or aromatic groups led to a loss of activity. However, replacement of the urea group with a thiourea led to an increase in antiproliferative activity in selected cell lines. Further studies using confocal fluorescence microscopy confirmed that the most potent biphenyl derivative identified thus far, compound 7, exerts its pharmacologic effect specifically in the M phase and induces monoaster formation. These studies confirm that chemical scope remains for improving the potency and treatment efficacy of antimitotic KSP inhibition in this class of biphenyl compounds.

Bright, efficient, deep blue-emissive polymer light-emitting diodes of suitable hole-transport layer and cathode design

This study reports the fabrication of efficient deep blue-emissive polymer light-emitting diodes (PLEDs), incorporating a polyfluorene derivative of nonsymmetric and bulky aromatic groups at C-9 position as the light-emissive layer. Another poly(fluorene-co-triphenylamine) (PFO-TPA) derivative of the highest occupied molecular orbital level, −5.3eV, is used as the hole-injection and -transport layer in the anode part. The thermally crosslinking of styryl groups in PFO-TPA inhibits the solvation of an interlayer in constructing the multilayer device architecture of PLEDs. While applying a cesium carbonate (Cs2CO3)/Aluminum (Al) cathode rather than Calcium (Ca)/Al, the device has the superior performance (i.e. one order of magnitude higher). Experimental results indicate that the interfacial reactions at the polymer/Ca junction, as characterized in this study, significantly degrade the luminescence properties and the device performance. Moreover, Cs2CO3/Al is a highly favorable cathode in fabricating polyflourene-based PLEDs. The device of the optimal configuration has a decent deep blue emission centered at 430–450nm of the Commission Internationale de l’Eclairage chromaticity coordinates, (0.15, 0.14), with a maximum brightness of 35054.2cd/m2 and luminous efficiency of 14.0cd/A (at 2975.0cd/m2).

Molecular simulation of a series of benzothiazole PI3Kα inhibitors: probing the relationship between structural features, anti-tumor potency and selectivity

The phosphatidylinositol 3-kinase α (PI3Kα) was genetically validated as a promising therapeutic target for developing novel anticancer drugs. In order to explore the structure-activity correlation of benzothiazole series as inhibitors of PI3Kα, comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA) were performed on 61 promising molecules to build 3D-QSAR models based on both the ligand- and receptor-based methods. The best CoMFA and CoMSIA models had a cross-validated coefficient r(cv)(2) of 0.618 and 0.621, predicted correlation coefficient r(pred) (2) of 0.812 and 0.83, respectively, proving their high correlative and predictive abilities on both the training and test sets. In addition, docking analysis and molecular dynamics simulation (MD) were also applied to elucidate the probable binding modes of these inhibitors at the ATP binding pocket. Based on the contour maps and MD results, some key structural factors responsible for the activity of this series of compounds were revealed as follows: (1) Ring-A has a strong preference for bulky hydrophobic or aromatic groups; (2) Electron-withdrawing groups at the para position of ring-B and hydrophilic substituents in ring-B region may benefit the potency; (3) A polar substituent like -NHSO(2)- between ring-A and ring-B can enhance the activity of the drug by providing hydrogen bonding interaction with the protein target. The satisfactory results obtained from this work strongly suggest that the developed 3D-QSAR models and the obtained PI3Kα inhibitor binding structures are reasonable for the prediction of the activity of new inhibitors and be helpful in future PI3Kα inhibitor design.

Synthesis and characterization of some new aromatic polyoxadiazoles through cyclodehydration of polyhydrazides

A series of new polyhydrazides containing pyridine heterocyclic ring, bearing bulky aromatic pendent groups, were synthesized from the reaction of diacid chlorides with dihydrazides via low-temperature solution polycondensation. All the polymers were readily soluble in polar solvents such as N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethylacetamide (DMAc), and 1-methyl-2-pyrrolidone (NMP) and showed inherent viscosities equal to 0.38–0.68 dL/g. They indicated glass transition temperatures (Tg) ranging from 190 to 220 °C. Polyhydrazides were subjected to cyclodehydration to prepare poly(1,3,4-oxadiazole)s either by thermally or chemically cyclodehydration approximately in the region of 150–320 °C. The poly(1,3,4-oxadiazole)s, made by chemically cyclodehydration exhibited Tgs of 220–250 °C and inherent viscosities equal to 0.38–0.62 dL/g, while the PODs made via thermally cyclodehydration of polyhydrazides did not show any glass transition and exhibited inherent viscosities equal to 0.39–0.66 dL/g. The former polymers were soluble in conc. H2SO4 and partially soluble in hot DMF, NMP, DMSO, and DMAc, and the latter were only soluble in conc. H2SO4. They had useful levels of thermal stability and were stable up to 450 °C in nitrogen. The structure of polymers was fully characterized by IR and NMR spectroscopies.

Opioid Receptor Probes Derived from Cycloaddition of the Hallucinogen Natural Product Salvinorin A

As part of our continuing efforts toward more fully understanding the structure-activity relationships of the neoclerodane diterpene salvinorin A, we report the synthesis and biological characterization of unique cycloadducts through [4+2] Diels-Alder cycloaddition. Microwave-assisted methods were developed and successfully employed, aiding in functionalizing the chemically sensitive salvinorin A scaffold. This demonstrates the first reported results for both cycloaddition of the furan ring and functionalization via microwave-assisted methodology of the salvinorin A skeleton. The cycloadducts yielded herein introduce electron-withdrawing substituents and bulky aromatic groups into the C-12 position. Kappa opioid (KOP) receptor space was explored through aromatization of the bent oxanorbornadiene system possessed by the cycloadducts to a planar phenyl ring system. Although dimethyl- and diethylcarboxylate analogues 5 and 6 retain some affinity and selectivity for KOP receptors and are full agonists, their aromatized counterparts 13 and 14 have reduced affinity for KOP receptors. The methods developed herein signify a novel approach toward rapidly probing the structure-activity relationships of furan-containing natural products.

ChemInform Abstract: Formation of Isoquinoline and 1-Azetine Derivatives via Novel Photocyclization of Substituted α-Dehydrophenylalanines.

Abstract The irradiation of substituted N -acetyl α-dehydrophenylalanines in MeOH with Pyrex-filtered light was found to give isoquinoline and 1-azetine derivatives in relatively good yields, which may be formed via intramolecular cyclization reactions from the ( Z )- and ( E )-isomers, respectively. Solvent viscosity effects on the product distribution and composition strongly suggested the minor role of a radical pair mechanism. In the presence of benzophenone as a triplet sensitizer, the starting ( Z )-isomer underwent an exclusive isomerization into the corresponding ( E )-isomer without yielding any cyclization products, being consistent with the occurrence of the novel photocyclization reactions from the excited singlet-state isomers. On the other hand, the irradiation of N -substituted benzoyl α-dehydrophenylalanines in MeOH afforded selectively 1-azetine derivatives without forming any isoquinolines. It was suggested that the stereoelectronic effects of bulky aromatic acyl groups are responsible for the complete suppression of the cyclization reactions, which eventually afford isoquinoline derivatives via the excited singlet-state ( Z )-isomers.

Development and characterization of self-aggregated nanoparticles from anacardoylated chitosan as a carrier for insulin

Nanoparticulate carriers made from biodegradable polymers especially from chitosan seems to be an excellent approach to increase the uptake and transport of orally administered insulin. Various approaches have been studied to develop nanoparticles from chitosan including self-aggregated nanoparticles from hydrophobically modified chitosan. Anacardic acid is a naturally occurring fatty acid having bulky aromatic group as well as long aliphatic chain and an amphiphilic monomer of great potential. An attempt has been made to develop and characterize self-aggregated nanoparticles from chitosan modified with anacardic acid. Anacardoylated chitosan spontaneously formed nanoparticles in aqueous insulin solution with a particles size of 214 nm diameter at neutral pH. The hydrophobic nature of the nanoparticles helped in the sustained release of insulin in the intestinal environment and the released insulin was stable and retained its conformation. However, it released insulin in acidic conditions and need to be encapsulated in alginate to render pH sensitiveness.