Central Heterocycle Research Articles

Characterization of Triplet State of Cyanine Dyes with Two Chromophores Effect of Molecule Structure

Quantum yields (φT) and energies (ET) of the first triplet state T1 for four molecules of cyanine dyes with two chromophores (BCDs), promising photoactive compounds for various applications, for example, as photosensitizers in photodynamic therapy (PDT) and fluorescence diagnostics (FD), were studied in 1-propanol solutions by steady-state and time-resolved optical absorption techniques. BCDs differ by the structure of the central heterocycle, connecting the chromophores. The heterocycle structure is responsible for electron tunneling between chromophores, for which efficiency can be characterized by splitting of the BCD triplet energy levels. It was shown that the increase in the tunneling efficiency reduces ET values and increases φT values. This aspect is very promising for the synthesis of new effective photosensitizers based on cyanine dyes with two interacting chromophores for various applications, including photodynamic therapy.

Through-bond/space conjugated nonaromatic dihydrobenzoquinolines: Luminogens with simple synthesis method, strong aggregation-induced emission and emissive excimers

In recent years, AIE (aggregation-induced emission) fluorophores have attracted great interest owing to their advantages in wide areas and many AIE fluorophores have be designed by combing conventional fluorophores with AIEgens that exhibiting AIE attributes. However, only few efficient AIEgens were developed. Here, novel dihydrobenzoquinolines (h-DHBQs 4a−e and f-DHBQ 5a), a new kind of AIEgens with strong AIE, are reported. DHBQs were synthesized by a catalyst-free multi-component reaction (MCR) in good overall yield and their optical properties were investigated through steady-state and transient fluorescence spectra, single-crystal diffraction, calculated HOMOs and LUMOs. It was found that DHBQs have these characteristics: a) strong AIE, that is, their fluorescence quantum yields lower than 4.1% in solutions, but high to 90.5% in crystals; b) efficient through-bond and -space conjugated nonaromatic central heterocycle; c) radiative-process-favored but non-radiative-decay-prevented self-assemblies; d) emissive excimers; and e) easily tunable fluorescence color. This work affords a new kind of AIEgens with excellent optical properties in solids and a strategy to develop AIEgens by constructing nonaromatic heterocycle using simple MCRs.

Achieving Multiple Quantum-Interfered States via Through-Space and Through-Bond Synergistic Effect in Foldamer-Based Single-Molecule Junctions.

The construction of multivalued logic circuits by multiple quantum-interfered states at the molecular level can make full use of molecular diversity and versatility, broadening the application of molecular electronics. Understanding charge transport through different conducting pathways and how they interact with each other in molecules with a secondary structure is an indispensable foundation to achieve this goal. Herein, we elucidate the synergistic effect from through-space and through-bond conducting pathways in foldamers derived from ortho-pentaphenylene by the separate modulation on these pathways. The shrinkage of central heterocycles' sizes allows foldamers to stack with larger overlap degrees, resulting in level-crossing and thus transformation from constructive quantum interference (CQI) to destructive quantum interference (DQI) in a through-space pathway. The alteration of central heterocycles' connection sites enhances through-bond conjugation, leading to amplified contribution from a through-bond pathway. The enhanced through-bond pathway destructively interferes with the through-space pathway, exerting a suppression effect on transmission. Therefore, four quantum-interfered states of through-space and through-bond combination are generated, including through-space CQI-dominated states, through-space DQI-dominated states, through-space CQI states with through-bond suppression, and through-space DQI states with through-bond suppression. These findings enable us to regulate charge transport within high-order structures via multiple conducting pathways and provide a proof of concept to construct multivalued logic circuits.

Palladium-Catalyzed Dual Annulation: A Method for the Synthesis of Norneocryptolepine.

A novel procedure for the Pd-catalyzed dual annulation reaction to synthesize the norneocryptolepine derivatives involving the concerted construction of two central heterocycles is reported. The further methylation of the norneocryptolepine to afford its alkaloid analog neocryptolepine implies that synthesis of various neocryptolepine derivatives is feasible. The oxidative addition of Pd(0) is indicated as the key step to activate the intramolecular addition of nitrile according to the mechanism study.

Some Considerations Regarding the 1H and 13C Spectra of 4-(1-azulenyl)-2,6-bis(2-heteroaryl-vinyl)- pyrylium and Pyridinium and their Corresponding Pyridines

The 1H and 13C NMR spectra of several 2,6-diheteroarylvinyl heterocycles containing 4-azulenyl moiety were recorded and their proton and carbon chemical shifts were compared with those of the compounds without double bond between the heterocycles. The influence of the nature of central and side heterocycles, molecule polarization and anisotropic effects were revealed. The highest chemical shifts were recorded for the pyrylium salts and the lowest at pyridines, but in the case of the pyridinium salts, the protons chemical shifts at the central heterocycle are more shielded due to a peculiar anisotropy of the attached vinyl groups.

Heteroaryl-linked norbornadiene dimers with redshifted absorptions.

Development of Molecular Solar Thermal (MOST) systems for harvesting and storing solar energy is based on molecular photoswitches that undergo photoisomerizations to metastable isomers. One challenge is to achieve low-molecular weight molecules that absorb at sufficiently long wavelengths to match the solar spectrum. Here we show that this can be achieved by linking two norbornadiene (NBD) photoswitches to a central heterocycle, thiophene or carbazole, via alkyne appendages. In this approach, the same heteroaryl is used to tune the properties of two photoswitches at the same time, thereby keeping the molecular weight as low as possible. A series of NBD dimers was prepared by Sonogashira coupling reactions, and these compounds showed remarkable redshifted absorptions, with onsets of absorption as high as 468 nm, and thermal half-lives ranging from 44 seconds to 16 hours.

Crystal structure of 2-azido-1,3-bis-(2,6-diiso-propyl-phen-yl)-1,3,2-di-aza-phospho-lidine.

The title compound, C26H38N5P, was synthesized by reacting 2-chloro-1,3-bis-(2,6-diiso-propyl-phen-yl)-1,3,2-di-aza-phospho-lidine with sodium azide and a catalytic amount of lithium chloride in tetra-hydro-furan. The title compound is the first structurally characterized 2-azido-1,3,2-di-aza-phospho-lidine and exhibits a P atom in a trigonal pyramidal geometry. The azide P-N bond length of 1.8547 (16) Å is significantly longer than the P-N separations for the chelating di-amine [P-N = 1.6680 (15) and 1.6684 (14) Å]. The sterically hindered 2,6-diiso-propyl-phenyl groups twist away from the central heterocycle, with dihedral angles between the central heteocyclic ring and benzene rings of 76.17 (10) and 79.74 (9)°. In the crystal, a weak C-H⋯N link to the terminal N atom of the azide group leads to [100] chains.

Crystal structure of 2-chloro-1,3-bis-(2,6-diiso-propyl-phen-yl)-1,3,2-di-aza-phospho-lidine 2-oxide.

The title compound, C26H38ClN2OP, was synthesized by reacting phosphoryl chloride with N,N'-bis-(2,6-diiso-propyl-phen-yl)ethane-1,2-di-amine in the presence of N-methyl-morpholine which acted as an auxilliary base to quench the HCl released as a by-product. The resultant N-heterocyclic phosphine five-membered ring adopts a half-chair conformation and features a tetra-coordinate P atom ligated by the chelating di-amine [P-N = 1.6348 (14) and 1.6192 (14) Å], one double-bonded O atom [P1-O1 = 1.4652 (12) Å] and one Cl atom [P1-Cl1 = 2.0592 (7) Å]. The sterically hindered 2,6-diiso-propyl-phenyl (Dipp) groups twist away from the central heterocycle, with torsion angles of -75.66 (19) and 83.39 (19)° for the P-N-Car-Car links. A number of intra-molecular C-H⋯N, C-H⋯O and C-H⋯Cl close contacts occur. In the crystal, mol-ecules are linked by C-H⋯O hydrogen bonds to generate [010] chains. C-H⋯π inter-actions are also observed.

Structural Basis of the Interaction of Cyclin-Dependent Kinase 2 with Roscovitine and Its Analogues Having Bioisosteric Central Heterocycles.

The structural basis for the interaction of roscovitine and analogues containing 13 different bioisosteric central heterocycles with the enzyme cyclin-dependent kinase 2 (CDK2) is elucidated. Although all the central scaffolds are very similar to the purine core of roscovitine, the experimentally determined IC50 values of the inhibitors span three orders of magnitude. By using an extensive computational chemistry approach, the affinities of the inhibitors to CDK2 are determined as calculated binding scores of complexes of the inhibitors with the protein. The interactions of the inhibitors with CDK2 are computationally described by using a hybrid quantum mechanics/semi-empirical quantum mechanics method (QM/SQM), which combines the DFT-D method for the QM part and the PM6-D3H4X method for the SQM part. The solvent effect is described by the COSMO implicit solvation model at the SQM level for the whole system. The contributions of the scaffolds and the individual substituents, quantified and evaluated in relation to conformations of optimized protein-inhibitor complexes, are found not to be simply additive. The inhibitory activity of the selected candidates, including two newly prepared compounds, is tested against CDK2. The results of the calculations are in close agreement with the experimental data.

Effect of the graft ratio on the properties of polythiophene‐g‐poly(ethylene glycol)

ABSTRACTGraft copolymers formed by anchoring poly(ethylene glycol) (PEG) chains to conjugated polythiophene have been prepared by copolymerizing two compounds: unsubstituted α‐terthiophene (Th3) and a thiophene‐derived macromonomer having an α‐terthiophene conjugated sequence and one Th3 bearing a PEG chain with molecular weight of 2000 as substitute at the 3‐position of the central heterocycle (Th3‐PEG2000). The grafting ratio of the resulting copolymers (PTh3*‐g‐PEG), which were obtained using 75:25 and 50:50 Th3‐PEG2000:Th3 weight ratios, is significantly smaller than that of copolymers derived from polymerization of macromonomers consisting of a α‐pentathiophene sequence in which the central ring bears a PEG chain of Mw = 2000 (PTh5‐g‐PEG). The electroactivity and electrochemical stability of PTh3*‐g‐PEG is not only higher than that of PTh5‐g‐PEG but also higher than that of PTh3, the latter presenting a very compact structure that makes difficult the access and escape of dopant ions into the polymeric matrix during the redox processes. Furthermore, the optical π‐π* lowest transition energy of PTh3*‐g‐PEG is lower than that of both PTh5‐g‐PEG and PTh3. These properties, combined with suitable wettability and roughness, result in an excellent behavior as bioactive platform of PTh3*‐g‐PEG copolymers, which are more biocompatible, in terms of cellular adhesion and proliferation, and electro‐compatible than PTh5‐g‐PEG. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2015, 53, 239–252

Abstract 2528: Optimization of small molecules targeting BMI1 protein expression. Part 2. Improved potency, oral bioavailability, and in vivo efficacy of amino-pyrazines and amino-pyridines

Abstract Earlier, in our efforts to identify molecules that selectively deplete tumor stem cells, we discovered and elaborated on a series of amino-thiazoles. These first-in-class small molecule inhibitors reduce the activity and levels of BMI1 protein in vitro and in vivo (see the preceding poster). Through our medicinal chemistry efforts, we developed a second generation of molecules that reduce levels of BMI1. In this new scaffold, the central thiazole ring has been replaced with a pyrazine or pyridine ring. There is a clear relationship between the structure of the central heterocycle and the ability of the compound to decrease the level of BMI1 protein. The most beneficial modification on the right wing of the molecule is the introduction of benzimidazole moiety. As a result, analogs with markedly improved oral bioavailability have been identified. The structure activity relationship on the left ring parallels the SAR observed with the amino-thiazole scaffold. The most successful analogs in this series can be dosed orally and demonstrate dose-dependent efficacy in mouse xenograft models including the HT1080 and L1210 cell lines. Citation Format: Ramil Baiazitov, Nadiya Sydorenko, Hongyu Ren, Wu Du, Steve Paget, Richard Wilde, Ronggang Liu, Chang-Sun Lee, Liangxian Cao, Thomas W. Davis, Neil G. Almstead, Young-Choon Moon. Optimization of small molecules targeting BMI1 protein expression. Part 2. Improved potency, oral bioavailability, and in vivo efficacy of amino-pyrazines and amino-pyridines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2528. doi:10.1158/1538-7445.AM2014-2528

(E)-3-Methyl-2,6-diphenylpiperidin-4-oneO-(3-methylbenzoyl)oxime

In the title compound, C26H26N2O2, the piperidine ring exhibits a chair conformation. The phenyl rings are attached to the central heterocycle in an equatorial position. The dihedral angle between the planes of the phenyl rings is 57.58 (8)°. In the crystal, C—H⋯O inter­actions connect the mol­ecules into zigzag chains along [001].

New Triazaborine Chromophores: Their Synthesis via Oxazaborines and Electrochemical and DFT Study of Their Fundamental Properties

Eight new and stable triazaborine chromophores featuring various substituents as donor and acceptor moieties were prepared and investigated. An interpretation of the measured electrochemical data (CV, RDV, and dc polarography) and UV−vis spectra and quantum chemical calculations are presented. In the homologous series the first reduction proceeds as a one-electron reversible process localized at the −N═C–C═N– part of the central heterocycle being in conjugation with the attached carbonyl. The first oxidation of triazaborines proceeds as a two-electron irreversible process, most probably of the ECE type, localized at the negatively charged boron atom and surrounding unsaturated structures, including the substituted phenyl ring. For a better understanding of the relationship between the structure and redox properties, the LFER approach was applied for the first oxidation as well as reduction potential using the Hammett σ (para) substituent constants. The energies of the longest-wavelength absorption bands t...

Identification of 2,4-diamino-6,7-dimethoxyquinoline derivatives as G9a inhibitors†Electronic supplementary information (ESI) available. See DOI: 10.1039/c4md00274a.

G9a is a histone lysine methyltransferase (HKMT) involved in epigenetic regulation via the installation of histone methylation marks. 6,7-Dimethoxyquinazoline analogues, such as BIX-01294, are established as potent, substrate competitive inhibitors of G9a. With an objective to identify novel chemotypes for substrate competitive inhibitors of G9a, we have designed and synthesised a range of heterocyclic scaffolds, and investigated their ability to inhibit G9a. These studies have led to improved understanding of the key pharmacophoric features of BIX-01294 and the identification of a new core quinoline inhibitory scaffold, which retains excellent potency and high selectivity. Molecular docking was carried out to explain the observed in vitro data.

Insight into bicyclic thiopeptide biosynthesis benefited from development of a uniform approach for molecular engineering and production improvement

The ribosomal origin of thiopeptide antibiotics, a class of sulfur-rich and highly modified poly(thi)azolyl natural products, has recently been uncovered and features complex post-translational modifications (PTMs) of a precursor peptide. Based on molecular engineering and production improvement, we report insight into the biosynthesis of two bicyclic thiopeptide compounds, thiostrepton and nosiheptide. The PTMs of thiostrepton tolerate variations in the first two amino acids of the core peptide part of the precursor peptide: (1) the mutation of Ile1 to Val had no apparent effect on molecular maturation, suggesting that attachment of the quinaldic moiety at position 1 is not residue-dependent for the construction of the side ring system; and (2) the change of Ala2 to Ser led exclusively to the production of an analog that bears a corresponding dehydroamino acid residue, indicating that dehydration at position 2 is site-selective or that the oxazoline formed by cyclodehydration is inaccessible for maturation. For nosiheptide biosynthesis in particular, we provide the first structural evidence that construction of the specific side ring system precedes formation of the common central heterocycle domain and therefore propose that formation of a characteristic thiopeptide framework interweaves both common and specific PTMs that are interdependent. The above efforts benefited from the development of a uniform approach to examine the effectiveness for trans expression of gene encoding precursor peptides and associated PTM capacity. This approach is independent of knowledge regarding organism-specific regulatory mechanisms and potentially applicable to other systems that produce ribosomally synthesized peptide natural products.

Highly Luminescent Dinuclear Platinum(II) Complexes Incorporating Bis-Cyclometallating Pyrazine-Based Ligands: A Versatile Approach to Efficient Red Phosphors

A series of luminescent dinuclear platinum(II) complexes incorporating diphenylpyrazine-based bridging ligands (L(n)H2) has been prepared. Both 2,5-diphenylpyrazine (L(2)H2) and 2,3-diphenylpyrazine (L(3)H2) are able to undergo cyclometalation of the two phenyl rings, with each metal ion binding to the two nitrogen atoms of the central heterocycle, giving, after treatment with the anion of dipivaloyl methane (dpm), complexes of formula {Pt(dpm)}2L(n). These compounds are isomers of the analogous complex of 4,6-diphenylpyrimidine (L(1)H2). Related complexes of dibenzo(f,h)quinoxaline (L(4)H2), 2,3-diphenyl-quinoxaline (L(5)H2), and dibenzo[3,2-a:2',3'-c]phenazine (L(6)H2) have also been prepared, allowing the effects of strapping together the phenyl rings (L(4)H2 and L(6)H2) and/or extension of the conjugation from pyrazine to quinoxaline (L(5)H2 and L(6)H2) to be investigated. In all cases, the corresponding mononuclear complexes, Pt(dpm)L(n)H, have been isolated too. All 12 complexes are phosphorescent in solution at ambient temperature. Emission spectra of the dinuclear complexes are consistently red shifted compared to their mononuclear analogues, as are the lowest energy absorption bands. Electrochemical data and TD-DFT calculations suggest that this effect arises primarily from stabilization of the LUMO. Introduction of the second metal ion also has the effect of substantially increasing the molar absorptivity and, in most cases, the radiative rate constants. Meanwhile, extension of conjugation in the heterocycle of L(5)H2 and L(6)H2 and planarization of the aromatic system favored by interannular bond formation in L(4)H2 and L(6)H2 leads to further red shifts of the absorption and emission spectra to wavelengths that are unusually long for cyclometalated platinum(II) complexes. The results may offer a versatile design strategy for tuning and optimizing the optical properties of d-block metal complexes for contemporary applications.

Opportunities and challenges from current investigations into the biosynthetic logic of nosiheptide-represented thiopeptide antibiotics

Nosiheptide is an archetypal thiopeptide antibiotic, possessing a characteristic macrocyclic core that contains a 6-membered heterocycle central to multiple azol(in)es and dehydroamino acids. The discovery of the ribosomal origin of thiopeptides revealed a unifying theme, showing that the structural complexity arises from post-translational modifications (PTMs) of precursor peptides. Thiopeptide framework formation proceeds via cyclodehydration/dehydrogenation (for azol(in)es), dehydration (for dehydroamino acids), and cycloaddition (for the central heterocycle domain). This common process has not been reproduced in vitro, partly due to the poorly understood logic of thiopeptide biosynthetic pathways. Utilizing nosiheptide biosynthesis as a model system, we herein consider how nature coordinates a number of highly interwined, common and specific PTMs to accomplish the complexity of ribosomally synthesized and post-translationally modified peptides.

Diarylheterocycle Core Ring Features Effect in Selective COX‐1 Inhibition

The COX-1 isoenzyme plays a significant role in a variety of diseases, as it catalyzes the bioprocesses behind many health problems. Among the diarylheterocycle class of COX inhibitors, the isoxazole ring has been widely used as a central heterocycle for the preparation of potent and selective COX-1 inhibitors such as P6 [3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole]. The role of the isoxazole nucleus in COX-1 inhibitor selectivity has been clarified by preparing a set of new diarylheterocycles with various heterocycle cores. Replacement of isoxazole with isothiazole or pyrazole gave a drastic decrease in COX-1 inhibitory activity, whereas the introduction of an electron-donating group (EDG) on the N-aryl pyrazole allowed recovery of COX-1 inhibitory activity and selectivity. The EDG-equipped 5-(furan-2-yl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (17) selectively inhibits COX-1 activity (IC(50) =3.4 μM; 28% COX-2 inhibition at 50 μM), in contrast to its inactive analogue, 3-(furan-2-yl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole, which does not bear the methoxy EDG. Molecular docking studies of compound 17 into the binding site of COX-1 shed light on its binding mode.

Three-carbazole-armed host materials with various cores for RGB phosphorescent organic light-emitting diodes

A series of three-carbazole-armed host materials containing various arylene cores, like benzene (1,3,5-tris(3-(carbazol-9-yl)phenyl)-benzene, TCPB), pyridine (2,4,6-tris(3-(carbazol-9-yl)phenyl)-pyridine, TCPY), and pyrimidine (2,4,6-tris(3-(carbazol-9-yl)phenyl)-pyrimidine, TCPM), were developed for red, green, and blue phosphorescent organic light-emitting diodes (OLEDs). An intramolecular charge transfer was observed for TCPY and TCPM with heterocyclic cores of pyridine and pyrimidine, giving bathochromic shifts in the photoluminescent spectrum and reduced energy band gaps in comparison with TCPB with a benzene core. In addition, lower energy singlet and triplet excited states, reduced lowest unoccupied molecular orbital (LUMO) energy level, smaller singlet–triplet exchange energy (ΔEST), and improved bipolarity were also achieved with introducing heterocycles of pyridine and pyrimidine instead of benzene. In contrast to the slightly decreased triplet energy (ET), a significantly decreased ΔEST was achieved by introducing heterocycles of pyridine and pyrimidine as the core, and the more nitrogen atoms in the central heterocycle, the smaller ΔEST is achieved. Reduced driving voltages were achieved for the green and red phosphorescent OLEDs by utilizing TCPY and TCPM as the host due to their decreased ΔEST and lower-lying LUMO energy level, proving that more carriers must be injected into the emitting layer through the host molecules rather than direct carrier trapping by the dopant. Moreover, improved efficiency and suppressed efficiency roll-off were also achieved for the green and red phosphorescent OLEDs based on TCPY and TCPM due to their improved bipolarity and thus improved carrier balance.

1,1′-[(2,3,3a,4,5,6,7,7a-Octahydro-1H-1,3-benzimidazole-1,3-diyl)bis(methylene)]bis(1H-benzotriazole)

The cyclo­hexane ring in the title compound, C21H24N8, adopts a chair conformation and the five-membered heterocyclic ring to which it is fused adopts a twist conformation on their common C—C bond. The substituents on the N atoms of the central five-membered heterocycle are arranged trans with respect to the central ring. The terminal benzotriazole rings are oriented at angles of 74.66 (8) and 84.18 (8)° with respect to the mean plane of the central heterocycle. The angle between the two benzotriazole rings is 30.80 (9)°. The bond lengths and angles are within normal ranges; the largest deviation from expecta­tion is for a long N—CH2 bond length [1.476 (2) Å] as a consequence of an anomeric effect. In the crystal, mol­ecules are connected by C—H⋯N hydrogen bonds.