Aromatic Scaffold Research Articles

Fluorescent DNA analog: 2-aminotroponyl-pyrrolyl-2’-deoxyuridinyl DNA oligo enhance fluorescence in DNA-duplex as compared to 2-aminotroponyl-ethynyl-2’-deoxyuridinyl DNA oligo

The nucleobase modified fluorescent DNA and RNA analogs are synthesized by the conjugation of aromatic scaffolds through linkers, comprising mostly ethyne/ethene or fused ring residues at the pyrimidine/purine ring. These scaffolds are mainly derived from the benzenoid aromatic molecules comprising electron withdrawing/donating characters. However, non-benzenoid aromatic scaffolds such as tropolone and related derivatives are constituents of various troponoid natural products. The conjugation of nucleobases with a troponyl moiety is underutilized for the synthesis of fluorescent DNA analogs. This report describes the synthesis and photophysical studies of 2-aminotroponyl conjugated deoxyuridine nucleosides and their DNA analogs. 2-Aminotropone derivatives are conjugated at the C-5 position of uridine through an ethynyl linker/pyrrolyl ring fusion and their DNA analogs. Their photophysical studies reveal that aminotroponyl deoxyuridine analogs exhibit solvent-dependent fluorescence properties. Moreover, pyrrolyl ring-fused aminotroponyl DNA oligonucleotides enhance the fluorescence after formation of duplexation with complementary sequences of native DNA oligonucleotides. Hence, these modified nucleosides and DNA are promising fluorescent analogs which could be useful to design the sequence-specific DNA probes.

A Quantum Chemical Deep-Dive into the π-π Interactions of 3-Methylindole and Its Halogenated Derivatives-Towards an Improved Ligand Design and Tryptophan Stacking.

Non-covalent π-π stacking interactions often play a key role in the stability of the secondary and tertiary structures of peptides and proteins, respectively, and can be a means of ensuring the binding of ligands within protein and enzyme binding sites. It is generally accepted that minor structural changes to the aromatic ring, such as substitution, can have a large influence on these interactions. Nevertheless, a thorough understanding of underpinning phenomena guiding these key interactions is still limited. This is especially true for larger aromatic structures. To expand upon this knowledge, elaborate ab initio calculations were performed to investigate the effect of halogenation on the stability of 3-methylindole stacking. 3-Methylindole served as a representation of the tryptophan side chain, and is a frequently used motif in drug design and development. Moreover, an expression is derived that is able to accurately predict the interaction stability of stacked halogenated 3-methylindole dimers as well as halogenated toluene dimers, based on monomer level calculated DFT descriptors. We aim for this expression to provide the field with a straightforward and reliable method to assess the effect of halogenation on the π-π stacking interactions between aromatic scaffolds.

Mechanochemically Induced Cross Dehydrogenative Coupling Reactions under Ball Milling

AbstractCross dehydrogenative coupling (CDC) reactions have become a convenient synthetic strategy for the synthesis of various (het)aromatic scaffolds. In recent times ball milling has emerged as a powerful tool to perform reactions in a greener way. The current review highlights various applications of cross dehydrogenative coupling reactions under ball milling towards synthesis of useful molecules in a more efficient and convenient manner.magnified image

Exploring the Acid-Catalyzed Reactions of 10,11-Epoxy-Dibenzo[a,d]cycloheptan-5-ol as the Synthetic Modules toward Polycyclic Aromatic Scaffolds.

The structural diversity of polycyclic aromatic hydrocarbons (PAHs) offers exciting opportunities for their applications. Yet, selective synthesis of such conjugated networks poses a formidable challenge. Compared to the prominence of transition-metal-catalyzed cross-coupling and oxidative Scholl reactions, cationic rearrangement in the synthesis of polycyclic aromatic hydrocarbon is an underexplored subject. In this study, we reveal that cationic intermediate generated from epoxy dibenzocycloheptanol can be transformed into acenes, azulene-embedded PAHs, and dibenzocycloheptanone derivatives. Reactive patterns, including Meinwald rearrangement, Nazarov cyclization, transannular aryl migration, and transannular Friedel–Crafts cyclization were identified. Both substrate structures and reaction temperature affect the reaction pathways in predictable and manageable manners. A mechanistic scheme was postulated as the working model to guide the reactivity for further application. Substrates containing heterocyclic and ferrocenyl groups exhibit similar reactivity profiles. The inquiry culminates in the selective synthesis of 5, 7, 12, 14-tetrasubstituted C2h and C2v pentacene derivatives. Our results demonstrate that polycyclic aromatic hydrocarbons can be selectively prepared with this cation-initiated strategy by methodically tuning the reactivity.

Transferring the available fused cyclic scaffolds for high—throughput combinatorial design of highly energetic materials via database mining

Recently, the fused cyclic compounds have been the object of an increased interest in the field of energetic materials (EMs) due to the trade-off between energy and safety. Compared with the fused cyclic EMs consisting of the azoles or azines, the oxazole-based fused EMs which possibly possess higher energy–density are very lacking. Here, we proposed an efficient approach to design the highly energetic oxazole-based fused materials. The domain-related knowledge promoted an advanced database search for the aromatic oxazole-based scaffolds from the buyable subset of the ZINC20 database, ensuring scaffolds are available for purchase. Then, 171 target scaffolds were transferred into the EM field and cooperated with combinatorial design to construct a chemical space containing over 107 potential energetic molecules. The high-throughput screening was performed in four aspects, namely, density, difficulty of synthesis, detonation performance, and sensitivity, to accelerate the search for candidates. Meanwhile, the statistical analysis through the hierarchical filtrations clarified the potential of 2r-3s and 2r-4s scaffold types for creating highly energetic molecules. Finally, several candidates stood out owing to nearly 10000 m/s detonation velocity and acceptable predicted sensitivity, elucidating the effectiveness of our approach. We anticipate this investigation could not only be a vital point for subsequent fused cyclic EM research, but also offered a new avenue for material design in other fields.

A Mini-Review On The Current Scenario Of Quinoline Scaffolds For Antimalarial Activity

Antimalarial agents are an important key for the prevention and eradication of malaria. The heterocyclic aromatic quinoline scaffold is a favored structure in drug development because its derivatives have a wide range of biological properties. The quinoline family contains a lot of antimalarial agents like chloroquine, piperaquine, quinine, etc. Chloroquine had been a significant antimalarial agent for more than five decades. To enhance the efficacy in malarial treatment a new system of several other quinoline-based drugs has been synthesized. This mini-review intends to provide a literature overview of antimalarial compounds containing a quinoline core, encompassing papers from 2018 to the present along with the synthesis and pertinent figures. It could be useful for researchers to design more effective antimalarial drugs in the future.

Central-to-Folding Chirality Control: Asymmetric Synthesis of Multilayer 3D Targets With Electron-Deficient Bridges.

New multilayer 3D chiral molecules have been designed and synthesized asymmetrically through the strategy of center-to-multilayer folding chirality control and double Suzuki couplings. Individual diastereoisomers were readily obtained and separated via flash column chromatography. The key diastereoisomer was further converted into corresponding enantiomers. These enantiomers possess electron-deficient aromatic bridges layered with top and bottom aromatic scaffolds. X-ray structural analysis has unambiguously confirmed the configuration, and intermolecular packing results in regular planar patterns in solid crystals. The synthesis was achieved in a total of ten steps starting from commercially available starting materials.

Quadruple Functionalization of a Tetraphenylethylene Aromatic Scaffold with Ynamides or Tetracyanobutadienes: Synthesis and Optical Properties

AbstractYnamides are useful and versatile building blocks in organic synthesis, from which 1,1,4,4‐tetracyanobutadienes (TCBD) can be prepared for application in molecular electronics. However, their insertion onto multi‐functional molecular scaffold remains a synthetic challenge. In this work, we report the two‐steps synthesis in good isolated yield (64 % overall, 89 % stepwise) of a tetraphenylethylene (TPE) bearing four ynamides, and its further one‐step conversion into the tetra‐TCBD derivative through a [2+2] cycloaddition‐retroelectrocyclization sequence. The concomitant formation of the four ynamides required a specific optimisation of the reaction conditions. Although a poor fluorescent emitter in solution, the tetra‐TCBD compound displayed near‐infrared luminescence in the solid state, which is an attractive optoelectronic feature when considering future applications in molecular electronic devices.

Bilateral Aromatic Extension of Corannulene Nucleus

AbstractHerein we show that a dibromo imide derivative of corannulene could be subjected to a palladium‐catalyzed Heck reaction in order to install aryl vinylene groups in a bilateral fashion on the C5‐symmetric aromatic nucleus. A photochemically‐induced oxidative cyclization then affords π‐extended structures in isolated overall yields of 35–44 %. Due to the aromatic area extension and the presence of electron withdrawing groups, the synthesized molecules exhibit an anodic shift of ≈1 V in their first reduction potential as compared to pristine corannulene. The bilateral growth of the aromatic scaffold, therefore, represents a viable strategy to prepare π‐extended corannulenes with an electron deficient character.

Screening of Scaffolds for the Design of G-Quadruplex Ligands

In the last decade, progress has been made in G-quadruplex (G4) ligands development, but for most compounds, the ligand binding mode is speculative or based on low resolution methods, with its discovery based on structure-based approaches. Herein, we report the synthesis of small (MW < 400 Da) heterocycle compounds, containing different aromatic scaffolds, such as phenyl, quinoline, naphthalene, phenanthroline and acridine moieties, in order to explore their stabilization effect towards different DNA G4s, such as those found in c-MYC, KRAS21 and VEGF promoters, 21G human telomeric motif and pre-MIR150. The fluorescence resonance energy transfer (FRET) melting assay indicates that the acridine moiety is the most active scaffold, followed by phenanthroline. The different scaffolds are promising in terms of drug-like properties and, in general, the IC50 values of the respective heterocycle compounds are lower in a cancer cell line, when compared with a normal cell line. The acridine derivative C5NH2 has the most favorable cytotoxic profile in terms of cell selectivity.

Chemoselective Preparation of New Families of Phenolic-Organoselenium Hybrids-A Biological Assessment.

Being aware of the enormous biological potential of organoselenium and polyphenolic compounds, we have accomplished the preparation of novel hybrids, combining both pharmacophores in order to obtain new antioxidant and antiproliferative agents. Three different families have been accessed in a straightforward and chemoselective fashion: carbohydrate-containing N-acylisoselenoureas, N-arylisoselenocarbamates and N-arylselenocarbamates. The nature of the organoselenium framework, number and position of phenolic hydroxyl groups and substituents on the aromatic scaffolds afforded valuable structure–activity relationships for the biological assays accomplished: antioxidant properties (antiradical activity, DNA-protective effects, Glutathione peroxidase (GPx) mimicry) and antiproliferative activity. Regarding the antioxidant activity, selenocarbamates 24–27 behaved as excellent mimetics of GPx in the substoichiometric elimination of H2O2 as a Reactive Oxygen Species (ROS) model. Isoselenocarbamates and particularly their selenocarbamate isomers exhibited potent antiproliferative activity against non-small lung cell lines (A549, SW1573) in the low micromolar range, with similar potency to that shown by the chemotherapeutic agent cisplatin (cis-diaminodichloroplatin, CDDP) and occasionally with more potency than etoposide (VP-16).

Programmed Macromolecular Assembly by Dipole-Dipole Interactions with Aggregation-Induced Enhanced Emission in Aqueous Medium.

Self-assembling polymers by bioinspired directional supramolecular interactions currently hold great scientific and technological interests. Herein, we report an unorthodox strategy based on a dipole-dipole interaction-mediated extended antiparallel dipolar assembly of a model merocyanine (MC) dye for maneuvering the self-assembly of a highly water-soluble MC-functionalized block copolymer (P2). Unlike traditional amphiphilic block copolymers featuring distinct hydrophobic segments (flexible aliphatic hydrocarbon chains or rigid nonpolar aromatic scaffolds), P2 comprises polyethylene glycol monomethyl ether (PEG) as a hydrophilic block and an unconventional structure-directing acrylate block functionalized with polar MC-dyes in the side chains of every repeat unit. In the absence of any additional hydrophobic assistance, P2 spontaneously self-assembles in water through the continuous opposite alignment of its pendant MCs by multiple dipole-dipole interactions to cancel out their ground state dipole moments, which initially generates an H-aggregated species with ill-defined morphology (Aggregate 1). Upon thermal annealing, Aggregate 1 reorganizes into higher-order core-shell nanodisc-like structures (Aggregate 2) driven by the orthogonal π-stacking interactions of the rigid aromatic framework derived from the extended cofacial MC-stacks. The aromatic interiors of the nanodiscs gain colloidal stability from the externally decorated hydrophilic PEG chains. While the initially formed Aggregate 1, predominantly by dipole-dipole interactions, showed remarkable thermal stability due to the cooperative effect of the polymer chain, the hierarchical assembly guided by relatively weaker dispersion forces of the MC-stacked π-surfaces could be tailored by dilution or thermal treatment. Such organized packing of pendant MCs by the dual effect of dipole-dipole interactions and π-stacking conferred several exciting properties to the P2 assembly in water. Long-range ordered antiparallel stacking of the pendant MCs rendered outstanding aggregation-induced enhanced emission (AIEE) properties to the resultant nanostructures in water with increased fluorescence lifetime, quantum yield, and Stokes shift compared to nonaggregating P2 in CHCl3. The remarkable thermal and kinetic stability of the nanodiscs, their guest loading ability, and very low critical aggregation concentration (CAC) were demonstrated by Förster resonance energy transfer (FRET) studies with an encapsulated donor-acceptor dye pair.

Dithiocarbamates effectively inhibit the α-carbonic anhydrase from Neisseria gonorrhoeae

Recently, inorganic anions and sulphonamides, two of the main classes of zinc-binding carbonic anhydrase inhibitors (CAIs), were investigated for inhibition of the α-class carbonic anhydrase (CA, EC 4.2.1.1) from Neisseria gonorrhoeae, NgCA. As an extension to our previous studies, we report that dithiocarbamates (DTCs) derived from primary or secondary amines constitute a class of efficient inhibitors of NgCA. KIs ranging between 83.7 and 827 nM were measured for a series of 31 DTCs that incorporated various aliphatic, aromatic, and heterocyclic scaffolds. A subset of DTCs were selected for antimicrobial testing against N. gonorrhoeae, and three molecules displayed minimum inhibitory concentration (MIC) values less than or equal to 8 µg/mL. As NgCA was recently validated as an antibacterial drug target, the DTCs may lead to development of novel antigonococcal agents.

Z‐Selective Fluoroalkenylation of (Hetero)Aromatic Systems by Iodonium Reagents in Palladium‐Catalyzed Directed C−H Activation

AbstractThe direct and catalytic incorporation of fluorine containing molecular motifs into organic compounds resulting high‐value added chemicals represents a rapidly evolving part of synthetic methodologies, thus this area is in the focus of pharmaceutical and agrochemical research. Herein we report a stereoselective procedure for direct fluorovinylation of aromatic and heteroaromatic scaffolds. This methodology development has been realized by palladium‐catalyzed ortho C−H activation reaction of aniline derivatives featuring the regioselectivity via directing groups such as secondary of tertiary amides, ureas or ketones. The application of non‐symmetrical aryl(fluoroalkenyl)‐iodonium salts as fluoroalkenylating agents allowed mild reaction conditions in general for this transformation. The scope and limitations have been thoroughly investigated and the feasibility has been demonstrated by more than 50 examples.magnified image

How to Install Boron into Aromatic Scaffolds～Chemistry of Diazadiborinines～

The concept of aromaticity has been of paramount significance in myriad fields of chemistry. To modulate the intrinsic electronic nature of aromatic molecules, partial incorporation of heteroatoms into the benzene scaffold represents a useful strategy in modern inorganic chemistry. This account presents how to incorporate boron into aromatic six-membered scaffolds, leading to hybrid organic/inorganic benzenes, namely diazadiborinines. In addition, their reactivity towards a variety of substrates are summarized.

Two asymmetrical perylene diimide derivatives: Synthesis, optical-electrochemical properties and morphologies of self-assembly

Perylene diimides (PDIs) belong to an important class of photoactive materials due to their excellent electrical and photophysical properties. Highly controlled aggregation and self-assembly attributed to the large π-conjugated aromatic scaffold have led to a variety of optoelectronic applications. In this manuscript, two PDI derivatives PDI-1 and PDI-2 with unsymmetrical N-substitution of amine and ester-bridge were designed and synthesized. These two compounds were characterized by NMR, Fourier transform infrared (FT-IR), and high-resolution mass spectrometry (HRMS). The photophysical properties were studied by UV–Vis absorption and fluorescence spectroscopy. Cyclic voltammograms of PDI-1 and PDI-2 were investigated and HOMO and LUMO energy levels of both two PDIs were estimated as −6.2 and −3.9 ​eV, respectively. Thermal properties were also studied by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). PDI-1 was assembled into nanotubes while PDI-2 was assembled into nanobelts respectively, via a reprecipitation method. PDI-1 and PDI-2 show good potential application in organic devices such as solar cells, organic field-effect transistors (OFETs) and so on.

Synthesis of Carbazoles and Dihydrocarbazoles by a Divergent Cascade Reaction of Donor-Acceptor Cyclopropanes.

An alkylation/olefination cascade of indolecarboxaldehydes and phosphonate-functionalized donor–acceptor cyclopropanes affords functionalized dihydrocarbazoles and cyclohepta[cd]indoles in formal (3 + 3) and (4 + 3) cycloadditions. A minor modification to the reaction conditions also allows access to the fully aromatic heterocyclic scaffolds by thermal loss of an electron-rich aryl moiety.

α-d-Mannoside ligands with a valency ranging from one to three: Synthesis and hemagglutination inhibitory properties

Six mono-, di-, and trivalent α-d-mannopyranosyl conjugates built on aromatic scaffolds were synthesized in excellent yields by Cu(I) catalyzed azide-alkyne cycloaddition reaction (CuAAC). These conjugates were designed to have unique, flexible tails that combine a mid-tail triazole ring, to interact with the tyrosine gate, with a terminal phenyl group armed with benzylic hydroxyl groups to avoid solubility problems as well as to provide options to connect to other supports. Biological evaluation of the prepared conjugates in hemagglutination inhibition (HAI) assay revealed that potency increases with valency and the trivalent ligand 6d (HAI = 0.005 mM) is approximately sevenfold better than the best meta-oriented monovalent analogues 2d and 4d (HAI ≈ 0.033 mM) and so may serve as a good starting point to find new lead ligands.

Another structural correction for 1-oxo-1H-phenalene-2,3-dicarbonitriles: Synthesis of a potent BCL-2 inhibiting 7-phenoxy derivative.

Aromatic scaffolds are an important part of biologically active compounds and molecular probes used to study biochemical pathways and the involved targeted proteins of interest. 1-Oxo-1H-phenalene-2,3-dicarbonitrile-based compounds have been described as inhibitors of the BCL-2 family of proteins, and this core structure represents numerous possibilities for modifications that could lead to improved inhibitory potencies. Many studies demonstrated intriguing characteristics of these compounds in terms of reactivity and, interestingly, some contradictory literature reports appeared about reaction outcomes to synthesize them. Here, we initially provide a condensed overview of transformations performed on the phenalene scaffold, followed by the resynthesis of a 6-phenoxy-substituted derivative. We show that the initial determination of this particular structure was wrong and provide two-dimensional nuclear magnetic resonance (NMR) evidence to assign the structure properly. When preparing new derivatives using the same synthetic route, we observed 6- and 7-substituted regioisomers. After confirming their structures by NMR experiments, the ability of these compounds to inhibit BCL-2 was evaluated. The most potent 1-oxo-1H-phenalene-2,3-dicarbonitrile derivatives inhibited BCL-2 in the nanomolar range and showed double-digit micromolar cytotoxicity against four different cancer cell lines.

Corannulene: A Curved Polyarene Building Block for the Construction of Functional Materials.

This Account describes a body of research in the design and synthesis of molecular materials prepared from corannulene. Corannulene (C20H10) is a molecular bowl of carbon that can be visualized as the hydrogen-terminated cap of buckminsterfullerene. Due to this structural resemblance, it is often referred to as a buckybowl. The bowl can invert, accept electrons, and form host-guest complexes. Due to these characteristics, corannulene presents a useful building block in materials chemistry.In macromolecular science, for example, assembly of amphiphilic copolymers carrying a hydrophobic corannulene block enables micelle formation in water. Such micellar nanostructures can host large amounts of fullerenes (C60 and C70) in their corannulene-rich core through complementarity of the curved π-surfaces. Covalent stabilization of the assembled structures then leads to the formation of robust water-soluble fullerene nanoparticles. Alternatively, use of corannulene in a polymer backbone allows for the preparation of electronic and redox-active materials. Finally, a corannulene core enables polymer chains to respond to solution temperature changes and form macroscopic fibrillar structures. In this way, the corannulene motif brings a variety of properties to the polymeric materials.In the design of non-fullerene electron acceptors, corannulene is emerging as a promising aromatic scaffold. In this regard, placement of sulfur atoms along the rim can cause an anodic shift in the molecular reduction potential. Oxidation of the sulfur atoms can further enhance this shift. Thus, a variation in the number, placement, and oxidation state of the sulfur atoms can create electron acceptors of tunable and high strengths. An advantage of this molecular design is that material solubility can also be tuned. For example, water-soluble electron acceptors can be created and are shown to improve the moisture resistance of perovskite solar cells.Host-guest complexation between corannulene and γ-cyclodextrin under flow conditions of a microfluidic chamber allows for the preparation of water-soluble nanoparticles. Due to an oligosaccharide-based sugarcoat, the nanoparticles are biocompatible while the corannulene component renders them active toward nonlinear absorption and emission properties. Together, these attributes allow the nanoparticles to be used as two-photon imaging probes in cancer cells.Finally, aromatic extension of the corannulene nucleus is seen as a potential route to nonplanar nanographenes. Typically, such endeavors rely upon gas-phase synthesis or metal-catalyzed coupling protocols. Recently, two new approaches have been established in this regard. Photochemically induced oxidative cyclization, the Mallory reaction, is shown to be a general method to access corannulenes with an extended π-framework. Alternatively, solid-state ball milling can achieve this goal in a highly efficient manner. These new protocols bring practicality and sustainability to the rapidly growing area of corannulene-based nanographenes.In essence, corannulene presents a unique building block in the construction of functional materials. In this Account, we trace our own efforts in the field and point toward the challenges and future prospects of this area of research.