Eaton’s Reagent‐Mediated Domino π‐Cationic Arylations of Aromatic Carboxylic Acids to Iasi‐Red Polymethoxylated Polycyclic Aromatic Hydrocarbons: Products with Unprecedented Biological Activities as Tubulin Polymerization Inhibitors

A rapid domino π‐cationic arylation of aromatic carboxylic acids, mediated by Eaton’s reagent, has been developed for the synthesis of Iasi‐red polymethoxylated polycyclic aromatic hydrocarbons (PAHs). This route is currently the easiest method to obtain such popular PAH compounds, which bear in addition numerous methoxy groups. The domino process was generalized, the structure of the obtained red products and the mechanism of their formations were elucidated, and some of their photophysical properties were determined. Newly synthesized polymethoxylated‐PAHs were tested for their interaction with tubulin polymerization as well as for their cytotoxicity on a panel of NCI‐60 human cancer cell lines. Interestingly, one of these rubicene derivatives exhibited remarkable cytotoxicity in vitro, including inhibition of leukemia, colon, melanoma, CNS, and ovarian cancer cell lines with GI₅₀ values in the low nanomolar range (GI₅₀<10 nM ).     

Novel 5‐Methyl‐2‐[(un)substituted phenyl]‐4‐{4,5‐dihydro‐ 3‐[(un)substituted phenyl]‐5‐(1,2,3,4‐tetrahydroisoquinoline‐2‐yl)pyrazol‐1‐yl}‐oxazole Derivatives: Synthesis and Anticancer Activity

Eleven novel 5‐methyl‐2‐[(un)substituted phenyl]‐4‐{4,5‐dihydro‐3‐[(un)substituted phenyl]‐5‐(1,2,3,4‐tetrahydroisoquinoline‐2‐yl)pyrazol‐1‐yl}‐oxazole derivatives were synthesized and characterized by elemental analysis, ESI‐MS, ¹H NMR and ¹³C NMR. All of the compounds have been screened for their antiproliferative activities against PC‐3 cell (human prostate cancer) and A431 cell (human epidermoid carcinoma cancer) lines in vitro. The results revealed that compounds 4g , 4j and 4k exhibited the strong inhibitory activities against the PC‐3 cell lines (with IC₅₀ values of 2.8±0.11, 3.1±0.10 and 3.0±0.06 μg/mL, respectively).     

O‐Doped Nanographenes: A Pyrano/Pyrylium Route Towards Semiconducting Cationic Mixed‐Valence Complexes

Herein we report an efficient synthesis to prepare O‐doped nanographenes derived from the π‐extension of pyrene. The derivatives are highly fluorescent and feature low oxidation potentials. Using electrooxidation, crystals of cationic mixed‐valence (MV) complexes were grown in which the organic salts organize into face‐to‐face π‐stacks, a favorable solid‐state arrangement for organic electronics. Variable‐temperature electron paramagnetic resonance (EPR) measurements and relaxation studies suggest a strong electron delocalization along the longitudinal axis of the columnar π‐stacking architectures. Electric measurements of single crystals of the MV salts show a semiconducting behavior with a remarkably high conductivity at room temperature. These findings support the notion that π‐extension of heteroatom‐doped polycyclic aromatic hydrocarbons is an attractive approach to fabricate nanographenes with a broad spectrum of semiconducting properties and high charge mobilities.     

On‐Top π‐Stacking of Quasiplanar Molecules in Hole‐Transporting Materials: Inducing Anisotropic Carrier Mobility in Amorphous Films

Dimers of partially oxygen‐bridged triarylamines were designed and synthesized as hole‐transporting materials. X‐ray structural analyses revealed that these compounds form on‐top π‐stacking aggregates in the crystalline state. TRMC measurements showed that high levels of anisotropic charge transport were induced in the direction of the π‐stacking. Surprisingly, even in vacuum‐deposited amorphous films, these compounds retained some of the face‐on π‐stacking, thus facilitating an out‐of‐plane carrier mobility.     

Corannulene‐Fused Anion‐Responsive π‐Conjugated Molecules that Form Self‐Assemblies with Unique Electronic Properties

The fusion of bowl‐shaped π‐conjugated corannulene units to anion‐responsive π‐conjugated dipyrrolyldiketone‐boron complexes resulted in new molecular materials with a unique self‐assembly capability. The bowl‐fused receptor with aliphatic tails could form both supramolecular gels and mesophases through π‐stacking interactions and also exhibited anion‐responsive characteristics. The presence of the π‐bowl unit not only afforded enhanced self‐assembly capability both in solution and in the mesophases, as evidenced by gelation experiments and phase‐transition profiles, but also enhanced intrinsic charge‐carrier mobility.     

Utility of 6‐Amino‐2‐thiouracils as a Core of Biologically Potent Polynitrogen–Sulfur Fused Heterocycles

One pot three‐component reaction was assisted to form some new pyridopyrimidine derivatives to be investigated as antimicrobial and antitumor agents. The newly synthesized compounds showed high significant antimicrobial activity against the applied strains of both Gram‐positive and Gram‐negative bacteria and fungi. The cytotoxic activity of some compounds was evaluated as inhibitor of growth in both human liver carcinoma and breast cell lines. The results showed that some compounds exhibited very high cytotoxicity against human liver cell line and breast cancer cells.     

N‐(2‐Bromoethyl)‐4‐piperidino‐1,8‐naphthalimide and N‐(3‐bromopropyl)‐4‐piperidino‐1,8‐naphthalimide

N‐(2‐Bromoethyl)‐4‐piperidino‐1,8‐naphthalimide, C₁₉H₁₉BrN₂O₂, (I), and N‐(3‐bromopropyl)‐4‐piperidino‐1,8‐naphthalimide, C₂₀H₂₁BrN₂O₂, (II), are an homologous pair of 1,8‐naphthalimide derivatives. The naphthalimide units are planar and each piperidine substituent adopts a chair conformation. This study emphasizes the importance of π‐stacking interactions, often augmented by other contacts, in determining the crystal structures of 1,8‐naphthalimide derivatives.     

A new methanol solvate and Hirshfeld analysis of π‐stacking in 2,3,6,7,10,11‐hexahydroxytriphenylene solvates

The structure of 2,3,6,7,10,11‐hexahydroxytriphenylene (hhtp) methanol monosolvate, C₁₈H₁₂O₆·CH₃OH, has triclinic symmetry (space group P). The compound has a three‐dimensional layered network structure formed by intermolecular hydrogen bonding. Structure analysis with Hirshfeld surfaces is shown to be a sensitive method for comparing π‐stacking effects in the five known solvates of hhtp. The title structure shows slightly weaker π‐stacking than the dihydrate, but stronger π‐stacking than the other three solvates.     

The ability of Ex2Box4+ to interact with guests containing π‐electron‐rich and π‐electron‐poor moieties

The ability of Ex 2 Box⁴⁺ as a host, able to trap guests containing both π‐electron rich (polycyclic aromatic hydrocarbons‐PAHs) and π‐electron poor (quinoid‐ and nitro‐PAHs) moieties was investigated to shed light on the main factors that control the host–guest (HG) interaction. The nature of the HG interactions was elucidated by energy decomposition (EDA‐NOCV), noncovalent interaction (NCI), and magnetic response analyses. EDA‐NOCV reveals that dispersion contributions are the most significant to sustain the HG interaction, while electrostatic and orbital contributions are very tiny. In fact, no significant covalent character in the HG interactions was observed. The obtained results point strictly to NCIs, modulated by dispersion contributions. Regardless of whether the guests contain π‐electron‐rich or π‐electron‐poor moieties, and no significant charge‐transfer was observed. All in all, HG interactions between guests 3‐14 and host 2 are predominantly modulated by π‐π stacking.     

Redesigning the DNA‐Targeted Chromophore in Platinum–Acridine Anticancer Agents: A Structure–Activity Relationship Study

Platinum–acridine hybrid agents show low‐nanomolar potency in chemoresistant non‐small cell lung cancer (NSCLC), but high systemic toxicity in vivo. To reduce the promiscuous genotoxicity of these agents and improve their pharmacological properties, a modular build–click–screen approach was used to evaluate a small library of twenty hybrid agents containing truncated and extended chromophores of varying basicities. Selected derivatives were resynthesized and tested in five NSCLC cell lines representing large cell, squamous cell, and adenocarcinomas. 7‐Aminobenz[c]acridine was identified as a promising scaffold in a hybrid agent ( P1–B1 ) that maintained submicromolar activity in several of the DNA‐repair proficient and p53‐mutant cancer models, while showing improved tolerability in mice by 32‐fold compared to the parent platinum–acridine ( P1–A1 ). The distribution and DNA/RNA adduct levels produced by the acridine‐ and benz[c]acridine‐based analogues in NCI‐H460 cells (confocal microscopy, ICP‐MS), and their ability to bind G‐quadruplex forming DNA sequences (CD spectroscopy, HR‐ESMS) were studied. P1–B1 emerges as a less genotoxic, more tolerable, and potentially more target‐selective hybrid agent than P1–A1 .     

Dramatic Enhancement of Binding Affinities Between Foldamer‐Based Receptors and Anions by Intra‐Receptor π‐Stacking

As a synthetic model for intra‐protein interactions that reinforce binding affinities between proteins and ligands, the energetic interplay of binding and folding was investigated using foldamer‐based receptors capable of adopting helical structures. The receptors were designed to have identical hydrogen‐bonding sites for anion binding but different aryl appendages that simply provide additional π‐stacking within the helical backbones without direct interactions with the bound anions. In particular, the presence of electron‐deficient aryl appendages led to dramatic enhancements in the association constant between the receptor and chloride or nitrate ions, by up to three orders of magnitude. Extended stacking within the receptor contributes to the stabilization of the entire folding structure of complexes, thereby enhancing binding affinities.     

Theoretical Studies on the Hydrogen‐bonding and π‐Stacking Interactions in the m‐Nisoldipine Polymorphism Dimers

The intermolecular interactions in the dimers of m‐nisoldipine polymorphism were studied by B3LYP calculations and quantum theory of "atoms in molecules" (QTAIM) studies. Four geometries of dimers were obtained: dimer I (a‐dimer, O···H? N), dimer II (b‐dimer, O···H? N), dimer III (b‐dimer, π‐stacking‐c), and dimer IV (b‐dimer, π‐stacking‐p). The interaction energies of the four dimers are along the sequence of II>I>III>IV. The intermolecular distance of the interactions follows the order: I (O···H? N)II>III>IV, and the electrostatic character decreases along the sequence: I>II>III>IV.     

Self‐Assembly of Pyridinium‐Tailored Anthracene Amphiphiles into Supramolecular Hydrogels

The mixing of a polyacid cross‐linker with a pyridinium‐functionalized anthracene amphiphile afforded a supramolecular hydrogel through a self‐assembly process that was primarily driven by π‐stacking and electrostatic interactions.     

Photo‐physical Properties of N‐methyl‐3,4‐fulleropyrrolidine and Its Derivatives: A DFT and TD‐DFT Investigation

A series of N‐methyl‐3,4‐fulleropyrrolidine (NMFP) derivatives were designed by selecting different π‐conjugated linkers and electron‐donating groups as D‐π‐A and D‐A systems. The optimised structures and photo‐physical properties of NMFP and its derivatives have been determined using density functional theory (DFT) and time‐dependent density functional theory (TD‐DFT) methods with the B3LYP functional and the 6‐31G basis set. According to the computation analysis, both the π‐conjugated linkers and the electron‐donating groups can influence the electronic and photo‐physical properties of the NMFP derivatives. Our calculated results demonstrated that the electron‐donating groups, with significant electron‐donating ability, had the tendency to increase the highest occupied molecular orbital (HOMO) energy. The π‐conjugated linkers with lower resonance energy decreased the lowest occupied molecular orbital (LUMO) energy and caused a significant decrease in the energy gap (E_g) between the E_HOMO and E_LUMO. A Natural Bond Orbital (NBO) analysis examines the effect of the electron‐donating group, π conjugated linker, and electron‐withdrawing group for these NMFP derivatives. For the NMFP derivatives, a projected density of state (PDOS) analysis demonstrated that the electron density of HOMO and LUMO are concentrated on the electron‐donating group and the π‐conjugated linker, respectively. A TD‐DFT/B3LYP calculation was performed to calculate the electronic absorption spectra of these NMFP derivatives. Both the electron‐donating group and the π‐conjugated linker contribute to the major absorption peaks, which are assigned as HOMO to LUMO transitions and are red‐shifted relative to those of non‐substituted NMFP.     

Interaction of Antitumor Drug Aclacinomycin‐A with DNA and Its Specific Sequence Site

Through UV and fluorescence spectrophotometries, the interaction of aclacinomycin‐A (ACM‐A) with DNA and its specific sequence have been investigated with the aid of circular dichroism spectrophotometry and differential pulse voltammetry method. The results demonstrated that ACM‐A was capable of intercalating DNA double helix, the π‐π electronic overlapping between π‐electrons of ACM‐A and base pair of DNA stabilized the ACM‐A‐DNA adduct, and through electrostatic interaction, the trisaccharide interacted with the minor groove of DNA owing to an amino group at C(3′). Electrochemical and spectroelectrochemical studies revealed that the original form of ACM‐A had higher affinity for DNA than the reduction form in which the trisaccharide group at C(7) was lost. According to the results obtained in this paper, ACM‐A showed preference for AT base pairs of the deoxyribonucleic acid duplex, and it was apt to interact with cytosine and thymine rather than the adenine of oligonucleotide.     

Synthesis and Anticancer Evaluation of Some Novel Thiophene,Thieno[3,2‐d]pyrimidine,Thieno[3,2‐b]pyridine,and Thieno[3,2‐e][1,4]oxazepine Derivatives Containing Benzothiazole Moiety

In an attempt to establish novel candidate with promising anticancer activity, two derivatives of (benzo[d]thiazol‐2‐yl)thiophene backbone 1 and 14 were synthesized, and they further reacted with various chemical reagents to afford the corresponding substituted thiophene derivatives 6 , 8 , 10 , 15 , 17 , and 20 , thieno[3,2‐d]pyrimidine derivatives 2 – 5 , 7 , 9 , 16 , 21 , 23 , and 24 , thieno[3,2‐b]pyridine derivatives 11 – 13 , and thieno[3,2‐e][1,4]oxazepine derivative 18 . Structures of prepared compounds were affirmed via spectral and elemental data. Among the obtained compounds, seven derivatives 2 , 3 , 4 , 5 , 11 , 12 , and 13 were chosen by National Cancer Institute, USA. Such compounds were screened for their antitumor activity versus 60 cancer cell lines in one‐dose (10 μmol) screening assay. The outcomes showed that all selected compounds exhibited moderate to high anticancer activity towards many cancer cell lines among which compounds 5 and 11 exerted potent antitumor activity against numerous malignant growth cell lines particularly Ovarian Cancer IGROV1.     

Synthesis and In Vitro Cytotoxic Activity of Novel Triazole‐Isoxazole Derivatives

New derivatives of triazole‐isoxazole were synthesized through a four‐step reaction starting from various ethyl 4‐aryl‐2,4‐dioxobutanoate derivatives. Finally, all compounds were examined by MTT assays for cytotoxic activity in two human breast cancer cell lines (MCF‐7 and T‐47D).     

Programmed‐Assembly System Using DNA Jigsaw Pieces

A novel method for assembling multiple DNA origami structures has been developed by using designed 2D DNA origami rectangles, so‐called “DNA jigsaw pieces” that have sequence‐programmed connectors. Shape and sequence complementarity were introduced to the concavity and convex connectors in the DNA rectangles for selective connection with the help of nonselective π‐stacking interactions between the side edges of the DNA jigsaw piece structures. Single DNA jigsaw piece units were assembled into unidirectional nanostructures with the correct alignment and uniform orientation. Three and five different DNA jigsaw pieces were assembled into predesigned and ordered nanostructures in a programmed fashion. Finally, three‐, four‐, and five‐letter words have been displayed by using this programmed DNA jigsaw piece system.     

Non‐Flat Bisbenzylisoquinoline Alkaloid Fangchinoline As a Class of Potent G‐Quadruplex Stabilizer with Anti‐cancer Activity

Compounds selectively binding and stabilizing G‐quadruplex structures could inhibit the telomerase or down‐ regulate the oncogenes and may act as anti‐cancer drugs. An alkaloid with non‐flat structure, fangchinoline, showed to strongly stabilize the intermolecular and intramolecular parallel stranded G‐quadruplex structure, increasing melting temperature by 20 and 23°C, respectively. The binding mode was investigated by using NMR and molecular modelling methods. Four human cell lines (HL‐60, BGC‐823, Bel‐7402 and KB) were taken to test the anti‐proliferation effects of fangchinoline and the IC₅₀ values were ranged from 16 to 32 µmol/L. These results showed that the fangchinoline or related moiety derivatives may represent a class of telomere‐targeted agents as potential anti‐cancer drugs.     

Columnar Mesophase Formation of Cyclohexa‐m‐phenylene‐Based Macrocycles

Two novel discotic macrocycles, substituted cyclohexa‐m‐phenylene (CHP) and cyclo‐3,6‐trisphenanthrylene (CTP), and the linear oligomer 3,3′:6′,3′′‐terphenanthrene (TP) as a model substance have been synthesized by repetitive cross‐coupling reactions. To correlate the molecular design with the supramolecular architecture and the established macroscopic order, 2D wide‐angle X‐ray scattering experiments were performed on mechanically extruded filaments. At room temperature in their crystalline phases, all three compounds revealed columnar assemblies in which the macrocycles self‐organized by π‐stacking interactions. The degree of macroscopic order was found to depend upon the planarity and stiffness of the aromatic core. The flexible CHP ring showed a poor macroscopic order of the columnar structures and a low isotropization temperature, whereas the more‐planar, less‐flexible CTP self‐assembled into well‐defined superstructures. The larger π‐stacking area and the more‐pronounced intermolecular interactions for CTP led to the formation of a mesophase over a very large temperature range. The surprising columnar organization of the “open” TP system was explained by back‐folding of the molecule into a ringlike structure.