Naphthalene Diimide Research Articles

Abstract A080: Target genes in pancreatic cancer cells of the pan-quadruplex clinical candidate compound QN-302 revealed by comparative transcriptome profiling

Abstract QN-302 is a tetra-substituted naphthalene derivative designed to have high affinity to quadruplexes in cancer-related genes, which have multiple quadruplex occurrence in their promoter sequences. QN-302 has ca 1 nM in vitro activity against a panel of pancreatic ductal adenocarcinoma (PDAC) cell lines and shows high activity against four distinct PDAC in vivo models, including the KPC genetic model. QN-302 is currently being developed for clinical trials in solid tumors including PDAC. It has also recently been granted orphan drug drug (ODD) status by the FDA. We have previously reported on whole-genome transcriptome studies for QN-302, which show that it selectively targets quadruplex-rich genes in PDAC-related pathways, and thus acts as a pan-quadruplex agent. We have recently extended our analysis to include two closely related analogs of QN-302 as well as data from a gemcitabine-resistant line. QN-302 is consistently ca 10-fold more potent in PDAC cells and in vivo than the second-best analog. RNA-seq whole-cell and comparative bioinformatics analyses have been used to probe these differences. This has resulted in the identification of those target genes that the naphthalene diimide family have in common, many of which are involved in PDAC pathways such as hedgehog, axon guidance, WNT/β-catenin and hippo. It has also been possible to identify a small number of quadruplex target genes that are highly and selectively down-regulated by QN-302, and which are also highly up-regulated in human PDAC. We suggest that these contribute to the exceptional in vivo potency of this compound. Citation Format: Ahmed Ahmed, Tariq Arshad, Maria Roman-Escorza, Dan M. Neidle, Stephen Neidle. Target genes in pancreatic cancer cells of the pan-quadruplex clinical candidate compound QN-302 revealed by comparative transcriptome profiling [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A080.

Thiolated Chiral Naphthalene Diimide Derivatives as Effective Selectors of the β‐Blocker Atenolol Enantiomers

AbstractAtenolol β‐blocker drug (ATN) to treat hypertension and cardiovascular disorders such as angina pectoris is manufactured commercially in a racemic form, while only its (S)‐enantiomer shows selective β1‐blocking activity. Here, a new axially chiral thiolated naphthalene diimide derivatives (HS‐BIN‐NDI) for the rapid, simple, and sensitive detection of ATN enantiomers is presented. The Surface Plasmon Resonance (SPR) and Atomic Force Microscopy (AFM) experiments show that interactions between a chiral selector and a chiral analyte occur only when their configurations are opposite. The extensive computational simulations support this finding. The association coefficient determined by SPR is high (105‐106 M−1 s−1) and indicates that the interactions are electrostatic. The analytical utility of atropisomeric HS‐BIN‐NDIs is proven, and the voltammetric sensors designed to determine ATN enantiomers are constructed. The developed sensors are characterized by a wide analytical operating range from 5.0·10−3 to 1.0 µm, nanomolar detection limit, high selectivity, and a long lifetime. Several additives like urea, creatinine, glucose, human albumin, and hemoglobin do not affect ATN sensing.

Synthesis of cyanated Naphthalene diimide−Hydroazaacenes: Amphoteric-redox, low-lying LUMO, bright-red emission, aggregation and aromaticity evaluation

Herein we explored the synthesis and functionalization of NDI-hydroazaacenes, via two routes, at both the peripheries along the long-axis of the molecules. For the first time, we successfully performed cyanation reactions at the hydroazaacenes without the use of Pd-catalyst, enabling straightforward access to symmetric and asymmetrically substituted molecules. We also accessed NDI-hydroazaacenes with shorter substituents at the axial-positions allowing us to realize the single crystal data, which interestingly revealed π-stacked dimers with slipped orientation with the axial groups self-sorted in a syn-syn and anti-anti fashion. The tetracyano-substituted NDI-hydroazaacene showed a DFT predicted LUMO of −4.34 eV, which makes it the most electron-deficient hydroazaacene reported till date. In addition, we explored the amphoteric-redox properties of the NDI-hydroazaacene by generating radical anion/dianion and radical cation states. The molecules showed interesting J-type aggregation with concomitant color change from pink to blue in solution. Further, the molecules exhibited bright-red emission with quantum yields of 29–72 %. Computational studies showed the aromaticity/antiaromaticity can be subtly modulated by the substituents (H/Br/CN) on the rings.

G-quadruplex structural dynamics at MAPK12 promoter dictates transcriptional switch to determine stemness in breast cancer.

P38γ (MAPK12) is predominantly expressed in triple negative breast cancer cells (TNBC) and induces stem cell (CSC) expansion resulting in decreased survival of the patients due to metastasis. Abundance of G-rich sequences at MAPK12 promoter implied the functional probability to reverse tumorigenesis, though the formation of G-Quadruplex (G4) structures at MAPK12 promoter is elusive. Here, we identified two evolutionary consensus adjacent G4 motifs upstream of the MAPK12 promoter, forming parallel G4 structures. They exist in an equilibria between G4 and duplex, regulated by the binding turnover of Sp1 and Nucleolin that bind to these G4 motifs and regulate MAPK12 transcriptional homeostasis. To underscore the gene-regulatory functions of G4 motifs, we employed CRISPR-Cas9 system to eliminate G4s from TNBC cells and synthesized a naphthalene diimide (NDI) derivative (TGS24) which shows high-affinity binding to MAPK12-G4 and inhibits MAPK12 transcription. Deletion of G4 motifs and NDI compound interfere with the recruitment of the transcription factors, inhibiting MAPK12 expression in cancer cells. The molecular basis of NDI-induced G4 transcriptional regulation was analysed by RNA-seq analyses, which revealed that MAPK12-G4 inhibits oncogenic RAS transformation and trans-activation of NANOG. MAPK12-G4 also reduces CD44High/CD24Low population in TNBC cells and downregulates internal stem cell markers, arresting the stemness properties of cancer cells.

A simple approach for improving the photovoltaic efficiency of organic solar cells through polymer modification via anion exchange as the interlayer

A simple anion exchange was used to synthesize polyelectrolytes based on naphthalene diimide (NDI), which were then applied as a cathode interlayer in organic solar cells (OSCs). These polyelectrolytes can be dissolved in alcohols and produce a beneficial interface dipole due to the ionic functionality in the side chain. The PCE of the OSC utilizing PFN-NDI-OH as the cathode interlayer showed an enhancement compared to the pristine ZnO-based device, increasing from 8.79 % to 8.91 %. This improvement can be attributed to the polar nature of PFN-NDI-OH, which facilitates a strong adhesion between the inorganic metal oxide and the organic active layer. The device with PFN-NDI-OTs exhibited an enhanced PCE of up to 9.41 % due to the size of the counteranion was found to be related to the PCE, as converting the hydroxide to a tosylate anion increased the PCE, with the larger size of the tosylate anion playing a role in enhancing the Jsc. These results indicate that these polyelectrolytes are a promising candidate for use as a cathode interlayer in OSCs, with the additional advantage of being able to improve interfacial properties through a simple anion exchange process without time-consuming purification steps.

Highly solvent-dependent naphthalene diimide-based fluorescent polymer sensors for detecting p-xylene

P-xylene (PX), as one of xylenes, is a kind of very important chemical raw material. It is generally fabricated using methanol (MeOH) and toluene (TOL), and serves as a useful intermediary. However, it is difficult to use a simple and convenient tool to distinguish it from TOL and MeOH. Herein, we reported a simple naphthalene diimide-based polycaprolactone polymer (NDI-PCL) as a high-sensitive fluorescent sensor for xylene detection from MeOH and TOL. NDI-PCL was synthesized via ring-opening polymerization (ROP) of ε-caprolactone. NDI-PCL showed a remarkable fluorescence change from blue to green and yellow because of the formation of charge transfer (CT) interaction between naphthalene diimide (NDI) and aromatic solvents. NDI-PCL was successfully applied as the high-sensitive sensor for discriminating binary solvent mixtures such as PX in TOL, MeOH in PX, and MeOH in TOL, and their limit of detection (LOD) were as low as 19 ppm, 16 ppm and 9 ppm. These excellent fluorescence properties ensured that NDI-PCL indicated great potential application in detecting aromatic solvents.

Naphthalene Diimide-Tetraazacycloalkane Conjugates Are G-Quadruplex-Based HIV-1 Inhibitors with a Dual Mode of Action.

Human immunodeficiency virus 1 (HIV-1) therapeutic regimens consist of three or more drugs targeting different steps of the viral life cycle to limit the emergence of viral resistance. In line with the multitargeting strategy, here we conjugated a naphthalene diimide (NDI) moiety with a tetraazacycloalkane to obtain novel naphthalene diimide (NDI)-tetraazacycloalkane conjugates. The NDI inhibits the HIV-1 promoter activity by binding to LTR G-quadruplexes, and the tetraazacycloalkane mimics AMD3100, which blocks HIV entry into cells by interfering with the CXCR4 coreceptor. We synthesized, purified, and tested the metal-free NDI-tetraazacycloalkane conjugate and the two derived metal-organic complexes (MOCs) that incorporate Cu2+ and Zn2+. The NDI-MOCs showed enhanced binding to LTR G4s as assessed by FRET and CD assays in vitro. They also showed enhanced activity in cells where they dose-dependently reduced LTR promoter activity and inhibited viral entry only of the HIV-1 strain that exploited the CXCR4 coreceptor. The time of addition assay confirmed the dual targeting at the different HIV-1 steps. Our results indicate that the NDI-MOC conjugates can simultaneously inhibit viral entry, by targeting the CXCR4 coreceptor, and LTR promoter activity, by stabilizing the LTR G-quadruplexes. The approach of combining multiple targets in a single compound may streamline treatment regimens and improve the overall patient outcomes.

Theoretical elucidation of the effect of the linkage and orientation of carbazole and naphthalenediimide on the TADF and RTP propensities.

Thermally activated delayed fluorescence (TADF) and room temperature phosphorescence (RTP) are most promising processes for harvesting triplet excitons in organic light-emitting diodes. In this work, the effect of the linkage between the carbazole (Cz) donor (D) and the naphthalenediimide (NDI) acceptor (A) on the TADF and RTP propensities is elucidated using density functional theory computations employing D-A, D-A-D, D-π-A, and D-π-A-π-D structural designs. The effects of the dihedral angle between the donor and acceptor units on the energy difference between the singlet and triplet excited states (ΔEST), the spin-orbit coupling (SOC) constants, and radiative (kr), intersystem crossing (kISC) and reverse intersystem crossing (kRISC) rates are unravelled. The molecules possessing a direct linkage between Cz and NDI exhibit large ΔEST values due to substantial overlap between the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO). However, the insertion of a phenyl spacer between the Cz and NDI units led to disjoint HOMO and LUMO and consequently resulted in a small ΔEST. Furthermore, the presence of two donors with and without a phenyl spacer on NDI resulted in a high-lying triplet state (T2) that is energetically lower than the lowest singlet excited state (S1), hence providing additional channels to the TADF and RTP processes. Also, the orientation of Cz and NDI in the ortho-positions of the phenyl unit resulted in a T1 state with dominant LE character which led to moderate spin-orbit coupling constants and highest kr rates compared to the analogous meta- and para-linked derivatives. Thus, the ortho-derivatives possessed small ΔEST, charge transfer dominated S1, joint holes and electrons for the T1 state, characteristic of local excitation, high SOC, and promising rISC and kr rates. Overall, the phenyl linked derivatives possess TADF characteristics, while the directly linked analogues show RTP propensity.

Real-time capture of nuclear motions influencing photoinduced electron transfer.

Although vibronic coupling phenomena have been recognized in the excite state dynamics of transition metal complexes, its impact on photoinduced electron transfer (PET) remains largely unexplored. This study investigates coherent wavepacket (CWP) dynamics during PET processes in a covalently linked electron donor-acceptor complex featuring a cyclometalated Pt(ii) dimer as the donor and naphthalene diimide (NDI) as the acceptors. Upon photoexciting the Pt(ii) dimer electron donor, ultrafast broadband transient absorption spectroscopy revealed direct modulation of NDI radical anion formation through certain CWP motions and correlated temporal evolutions of the amplitudes for these CWPs with the NDI radical anion formation. These results provide clear evidence that the CWP motions are the vibronic coherences coupled to the PET reaction coordinates. Normal mode analysis identified that the CWP motions originate from vibrational modes associated with the dihedral angles and bond lengths between the planes of the cyclometalating ligand and the NDI, the key modes altering their π-interaction, consequently influencing PET dynamics. The findings highlight the pivotal role of vibrations in shaping the favorable trajectories for the efficient PET processes.

Realizing one-step two-electron transfer of naphthalene diimides via a regional charge buffering strategy for aqueous organic redox flow batteries.

Naphthalene diimide derivatives show great potential for application in neutral aqueous organic redox flow batteries (AORFBs) due to their highly conjugated molecular structure and stable two-electron storage capacity. However, the two-electron redox process of naphthalene diimides typically occurs via two separate steps with the transfer of one electron per step ("two-step two-electron" transfer process), which leads to an inevitable loss of voltage and energy. Herein, we report a novel regional charge buffering strategy that utilizes the core-substituted electron-donating group to adjust the redox properties of naphthalene diimides, realizing two electron transfer via a single-step redox process ("one-step two-electron" transfer process). The symmetrical battery testing of NDI-DEtOH revealed exceptional intrinsic stability lasting for 11 days with a daily decay rate of only 0.11%. Meanwhile, AORFBs with NDI-DMe/FcNCl and NDI-DEtOH/FcNCl exhibited a remarkable 40% improvement in peak power density at 50% state of charge (SOC) in comparison to NDI/FcNCl-based AORFBs. In addition, the battery's energy efficiency has increased by 24%, resulting in much more stable output power and significantly improved energy efficiency. These results are of great significance to practical applications of AORFBs.

Enhancement of the charge-generation efficiency for a naphthalene diimide-based polymer semiconductor by using a pyrene-substituted n-dopant

A new n-type dopant featuring a pyrene unit was developed, which shows better charge-generation efficiency for a naphthalene diimide (NDI)-based conjugated polymer than N-DMBI due to the distinctive interaction between the pyrene and the NDI units.

Unravelling the intramolecular n → σ* interaction in ultra-electron deficient naphthalenediimides and their radical ions.

In this work, the role of non-covalent n → σ* intramolecular interactions in bestowing stabilization to exceptionally low-lying LUMO molecules of Naphthalenediimides (NDI) and their radical ions have been investigated utilizing different electronic structure calculation methods at the DFT level of theory and X-ray crystallography. We compared the effect of electron donating groups (EDGs) and electron-withdrawing groups (EWGs), e.g., OMe and F, respectively, at the para-positon of the phenylphosphonium groups integrated at the 2,6-positions of the NDI scaffold on the intramolecular P-O interactions and the evolving electronic effects. The natural bond orbital (NBO) analysis exhibited strong charge transfer from the imide O atoms of the NDI to the phosphorus atom of the phosphonium groups validating a donor-acceptor type of orbital interaction. Atoms in molecule (AIM) analysis also illustrated the strong P-O interaction, as the charge density, ρ(r), and the Laplacian of the density ∇2ρ(rb) at BCP is within the range of well-known non-covalent interactions. These calculations also revealed long-range electronic communication between the EDGs/EWGs at the phenyl groups and the NDI scaffold.

Syntheses, structures and magnetic properties of three dinuclear, one-dimensional and two-dimensional dysprosium(iii) complexes based on naphthalene diimide salicylic acid

Three new dysprosium(iii) complexes with dinuclear, one-dimensional chain and two-dimensional network structures were synthesized and characterized.

Non-contact computer vision enables analysis of the dynamic performance of naphthalene diimide electrochromic films

Non-contact multi modal analysis of naphthalene diimide chromic films using Kineticolor computer vision software.

Synthesis of luminescent naphthalene diimide based nano Co/Zn organic frameworks: Cell imaging, sensing studies of explosive compound and pesticide

The solvothermal reaction of cobalt nitrate/zinc nitrate with 2,7-di(4H-1,2,4-triazol-4-yl)benzo[lmn]-[3,8]phenanthroline-1,3,6,8(2H,7H)-tetraone (L1) ligand and 1,3,5-tricarboxylic acid (TCA)/5-sulphoisophthalic acid (5-SIA) resulted in the formation of Co(II)/Zn(II) organic frameworks. The synthesised MOFs were structurally characterised by single crystal X-ray diffraction studies including IR and NMR techniques. The approximate particle size of the MOFs was calculated by Debye-Scherrer formula using the powder X-ray diffraction (PXRD) technique, which came out to be 40 nm for Co-MOF and 62 nm for Zn-MOF. The particle size encouraged us to investigate these as imaging probes for human colon cancer cell line (HCT-15). Cytotoxicity assay studies show that the MOFs are non-toxic to the cells and show good cellular internalisation. The emission properties of MOFs were further utilised for the sensing of 2,6-dichloro-4-nitroaniline (DCN) and 2,4,6-trinitophenol (TNP) as sensitive and selective detection of pesticide DCN and explosive TNP. Co/Zn-MOFs show good quenching response to the analytes with low limit of detection (LOD). The quenching efficiency of Zn-MOF is more than that of Co-MOF which may be attributed to the interaction of co-ligands with the analyte. The quenching mechanism was further encountered and it was found out that electron and energy transfer is responsible for the quenching of emission of the MOFs. The LUMO and HOMO energy levels were evaluated by density function theory (DFT) calculations.

Novel Polyelectrolytes Based on Naphthalene Diimide with Different Counteranions for Cathode Interlayers in Polymer Solar Cells.

We synthesized novel polyelectrolytes based on naphthalene diimide with quaternary amine featuring hydroxyl groups at the side chain, along with different counteranions (PF-NDIN-Br-OH and PF-NDIN-I-OH) for polymer solar cell (PSC) application as the interlayer. The polyelectrolytes establish a beneficial interface dipole through the ionic moieties and synergistic effects arising from the hydroxyl groups located at the side chain. Incorporating polyelectrolytes as the cathode interlayer resulted in an enhancement of the power conversion efficiency (PCE). The PCE of the device with PF-NDIN-Br-OH increased from 8.96% to 9.51% compared to the ZnO-only device. The best PCE was obtained with the device based on PF-NDIN-I-OH, up to 9.59% resulting from the Jsc enhancement. This outcome implies a correlation between the performance of the device and the synergistic effects observed in polyelectrolytes containing hydroxyl groups in the side chain, along with larger anions when employed in PSCs.

Effect of the charge-separated state on the 3MLCT state: Synthesis and study of the photophysics of electron donor-acceptor dyads based on Pt(II)-Schiff base coordination framework and naphthalenediimide chromophore

We prepared Pt(II)-Salen Schiff base complexes with a naphthalenediimide (NDI) unit attached on the coordination framework, to study the intersystem crossing (ISC), the charge separation, and the possible formation of a long-lived triplet charge separated (CS) state. The Pt(II)-Schiff base coordination framework acts as electron donor and it shows ultrafast ISC (<1 ps) and small Stokes shift. NDI acts as electron acceptor. The two units are attached either via a phenyl linker (Pt-NDI) or phenyl ethynyl linker (Pt-CC-NDI). Negligible electronic interaction between the Pt(II)-Schiff base coordination framework and the NDI unit at ground state was observed for both dyads, whereas the phosphorescence of the Pt(II)-Schiff base coordinated framework was quenched to large extent in the dyads, as compared to the reference complexes containing no NDI unit, especially in polar solvents. Electrochemical and optical spectral data show that the CS state energy is 1.93 eV, 1.82 eV, 1.54 eV, 1.43 eV in n-hexane (HEX), toluene (TOL), tetrahydrofuran (THF), acetonitrile (ACN), respectively. In comparison, the 3MLCT state and 3NDI state energy are 1.97 and 2.04 eV, respectively. Nanosecond transient absorption spectra show the formation of the 3MLCT state for Pt-CC-NDI, whose lifetimes is shortened in polar solvents (τT = 3.5 µs, 2.1 µs, 22 ns, and 19 ns in HEX, TOL, THF and ACN, respectively), similar trend was observed for Pt-NDI. Femtosecond transient absorption spectra show that the charge separation takes less than 1 ps both in toluene and acetonitrile. Quenching of the otherwise long-lived triplet excited state (3.5 µs) by a short lived CS state may be developed as a photo-protection mechanism similar to that found in natural photosynthetic apparatus.

Symmetry breaking charge transfer behaviour in D-A-D triad system by selective excitation

Multichromophoric D-A-D triads synthesized using perylenediimde (PDI) bonded with naphthalenediimide (NDI) units via aliphatic (Triad 1) or aromatic (Triad 2) linker is studied for symmetry breaking charge separation (SB-CS) by selective excitation of the NDI/PDI chromophores. NDI chromophore on excitation transfers electron to PDI chromophore and type of linker played crucial role in stability of generated CS state. Photoluminescence, time resolved fluorescense and transient absorption spectroscopy tools have been used to study the phenomenon. The optical as well as electrochemical study confirmed intramolecular electron transfer from NDI to PDI chromophore. Stable SB-CS state formation is directly resulted in increased open circuit voltage (Voc) of Triad 2 based organic solar cell devices. The selective excitation of chromophoric center and SB-CS in D-A-D type triad is the demand of present electronic device for the formation of long lived charge carrier.

Elucidating Oxygen Reduction Mechanisms on Organic Mixed Ionic-Electronic Conducting Polymers

Atmospheric oxygen is an attractive oxidant for the generation of electricity from chemical fuels and for the electrochemical production of hydrogen peroxide. Although not universal, it is generally assumed that an electrocatalyst is needed to reduce oxygen. Recently, a variety of organic mixed ionic-electronic conducting polymers (OMIECs) have been reported to exhibit catalytic behavior for both the 4-electron/4-proton and the 2-electron/2-proton oxygen reduction reaction (ORR).This work sets out to identify the oxygen reduction mechanism of OMIECs through a multi-faceted experimental and theoretical approach. We primarily focus our efforts on p(NDI-T2 P75)—a random copolymer comprised of naphthalene diimide (NDI) and bithiophene (T2) units with 75% polar sidechains—and then expand the understanding built on this system to a range of other OMIECs. Using rotating ring disk electrochemistry, we find that the investigated OMIECs exhibit a high selectivity towards the 2-electron ORR product. Using operando UV-Vis and Raman spectroscopy measurements, we identify changes in OMIEC performance when in the presence of O2. To gain further insights about the catalytic reaction path, we construct and test a microkinetic model. Through this model, we show that the performance of the tested OMIECs can be rationalized through an EC’D reaction mechanism. Our results suggest that these materials do not operate as electrocatalysts for the initial reduction of oxygen to superoxide but do function as catalysts for the disproportionation of superoxide.

Synthesis and Characterization of Two Novel Naphthalenediimide/Zinc Phosphonate Crystalline Materials Precipitated from Different Solvents.

Hybrid naphthalenediimide/zinc phosphonate materials (NDI/Zn) were prepared by mixing solutions of N,N'-bis(2-phosphonoethyl)-1,4,5,8-naphthalenediimide (PNDI) and zinc nitrate, resulting in the precipitation of the desired compounds. Samples precipitated from water and N,N-dimethylformamide (DMF) were produced. The obtained samples had the expected elemental composition, and the presence of naphthalenediimides (NDI) was ascertained by infrared and UV-visible spectroscopy. All the samples were crystalline, according to powder X-ray diffraction. Nitrogen adsorption isotherms showed the presence of porosity in the NDI/Zn samples. Mesopores with a diameter = 4.1 nm were present in the sample from DMF, with total pore volume reaching 0.13 cm3/g.