Sustained activation of non-canonical NF-κB signalling drives glycolytic reprogramming in doxorubicin-resistant DLBCL.

DLBCL is the most common lymphoma with high tumor heterogeneity. Treatment refractoriness and relapse from R-CHOP therapy in patients remain a clinical problem. Activation of the non-canonical NF-κB pathway is associated with R-CHOP resistance. However, downstream targets of non-canonical NF-κB mediating R-CHOP-induced resistance remains uncharacterized. Here, we identify the common mechanisms underlying both intrinsic and acquired resistance that are induced by doxorubicin, the main cytotoxic component of R-CHOP. We performed global transcriptomic analysis of (1) a panel of resistant versus sensitive and (2) isogenic acquired doxorubicin-resistant DLBCL cell lines following short and chronic exposure to doxorubicin respectively. Doxorubicin-induced stress in resistant cells activates a distinct transcriptional signature that is enriched in metabolic reprogramming and oncogenic signalling. Selective and sustained activation of non-canonical NF-κB signalling in these resistant cells exacerbated their survival by augmenting glycolysis. In response to doxorubicin, p52-RelB complexes transcriptionally activated multiple glycolytic regulators with prognostic significance through increased recruitment at their gene promoters. Targeting p52-RelB and their targets in resistant cells increased doxorubicin sensitivity in vitro and in vivo. Collectively, our study uncovered novel molecular drivers of doxorubicin-induced resistance that are regulated by non-canonical NF-κB pathway. We reveal new avenues of therapeutic targeting for R-CHOP-treated refractory/relapsed DLBCL patients.

Fully Bridged Triphenylamine Derivatives as Color-Tunable Thermally Activated Delayed Fluorescence Emitters.

Three emissive bridged-triphenylamine derivatives are designed and synthesized by incorporating carbon (DQAO), oxygen (OQAO), and sulfur (SQAO) atoms with two carbonyl groups. The fully bridged geometry and unique frontier molecular orbital distribution reveal its potential as narrowband thermally activated delayed fluorescence emitters. DQAO-, OQAO-, and SQAO-based organic light-emitting diodes exhibit the maximum external quantum efficiency (EQEmax) of 15.2%, 20.3%, and 17.8% for blue, green, and yellow, respectively.

Circularly Polarized Thermally Activated Delayed Fluorescence Emitters in Through-Space Charge Transfer on Asymmetric Spiro Skeletons.

This work describes a strategy to produce circularly polarized thermally activated delayed fluorescence (CP-TADF). A set of two structurally similar organic emitters SFST and SFOT are constructed, whose spiro architectures containing asymmetric donors result in chirality. Upon grafting within the spiro frameworks, the donor and acceptor are fixed proximally in a face-to-face manner. This orientation allows intramolecular through-space charge transfer (TSCT) to occur in both emitters, leading to TADF properties. The donor units in SFST and SFOT have a sulfur and oxygen atom, respectively; such a subtle difference has great impacts on their photophysical, chiroptical, and electroluminescence (EL) properties. SFOT exhibits greatly enhanced EL performance in doped organic light-emitting diodes, with external quantum efficiency (EQE) up to 23.1%, owing to the concurrent manipulation of highly photoluminescent quantum efficiency (PLQY, ∼90%) and high exciton utilization. As a comparison, the relatively larger sulfur atom in SFST introduces heavy atom effects and leads to distortion of the molecular backbone that lengthens the donor-acceptor distance. SFST thus has lower PLQY and faster nonradiative decay rate. The collective consequence is that the EQE value of SFST, i.e., 12.5%, is much lower than that of SFOT. The chirality of these two spiro emitters results in circularly polarized luminescence. Because SFST has a more distorted molecular architecture than SFOT, the luminescence dissymmetry factor (|glum|) of circularly polarized luminescence of one enantiomer of the former, namely, either (S)-SFST or (R)-SFST, is almost twice that of (S)-SFOT/(R)-SFOT. Moreover, the CP organic light-emitting diodes (CP-OLEDs) show obvious circularly polarized electroluminescence (CPEL) signals with gEL of 1.30 × 10-3 and 1.0 × 10-3 for (S)-SFST and (S)-SFOT, respectively.

Highly Efficient Thermally Activated Delayed Fluorescence via an Unconjugated Donor-Acceptor System Realizing EQE of Over 30.

In this work, two novel thermally activated delayed fluorescence (TADF) emitters, 2tDMG and 3tDMG, are synthesized for high-efficiency organic light-emitting diodes (OLEDs), The two emitters have a tilted face-to-face alignment of donor (D)/acceptor (A) units presenting intramolecular noncovalent interactions. The two TADF materials are deposited either by an evaporation-process or by a solution-process, both of them leading to high OLED performance. 2tDMG used as the emitter in evaporation-processed OLEDs achieves a high external quantum efficiency (EQE) of 30.8% with a very flat efficiency roll-off of 7% at 1000 cd m-2 . The solution-processed OLEDs also display an interesting EQE of 16.2%. 3tDMG shows improved solubility and solution processability as compared to 2tDMG, and thus a high EQE of 20.2% in solution-processed OLEDs is recorded. The corresponding evaporation-processed OLEDs also reach a reasonably high EQE of 26.3%. Encouragingly, this work provides a novel strategy to address the imperious demands for OLEDs with high EQE and low roll-off.

Near-Infrared Electroluminescence beyond 800†nm with High Efficiency and Radiance from Anthracene Cored Emitters.

Derivatives based on anthryleno[1,2-b]pyrazine-2,3-dicarbonitrile (DCPA) are used as luminescent materials, to realize near-infrared (NIR) electroluminescence. By functionalizing DCPA with aromatic amine donors, two emitters named DCPA-TPA and DCPA-BBPA are designed and synthesized. Both molecules have large dipole moments owing to the strong intramolecular charge transfer interactions between the amine donors and the DCPA acceptor. Thus, compared with doped films, the emission of neat films of DCPA-TPA and DCPA-BBPA can fully fall into the NIR region (>700 nm) with increasing surrounding polarity by increasing doping ratio. Moreover, the non-doped devices based on DCPA-TPA and DCPA-BBPA provide NIR emission with peaks at 838 and 916 nm, respectively. A maximum radiance of 20707 mW Sr-1 m-2 was realized for the further optimized device based on DCPA-TPA. This work provides a simple and efficient strategy of molecular design for developing NIR emitting materials.

Synthesis, anionophoric activity and apoptosis-inducing bioactivity of benzimidazolyl-based transmembrane anion transporters.

In this paper we show that a series of 1,3-bis(benzimidazol-2-yl)benzene (m-Bimbe) derivatives exhibit excellent performance as transmembrane anion transporters with anticancer activity. The transport efficiency of m-Bimbe and its derivatives has been firstly optimized by adding a strong electron-withdrawing nitro group at the 5-position of the central phenyl subunits to enhance the CH···anion interactions. Evidences for the interactions were obtained from ESI MS, spectrophotometric and 1H NMR titrations. These compounds exhibit potent anionophoric activity in both liposomal models and live cells. In particular, the 5-nitrated derivatives having nitro or trifluoromethyl groups at the benzimidazoloyl subunits exhibit 2370- and 1721-fold enhanced anionophoric activity with the EC50 values as low as 36 and 50 nM, respectively. These compounds can disturb the cellular homeostasis of chloride anions, modify the intracellular pH and induce the basification of acidic organelles. Most of this series of m-Bimbe derivatives exhibit potent cytotoxicity toward the tested human solid tumor cell lines, and the 5-nitrated derivative bearing trifluoromethyl groups at the benzimidazoloyl subunits is the most active with the IC50 value in the low micromolar range. Mechanistic studies suggest that the transport of chloride anions across the cellular membranes plays a critical role in the cytotoxic effect and these compounds induce cell death probably via an apoptotic process.

Highly efficient anion transport mediated by 1,3-bis(benzimidazol-2-yl)benzene derivatives bearing electron-withdrawing substituents.

1,3-Bis(benzimidazol-2-yl)benzene exhibits potent anionophoric activity through a process of anion exchange with a minor level of proton/anion symport. Modification of 1,3-bis(benzimidazol-2-yl)benzene with strong electron-withdrawing substituents, such as trifluoromethyl and nitro groups, leads to up to 789-fold increase in the activity. The benzimidazolyl-NH fragments, the relative position and the number of the benzimidazolyl groups on the central phenyl scaffold play an essential role in the transport.

2,6-Bis(benzimidazol-2-yl)pyridine as a potent transmembrane anion transporter.

2,6-Bis(benzimidazol-2-yl)pyridine was shown to exhibit potent anionophoric activity via a process of both Cl(-)/NO3(-) antiport and H(+)/Cl(-) symport. This is in sharp contrast to the finding that its corresponding N-methylated analog exhibited negligible activity and reveals the importance of the imidazolyl-NH fragments in the anion-transport process.