Cardiotoxicity, especially human ether-a-go-go-related gene (hERG)-related toxicity, is a leading cause of drug failure or market withdrawal. Reducing hERG binding to obviate potential cardiac toxicity is crucial. Nanotechnology has been applied to drug delivery for reducing drug toxicity and improving efficacy, but few studies have addressed hERG-related cardiotoxicity. We report the use of self-assembling dendrimer nanosystems for drug formulation and delivery, which effectively reduced hERG binding and associated toxicity while promoting therapeutic efficacy. Specifically, these dendrimer nanosystems efficiently encapsulated the antimalarial drug chloroquine, the anticancer agent doxorubicin, and the NUPR1 inhibitor ZZW115, all three having high affinity to hERG channels. These nanoformulations showed three- to eightfold reduced hERG binding affinity, which, in animal models, translated to abolished toxicity. These nanodrugs exhibited prolonged circulation, leading to enhanced accumulation at disease sites and improved treatment outcomes. This study highlights the potential of nanotechnology to reduce hERG binding and related toxicity while improving drug efficacy, offering valuable perspectives for drug development.

Targeting glial cells in the brain constitutes a formidable challenge due to the presence of the blood-brain barrier (BBB) and the difficulty in achieving specific targeting. Intranasal (IN) administration offers a promising solution to bypass the BBB for delivery directly to the brain, while nanotechnology-based delivery provides tailored targeting capabilities. Here, we report dendrimer-based nanosystems developed for IN administration to target astrocytes and microglia, two types of glial cells that play important roles in maintaining brain homeostasis. Specifically, we demonstrate that bola-amphiphilic glycodendrimers, Ia and Ib, which bear glucose and mannose terminals, respectively, target astrocytes and microglia in the mouse brain. These two glycodendrimers, composed of a hydrophobic bola-lipid in the middle connected with two hydrophilic poly(amidoamine) dendrons, were effectively synthesized via a click reaction using unprotected carbohydrate building units, and self-assembled into small and spherical nanoparticles by virtue of their amphiphilicity. In a mouse model, both dendrimer nanoparticles successfully reached the brain following IN administration, where the glucose-dendrimer Ia selectively targeted astrocytes and the mannose-dendrimer Ib targeted microglia. These findings highlight the potential of glycodendrimer-based nanosystems for precise targeting in the brain and offer a promising perspective for treating central nervous system (CNS) diseases.

Accurately predicting lattice thermal conductivity (kL) from first principles remains a challenge in identifying materials with extreme thermal behavior. While modern lattice dynamics methods enable routine predictions of kL within the harmonic approximation and three-phonon scattering framework (HA+3ph), reliable results, especially for low-kL compounds, require higher-order anharmonic effects, including self-consistent phonon renormalization, four-phonon scattering, and off-diagonal heat flux (SCPH+3,4ph+OD). We present a high-throughput workflow integrating these effects into a unified framework. Using this, we compute kL for 773 cubic and tetragonal inorganic compounds across diverse chemistries and structures. From 562 dynamically stable compounds, we assess the hierarchical effects of higher-order anharmonicity. For about 60

Drug resistance remains a major obstacle in treating pancreatic ductal adenocarcinoma (PDAC). Nuclear protein 1 (NUPR1), a stress-responsive protein implicated in cancer progression and treatment resistance, represents a potential therapeutic target. Our laboratory has developed NUPR1 inhibitors such as ZZW-115. In this study, we established a ZZW-115 resistance model in MiaPaCa-2 cells by applying repeated cycles of drug exposure and recovery, leading to a subpopulation (Resistant(+) MiaPaCa-2 cells) with increased expression of NUPR1. These cells exhibit various adaptations, including increased mitochondrial activity, maintenance of redox homeostasis, and enhanced tolerance to genotoxic damage. Although partial reversion of resistance was observed upon drug withdrawal, several molecular changes persisted. Transcriptomic analysis revealed upregulation of stress response and survival pathways (p53, UPR) and downregulation of proliferative and metabolic programs, suggesting a “reinforced survival” phenotype. NUPR1 overexpression appears to contribute to the resistance process by enhancing cellular defenses against ZZW-115. These findings suggest that targeting NUPR1 signaling and associated metabolic rewiring could help overcome drug resistance. The resistance model presented may serve as a useful tool to explore combination strategies for improving therapeutic outcomes in PDAC.

Over the past 25 years, the pivotal functions of the nuclear protein 1, NUPR1, have been described. NUPR1 is an intrinsically disordered stress protein whose expression is markedly upregulated under adverse conditions and in various cancers, particularly pancreatic ductal adenocarcinoma (PDAC). NUPR1 is essential for cellular survival by orchestrating responses to both extrinsic and intrinsic stressors, including oncogenic stress driven by mutations such as KRASG12D. Indeed, genetic studies have shown that inactivating NUPR1 effectively halts tumor growth, underscoring its promise as a therapeutic target. Applying a multidisciplinary approach, we identified the trifluoperazine-derived compound ZZW-115 with a remarkable efficacy. Treatment with ZZW-115 induces a mitochondrial catastrophe characterized by a mitochondrial hyperPARylation, with a shift in the utilization of glucose to glycolysis instead of oxidative phosphorylation (OXPHOS), which together with the Warburg effect, culminate in cellular glucose and energy collapse. This mitochondrial dysfunction triggers several cell death pathways, including apoptosis, necroptosis, and ferroptosis. In vivo studies have validated the antitumoral efficacy of ZZW-115, reinforcing its potential as a novel therapeutic strategy for cancers cells. The inactivation of NUPR1 via ZZW-115 represents an innovative therapeutic strategy by exploiting specific vulnerabilities in tumor cells. By inducing severe mitochondrial dysfunction and disrupting energy metabolism, this approach selectively eliminates cancer cells, opening new avenues for the treatment of aggressive tumors resistant to conventional therapies.

Pancreatic cancer is highly lethal and has limited treatment options available. Our team had previously developed ZZW-115, a promising drug candidate that targets the nuclear protein 1 (NUPR1), which is involved in pancreatic cancer development and progression. However, clinical translation of ZZW-115 was hindered due to potential cardiotoxicity caused by its interaction with the human Ether-à-go-go-Related Gene (hERG) potassium channel. To address this, we have performed a high-throughput screening of 10,000 compounds from the HitFinder Chemical Library, and identified AJO14 as a lead compound that binds to NUPR1, without having favorable affinity towards hERG. AJO14 induced cell death through apoptosis, necroptosis, and parthanatos (induced by the poly-ADP ribose polymerase (PARP) overactivation), driven by mitochondrial catastrophe and decreased ATP production. This process seemed to be mediated by the hyperPARylation (an excessive modification of proteins by PARP, leading to cellular dysfunction), as it could be reversed by Olaparib, a PARP inhibitor. In xenografted mice, AJO14 demonstrated a dose-dependent tumor reduction activity. Furthermore, we attempted to improve the anti-cancer properties of AJO14 by molecular modification of the lead compound. Among the 51 candidates obtained and tested, 8 compounds exhibited a significant increase in efficacy and have been retained for further studies, especially LZX-2-73. These AJO14-derived compounds offer potent NUPR1 inhibition for pancreatic cancer treatment, without cardiotoxicity concerns.

Six Zn(II)/Cd(II) coordination polymers (CPs), namely, {[Zn2(bimphtpy)(p-bdc)1.5(OH)].(H2O)0.5}n (1), [Zn2(bimphtpy)2(tdc)2]n (2), {[Zn(bimphtpy)(cpoa)].4H2O}n (3), [Cd2(bimphtpy)(p-bdc)2(H2O)]n (4), {[Cd2(bimphtpy)(m-bdc)2(H2O)2].(H2O)0.75}n (5), and {[Cd(bimphtpy)(qda)].H2O}n (6), constructed from Nheterocyclic ligand 4'-(4-(benzimidazol-1-yl)phenyl)-4,2':6',4"-terpyridine (bimphtpy) and five dicarboxylic acids, (p-H2bdc = 1,4-benzenedicarboxylic acid, H2tdc = 2,5-thiophenedicarboxylic acid, H2cpoa =4-carboxyphenoxyacetatic acid, m-H2bdc = 1,3-benzenedicarboxylic acid, H2qda = hydroquinone-o,o'-diacetic acid), have been solvothermally synthesized and structurally characterized mainly by single-crystal X-ray diffraction along with elemental analysis, IR spectroscopy, PXRD and TG analysis. Complex 1 exhibits a 2D + 2D -* 3D polycatenated framework with bilayers showing the uninodal 5-c (4,4)Ia topology if Zn2(CO2)(OH) SBU (secondary building unit) are considered. Complex 2 reveals a 2D -* 2D polycatenane of two-fold interpenetrated network with rods threading loops showing 63-hcb topology. Complex 3 presents a highly undulated 2D 44-sql sheet with thickness of about 18.5 & Aring;. Complex 4 displays a single 3D network constructed by binuclear Cd2(CO2)4O2 SBU showing the uninodal 6-c pcu topology. Complex 5 features a 2D + 2D -* 3D polycatenated framework showing an unidentified topology with point symbol of {42.6.72.9}{42.6}{6.72}{64.8.10}. Complex 6 shows a single 3D network constructed by binuclear Cd2O4C2 SBU with 8-c cds topology. Moreover, the fluorescent properties of complexes 1-6 in the solid state at room temperature as well as the adsorption properties of complex 3 are also investigated, suggesting their potential applications as luminescence materials and gas adsorption selectivity materials.

The first iron‐catalyzed oxophosphorylation of styrene derivatives with dialkyl H‐phosphonates under open air conditions is developed, which generates a range of previously underexplored α ‐substituted β ‐ketophosphonates in 55~70% yields. Furthermore, a convenient one‐pot procedure by direct conversion of styrenes to α , β ‐unsaturated ketones is also developed based on the new catalytic reactions, thus offering a protocol to access two classes of valuable products from simple starting materials.

Molecular complexity plays an increasingly important role in the modern pharmaceutical industry. Setting up multiple stereogenic centers in privileged substructures may give rise to improved or even unprecedented bioactivities; however, this area remains largely unexplored due to the tremendous synthetic challenges. Herein, we report a series of multisubstituted pyrrolidines with four continuous stereogenic centers, including up to two aza-QSCs (quaternary stereogenic centers). Systematic evaluations, including phenotypic screening, molecular docking, molecular dynamics, bioinformatics, and bioactivity analysis, have been performed to screen entities with pharmacological properties of interest. Among them, compound 4m with two QSCs was identified to be a potent antiproliferation agent through disturbing mitosis exit, and the presence of QSCs was found to be crucial for anticancer efficacy. This work illustrates that the introduction of QSCs in privileged scaffolds not only helps to expand the unpatented chemical space but also provides new opportunities for the discovery of novel therapeutic agents.

Breast cancer is the most frequent malignancy affecting women, yet current therapeutic strategies remain ineffective for patients with late-stage or metastatic disease. Here an effective strategy is reported for treating metastatic breast cancer. Specifically, a self-assembling dendrimer nanosystem decorated with an antibody against programmed cell death ligand 1 (PD-L1) is established for delivering a small interfering RNA (siRNA) to target 3-phosphoinositide-dependent protein kinase-1 (PDK1), a kinase involved in cancer metabolism and metastasis. This nanosystem, named PPD, is designed to target PD-L1 for cancer-specific delivery of the siRNA to inhibit PDK1 and modulate cancer metabolism while promoting programmed cell death 1 (PD-1)/PD-L1 pathway-based immunotherapy. Indeed, PPD effectively generates simultaneous inhibition of PDK1-induced glycolysis and the PD-1/PD-L1 pathway-related immune response, leading to potent inhibition of tumor growth and metastasis without any notable toxicity in tumor-bearing mouse models. Collectively, these results highlight the potential use of PPD as an effective and safe tumor-targeting therapy for breast cancer. This study constitutes a successful proof of principle exploiting the intrinsic features of the tumor microenvironment and metabolism alongside a unique self-assembling dendrimer platform to achieve specific tumor targeting and siRNA-based gene silencing in combined and precision cancer therapy.

An organocatalyzed stereoselective domino reaction as a facile approach to multicyclic spirooxindole derivatives bearing two stereogenic quaternary carbon atoms is reported. The alkyl substituted chiral thiourea catalyst was efficient for the reaction to tolerate a wide range of substrates, furnishing a new class of spirooxindole derivatives bearing an O,O-acetal-fused tricyclic skeleton or tetrahydroxanthone moiety in moderate to good yields with good to excellent selectivities. The products generated from this method have promising anticancer activities.

Tumor Targeting In article number 2305215, Ling Peng, Jing Ma, and co-workers developed a self-assembling dendrimer nanosystem decorated with an anti-PD-L1 antibody to deliver an siRNA targeting pyruvate dehydrogenase kinase 1 for simultaneously inhibiting glycolysis and immune escape, hence blocking tumor growth and metastasis. This study highlights the potential of self-assembling dendrimer platform for targeted delivery in combined and precision therapy.

An entry from the Inorganic Crystal Structure Database, the world’s repository for inorganic crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the joint CCDC and FIZ Karlsruhe Access Structures service and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

An entry from the Inorganic Crystal Structure Database, the world’s repository for inorganic crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the joint CCDC and FIZ Karlsruhe Access Structures service and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Dendrimers are appealing scaffolds for creating carbohydrate mimics with unique multivalent cooperativity. We report here novel bola-amphiphilic glycodendrimers bearing mannose and glucose terminals, and a hydrophobic thioacetal core responsive to reactive oxygen species. The peculiar bola-amphiphilic feature enabled stronger binding to lectin compared to conventional amphiphiles. In addition, these dendrimers are able to target mannose receptors and glucose transporters expressed at the surface of cells, thus allowing effective and specific cellular uptake. This highlights their great promise for targeted delivery.

Proteomic, cellular and biochemical analysis of the stress protein NUPR1 reveals that it binds to PARP1 into the nucleus and inhibits PARP1 activity in vitro. Mutations on residues Ala33 or Thr68 of NUPR1 or treatment with its inhibitor ZZW-115 inhibits this effect. PARylation induced by 5-fluorouracil (5-FU) treatment is strongly enhanced by ZZW-115 and associated with a decrease of NAD + /NADH ratio and rescued by the PARP inhibitor olaparib. Cell death induced by ZZW-115 treatment of pancreas cancer-derived cells is rescued by olaparib and improved with PARG inhibitor PDD00017273. The mitochondrial catastrophe induced by ZZW-115 treatment or by genetic inactivation of NUPR1 is associated to a hyperPARylation of the mitochondria, disorganization of the mitochondrial network, mitochondrial membrane potential decrease, and with increase of superoxide production, intracellular level of reactive oxygen species (ROS) and cytosolic levels of Ca 2+ . These features are rescued by olaparib or NAD + precursor nicotinamide mononucleotide in a dose-dependent manner and partially by antioxidants treatments. In conclusion, inactivation of NUPR1 induces a hyperPARylation, which in turn, induces a mitochondrial catastrophe and consequently a cell death through a non-canonical Parthanatos, since apoptosis inducing-factor (AIF) is not translocated out of the mitochondria.

Self-assembly is a powerful approach in molecular engineering for biomedical applications, in particular for creating self-assembling prodrugs. Here, we report a self-assembling prodrug of the anticancer drug gemcitabine (Gem) based on amphiphilic dendrimer approach. The prodrug reported in this study demonstrates high drug loading (40%) and robust ability to self-assemble into small nanomicelles, which increase the metabolic stability of Gem and enable entry into cells via endocytosis, hence bypassing transport-mediated uptake. In addition, this prodrug nanosystem exhibited an effective pH- and enzyme-responsive release of Gem, resulting in enhanced anticancer activity and reduced toxicity. Harboring advantageous features of both prodrug- and nanotechnology-based drug delivery, this self-assembling Gem prodrug nanosystem constitutes a promising anticancer candidate. This study also offers new perspectives of the amphiphilic dendrimer nanoplatforms for the development of self-assembling prodrugs.

An entry from the Inorganic Crystal Structure Database, the world’s repository for inorganic crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the joint CCDC and FIZ Karlsruhe Access Structures service and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Correction for 'Assembly of fluorinated chromanones via enantioselective tandem reaction' by Mengxue Lu et al., Chem. Commun., 2021, 57, 4722-4725, DOI: 10.1039/D1CC01187A.