Identification of the atypical antipsychotic Asenapine as a direct survivin inhibitor with anticancer properties and sensitizing effects to conventional therapies.

Therapy resistance in human cancers is a major limitation in Clinical Oncology. In this regard, overexpression of anti-apoptotic proteins, such as survivin, has been described in several tumors, contributing to this clinical issue. Survivin has a dual role in key cellular functions, inducing cell cycle progression and inhibiting apoptosis; thus, survivin is an attractive target for cancer therapy.

Synthesis of 1,10-Phenanthroline-2,9-bistriazoles: Evaluation as G-Quadruplex Binders and Anti-Tumor Activity.

Novel 1,10-phenanthroline-2,9-bistriazoles derivatives have been synthesized by copper-catalyzed azide/alkyne cycloaddition reactions and assessed for their ability to bind and stabilize G-quadruplex (G4) structures. Ten novel compounds were evaluated using Förster resonance energy transfer (FRET) melting, circular dichroism (CD), and fluorescence spectroscopy on several G4 sequences. Biophysical characterization led to the identification of compounds 4 a, 4 b, and 5 b as good G4 ligands of KRAS G4 sequences.

Deregulation of lactate permeability using a small-molecule transporter (Lactrans-1) disturbs intracellular pH and triggers cancer cell death.

Due to the relevance of lactic acidosis in cancer, several therapeutic strategies have been developed targeting its production and/or regulation. In this matter, inhibition approaches of key proteins such as lactate dehydrogenase or monocarboxylate transporters have showed promising results, however, metabolic plasticity and tumor heterogeneity limits their efficacy. In this study, we explored the anticancer potential of a new strategy based on disturbing lactate permeability independently of monocarboxylate transporters activity using a small molecule ionophore named Lactrans-1.

Harnessing unprotected deactivated amines and arylglyoxals in the Ugi reaction for the synthesis of fused complex nitrogen heterocycles.

Piperazines and diazepines are examples of nitrogen heterocycles present in many marketed drugs highlighting their importance in the discovery of novel bioactive compounds. However, their synthesis often faces challenges, including complex functionalization and lengthy reaction sequences. Multicomponent reactions, notably the Ugi reaction, have emerged as powerful tools to address these hurdles.

Small molecule anion carriers facilitate lactate transport in model liposomes and cells.

An excessive production of lactate by cancer cells fosters tumor growth and metastasis. Therefore, targeting lactate metabolism and transport offers a new therapeutic strategy against cancer, based on dependency of some cancer cells for lactate as energy fuel or as oncogenic signal. Herein we present a family of anionophores based on the structure of click-tambjamines that have proved to be extremely active lactate carriers across phospholipid membranes.

Formulation and evaluation of anion transporters in nanostructured lipid carriers.

Six novel click-tambjamines (1-6) bearing an alkyl chain of varying length linked to the imine moiety have been formulated in nanostructured lipid carriers (NLCs) to evaluate their transmembrane anion transport activity both when free (, not encapsulated) and nanoformulated. Nanostructured lipid carriers (NLCs) are an example of drug delivery systems (DDSs) that stand out because of their versatility. In this work we show that NLCs can be used to efficiently formulate highly lipophilic anionophores and experiments conducted in model liposomes reveal that these formulations are adequate to deliver anionophores without compromising their transport activity.

Anticooperative Supramolecular Oligomerization Mediated by V-Shaped Monomer Design and Unconventional Hydrogen Bonds.

After more than three decades of extensive investigations on supramolecular polymers, strategies for self-limiting growth still remain challenging. Herein, we exploit a new V-shaped monomer design to achieve anticooperatively formed oligomers with superior robustness and high luminescence. In toluene, the monomer-oligomer equilibrium is shifted to the monomer side, enabling the elucidation of the molecular packing modes and the resulting (weak) anticooperativity.

Antimetastatic Properties of Prodigiosin and the BH3-Mimetic Obatoclax (GX15-070) in Melanoma.

Metastasis is the primary cause of death in cancer patients. Many current chemotherapeutic agents only show cytotoxic, but not antimetastatic properties. This leads to a reduction in tumor size, but allows cancer cells to disseminate, which ultimately causes patient death.

Synthesis and evaluation of 2,9-disubstituted-1,10-phenanthroline derivatives as G-quadruplex binders.

G-quadruplex (G4) structures are non-canonical DNA/RNA secondary structures able to form within guanine rich nucleic acids sequences. They are present in several regions of the human genome including gene promoters, untranslated sequences, and telomeres. Due to their biological relevance G4 structures are considered important drug targets, in particular for anticancer therapies, leading to the development of G4 stabilizing small molecules.

The role of indolyl substituents in squaramide-based anionophores.

A new family of squaramide-based anionophores (L1-L8) have been synthesised and fully characterised with the aim to investigate the effect of indolyl substituents on their anion binding and transmembrane transport properties. L1, L2, L6, and L8, bearing a 7-indolyl/indol-7-yl moiety as the substituent, were found to be the most efficient of the series in binding chloride with high stability constants. L1, L6, and L8 were also found to be the most potent anionophores of the series, able to mediate transmembrane anion transport.

A Novel Late-Stage Autophagy Inhibitor That Efficiently Targets Lysosomes Inducing Potent Cytotoxic and Sensitizing Effects in Lung Cancer.

Overcoming resistance is one of the most challenging features in current anticancer therapy. Autophagy is a cellular process that confers resistance in some advanced tumors, since it enables cancer cells to adapt to stressful situations, such as anticancer treatments. Hence, the inhibition of this cytoprotective autophagy leads to tumor cells sensitization and death.

One-Pot Diastereoselective Synthesis of Pyrrolopiperazine-2,6-diones by a Ugi/Nucleophilic Substitution/N-Acylation Sequence.

The diastereoselective synthesis of two families of pyrrolopiperazine-2,6-diones is presented. These compounds were prepared by one-pot Ugi/nucleophilic substitution/N-acylation/debenzoylation/(elimination) sequences. This novel route provides straightforward access to a wide variety of pyrrolopiperazine-2,6-diones with high chemical yields and complete diastereoselectivities.

Transmembrane anion transport promoted by thioamides.

Thioamide groups represent useful hydrogen-bonding motifs for the development of active transmembrane anion transporters. Using a 1,8-di(thioamido)carbazole scaffold the superior performance of thioamides compared with the parent amides has been demonstrated.

Photocatalytic Aerobic Dehydrogenation of N-Heterocycles with Ir(III) Photosensitizers Bearing the 2(2'-Pyridyl)benzimidazole Scaffold.

Photoredox catalysis constitutes a very powerful tool in organic synthesis, due to its versatility, efficiency, and the mild conditions required by photoinduced transformations. In this paper, we present an efficient and selective photocatalytic procedure for the aerobic oxidative dehydrogenation of partially saturated N-heterocycles to afford the respective N-heteroarenes (indoles, quinolines, acridines, and quinoxalines). The protocol involves the use of new Ir(III) biscyclometalated photocatalysts of the general formula [Ir(C^N)(N^N')]Cl, where the C^N ligand is 2-(2,4-difluorophenyl)pyridinate, and N^N' are different ligands based on the 2-(2'-pyridyl)benzimidazole scaffold.

A Simulation Model for the Non-Electrogenic Uniport Carrier-Assisted Transport of Ions across Lipid Membranes.

Impressive work has been completed in recent decades on the transmembrane anion transport capability of small synthetic transporters from many different structural classes. However, very few predicting models have been proposed for the fast screening of compound libraries before spending time and resources on the laboratory bench for their synthesis. In this work, a new approach is presented which aims at describing the transport process by taking all the steps into explicit consideration, and includes all possible experiment-derived parameters.

Rational design of mitochondria targeted thiabendazole-based Ir(III) biscyclometalated complexes for a multimodal photodynamic therapy of cancer.

Despite their outstanding properties as potential photosensitizers for photodynamic therapy (PDT), Ir(III) biscyclometalated complexes need both further developments to overcome remaining limitations and in-depth investigations into their mechanisms of action to reach clinic application in the treatment of cancer. This work describes the synthesis of a family of Ir(III) complexes of general formula [Ir(C^N)(N^N')]Cl (N^N' = thiabendazole-based ligands; C^N = ppy (2-phenylpyridinate) (Series A), or dfppy (2-(2,4-difluorophenyl)pyridinate) (Series B)) and their evaluation as potential PDT agents. These complexes are partially soluble in water and exhibit cytotoxic activity in the absence of light irradiation versus several cancer cell lines.

Structure-antitumor activity relationships of tripodal imidazolium-amino acid based salts. Effect of the nature of the amino acid, amide substitution and anion.

The antitumor activity of imidazolium salts is highly dependent upon their lipophilicity that can be tuned by the introduction of different hydrophobic substituents on the nitrogen atoms of the imidazolium ring of the molecule. Taking this into consideration, we have synthesized and characterized a series of tripodal imidazolium salts derived from L-valine and L-phenylalanine containing different hydrophobic groups and tested them against four cancer cell lines at physiological and acidic pH. At acidic pH (6.

Tambjamines and Prodiginines: Biocidal Activity against .

The aim of this work was to explore new therapeutic options against Chagas disease by the in vitro analysis of the biocidal activities of several tambjamine and prodiginine derivatives, against the CLB strain (DTU TcVI). The compounds were initially screened against epimastigotes. The five more active compounds were assayed in intracellular forms.

Multi-Smart and Scalable Bioligands-Free Nanomedical Platform for Intratumorally Targeted Tambjamine Delivery, a Difficult to Administrate Highly Cytotoxic Drug.

Cancer is one of the leading causes of mortality worldwide due, in part, to limited success of some current therapeutic approaches. The clinical potential of many promising drugs is restricted by their systemic toxicity and lack of selectivity towards cancer cells, leading to insufficient drug concentration at the tumor site. To overcome these hurdles, we developed a novel drug delivery system based on polyurea/polyurethane nanocapsules (NCs) showing pH-synchronized amphoteric properties that facilitate their accumulation and selectivity into acidic tissues, such as tumor microenvironment.

Keto-Enol Tautomerism in Passerini and Ugi Adducts.

The use of arylglyoxal as starting material in Passerini and Ugi reactions affords β-ketoamides. This has allowed to study keto-enol tautomerism in these systems and assess the way in which the presence of acyloxy or aminoacyl groups bound to the C2 position affects such tautomerism, and to investigate the reactivity of both the enol and carbonyl forms. In this work we also prove the versatility of the Passerini reaction, since depending on the conditions to which the corresponding adducts are subjected different products of synthetic interest can be obtained.

Toxicological assessment of commercial monolayer tungsten disulfide nanomaterials aqueous suspensions using human A549 cells and the model fungus Saccharomyces cerevisiae.

The utilization of tungsten disulfide (WS) nanomaterials in distinct applications is raising due to their unique physico-chemical properties, such as low friction coefficient and high strength, which highlights the necessity to study their potential toxicological effects, due to the potential increase of environmental and human exposure. The aim of this work was to analyze commercially available aqueous dispersions of monolayer tungsten disulfide (2D WS) nanomaterials with distinct lateral size employing a portfolio of physico-chemical and toxicological evaluations. The structure and stoichiometry of monolayer tungsten disulfide (WS-ACS-M) and nano size monolayer tungsten disulfide (WS-ACS-N) was analyzed by Raman spectroscopy, whereas a more quantitative approach to study the nature of formed oxidized species was undertaken employing X-ray photoelectron spectroscopy.

Assessment of Physico-Chemical and Toxicological Properties of Commercial 2D Boron Nitride Nanopowder and Nanoplatelets.

Boron nitride (BN) nanomaterials have been increasingly explored for potential applications in chemistry and biology fields (e.g., biomedical, pharmaceutical, and energy industries) due to their unique physico-chemical properties.

One-Pot Synthesis of Enantiopure Pyrrolopiperazines.

A simple one-pot protocol for the synthesis of fused pyrrolopiperazines with a complete diastereoselectivity has been developed. This novel methodology combined the Ugi reaction with a spontaneous enamine alkylation on a multicomponent domino reaction, starting from nonprotected diamines and arylglyoxals.

Simple squaramide receptors for highly efficient anion binding in aqueous media and transmembrane transport.

A family of acyclic squaramide receptors (L1-L5) have been synthesised with the aim to bind anions in a competitive solvent mixture and to evaluate how the presence of additional H-bond donor groups on the squaramide scaffold could affect the affinity towards anions and the transmembrane transport ability.

Advances in anion transport and supramolecular medicinal chemistry.

Advances in anion transport by synthetic supramolecular systems are discussed in this article. Developments in the design of discrete molecular carriers for anions and supramolecular anion channels are reviewed followed by an overview of the use of these systems in biological systems as putative treatments for diseases such as cystic fibrosis and cancer.