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Indolo[3,2-d][1]benzazepines (paullones), indolo[3,2-d][2]benzazepines, and indolo[2,3-d][2]benzazepines (latonduines) are isomeric scaffolds of current medicinal interest. Herein, we prepared a small library of novel indolo[3,2-d][2]benzazepine-derived ligands HL1–HL4and copper(II) complexes 1–4. All compounds were characterized by spectroscopic methods (1H and 13C NMR, UV–vis, IR) and electrospray ionization (ESI) mass spectrometry, while complexes 2and 3, in addition, by X-ray crystallography. Their purity was confirmed by HPLC coupled with high-resolution ESI mass spectrometry and/or elemental analysis. The stability of compounds in aqueous solutions in the presence of DMSO was confirmed by 1H NMR and UV–vis spectroscopy measurements. The compounds revealed high antiproliferative activity in vitro in the breast cancer cell line MDA-MB-231 and hepatocellular carcinoma cell line LM3 in the low micromolar to nanomolar concentration range. Important structure–activity relationships were deduced from the comparison of anticancer activities of HL1–HL4and 1–4with those of structurally similar paullone-derived (HL5–HL7and 5–7) and latonduine-derived scaffolds (HL8–HL11and 8–11). The high anticancer activity of the lead drug candidate 4was linked to reactive oxygen species and endoplasmic reticulum stress induction, which were confirmed by fluorescent microscopy and Western blot analysis.

Game-based learning has been shown to promote active learning. We have designed a card game termed CountQuest, played on the online platform Zoom, to facilitate the revision of the effective atomic number (EAN) concept for metal complexes previously taught in lectures. This game was played by undergraduate and graduate chemistry students during their respective 1 h tutorial sessions. The efficacy of the intervention was shown using pre/post surveys. The results of our activity demonstrate that judiciously designed card games can be used to improve teaching of key concepts in inorganic chemistry at both undergraduate and graduate levels.

The limited recapitulation of critical cancer features in 2D cultures causes poor translatability of preclinical results from in vitro assays to in vivo tumor models. This contributes to slow drug development with a low success rate. 3D cultures better recapitulate the tumor microenvironment, enabling more accurate predictions when screening drug candidates and improving the development of chemotherapeutics. Platinum (Pt) (IV) compounds are promising prodrugs designed to reduce the severe systemic toxicity of widely used Food and Drug Administration (FDA)‐approved Pt(II) drugs such as cisplatin. Here, this work presents spatiotemporal evaluations in 3D colorectal cancer (CRC) spheroids of mitochondria‐targeting Pt(IV) complexes. CRC spheroids provide a greater pathophysiological recapitulation of in vivo tumors than 2D cultures by a marked upregulation of the ABCG2 chemoresistance marker expression. Furthermore, new 3D‐staining protocols are introduced to evaluate the real‐time decrease in mitochondria membrane potential (ΔΨ) in CRC spheroids, and a Pt‐sensing dye to quantify the Pt mitochondrial accumulation. Finally, this work demonstrates a correlation between in vitro results and the efficacy of the compounds in vivo. Overall, the CRC spheroids represent a fast and cost‐effective model to assess the behavior of Pt compounds in vitro and predict their translational potential in CRC treatment. While 3D spheroid models are gaining increasing attention for their utility in drug screening, most models focus exclusively on the cytotoxicity of drugs, neglecting valuable information on the drug diffusion gradient across tumors and expression of key chemoresistance markers. Here, this work presents fluorescent‐based quantitative analyses of 3D CRC spheroids for the systematic progressive evaluations of drug candidates.

A common challenge in Pt(IV) prodrug design is the limited repertoire of linkers available to connect the Pt(IV) scaffold with the bioactive payload. The commonly employed linkers are either too stable, leading to a linker artifact on the payload upon release, or too unstable, leading to premature release. In this study, we report the synthesis of a new class of Pt(IV) prodrugs using masked self-immolative 4-aminobenzyl linkers for controlled and traceless codrug delivery. Upon reduction of self-immolative Pt(IV) prodrugs, the detached axial ligands undergo decarboxylation and 1,6-elimination for payload release. Introduction of self-immolative linkers conferred good aqueous stability to the Pt(IV) codrug complex. Investigation revealed that efficient 1,6-elimination could be attributed to stabilization of the p-aza-quinone-methide intermediate. In particular, the self-immolative Pt(IV) prodrugs with cinnamate and coumarin derivatives were more potent than the coadministration of cisplatin with an unconjugated cinnamate or coumarin payload in vitro.

Tracking caspofungin accumulation is key for a better understanding of drug resistance in pathogenic fungi.

With the aim of enhancing the biological activity of ruthenium–nitrosyl complexes, new compounds with four equatorially bound indazole ligands, namely, trans-[RuCl(Hind)4(NO)]Cl2·H2O ([3]Cl2·H2O) and trans-[RuOH(Hind)4(NO)]Cl2·H2O ([4]Cl2·H2O), have been prepared from trans-[Ru(NO2)2(Hind)4] ([2]). When the pH-dependent solution behavior of [3]Cl2·H2Oand [4]Cl2·H2Owas studied, two new complexes with two deprotonated indazole ligands were isolated, namely [RuCl(ind)2(Hind)2(NO)] ([5]) and [RuOH(ind)2(Hind)2(NO)] ([6]). All prepared compounds were comprehensively characterized by spectroscopic (IR, UV–vis, 1H NMR) techniques. Compound [2], as well as [3]Cl2·2(CH3)2CO, [4]Cl2·2(CH3)2CO, and [5]·0.8CH2Cl2, the latter three obtained by recrystallization of the first isolated compounds (hydrates or anhydrous species) from acetone and dichloromethane, respectively, were studied by X-ray diffraction methods. The photoinduced release of NO in [3]Cl2and [4]Cl2was investigated by cyclic voltammetry and resulting paramagnetic NO species were detected by EPR spectroscopy. The quantum yields of NO release were calculated and found to be low (3–6%), which could be explained by NO dissociation and recombination dynamics, assessed by femtosecond pump–probe spectroscopy. The geometry and electronic parameters of Ru species formed upon NO release were identified by DFT calculations. The complexes [3]Cl2and [4]Cl2showed considerable antiproliferative activity in human cancer cell lines with IC50values in low micromolar or submicromolar concentration range and are suitable for further development as potential anticancer drugs. p53-dependence of Ru–NO complexes [3]Cl2and [4]Cl2was studied and p53-independent mode of action was confirmed. The effects of NO release on the cytotoxicity of the complexes with or without light irradiation were investigated using NO scavenger carboxy-PTIO.

Current anticancer drug discovery efforts focus on the identification of first-in-class compounds with a mode-of-action distinct from conventional DNA-targeting agents for chemotherapy. An emerging trend is the identification of endoplasmic reticulum (ER) targeting compounds that induce ER stress in cancer cells, leading to cell death. However, a limited pool of such compounds has been identified to date, and there are limited studies done on such compounds to allow for the rational design of ER stress-inducing agents. In our present study, we present a series of highly cytotoxic, ER stress-inducing Ru(II)-arene Schiff-Base (RAS) complexes, bearing iminoquinoline chelate ligands. We demonstrate that by structural modification to the iminoquinoline ligand, we could tune its π-acidity and influence reactive oxygen species (ROS) induction, switching between a ROS-mediated ER stress pathway activation and one that is not mediated by ROS induction. Our current study adds to the available ER stress inducers and shows how structural tuning could be used as a means to modulate the mode-of-action of such compounds.

Nitroreductases (NTRs) constitute an important class of oxidoreductase enzymes that have evolved to metabolize nitro-containing compounds. Their unique characteristics have spurred an array of potential uses in medicinal chemistry, chemical biology, and bioengineering toward harnessing nitro caging groups and constructing NTR variants for niche applications. Inspired by how they carry out enzymatic reduction via a cascade of hydride transfer reactions, we sought to develop a synthetic small-molecule NTR system based on transfer hydrogenation mediated by transition metal complexes harnessing native cofactors. We report the first water-stable Ru–arene complex capable of selectively and fully reducing nitroaromatics into anilines in a biocompatible buffered aqueous environment using formate as the hydride source. We further demonstrated its application to activate nitro-caged sulfanilamide prodrug in formate-abundant bacteria, specifically pathogenic methicillin-resistant Staphylococcus aureus. This proof of concept paves the way for a new targeted antibacterial chemotherapeutic approach leveraging on redox–active metal complexes for prodrug activation via bioinspired nitroreduction.

p53 is a key tumor suppressor gene involved in key cellular processes and implicated in cancer therapy. However, it is inactivated in more than 50% of all cancers due to mutation or overexpression of its negative regulators. This leads to drug resistance and poor chemotherapeutic outcome as most clinical drugs act via a p53-dependent mechanism of action. An attractive strategy to circumvent this resistance would be to identify new anticancer drugs that act via p53-independent mode of action. In the present study, we identified 9 Ru (II)-Arene Schiff-base (RAS) complexes able to induce p53-independent cytotoxicity and discuss structural features that are required for their p53-independent activity. Increasing hydrophobicity led to an increase in cellular accumulation in cells with a corresponding increase in efficacy. We further showed that all nine complexes demonstrated p53-independent activity. This was despite significant differences in their physicochemical properties, suggesting that the iminoquinoline ligand, a common structural feature for all the complexes, is required for the p53-independent activity.

The release dynamics of cisplatin from the interior of a carbon nanotube is studied using molecular dynamics simulations. The nanotube is initially capped by magnetic nanoparticles which, upon exposure to an external magnetic field, detach from the nanotube tips, and the initially encapsulated cisplatin molecules leave the nanotube interior according to the diffusion mechanism. Diffusivities of cisplatin in bulk water and inside the nanotube were determined by analyzing the mean-square displacements, and they take the values 2.1 × 10–5and (0.6–0.9) × 10–5cm2s–1, respectively, at 310 K. The release of cisplatin was found to be an activated process with the activation barrier ∼25 kJ mol–1in an ideal system. Analysis of experimental data allowed for the estimation of the diffusion barrier in the actual system which was found to be ca. 85 kJ mol–1. The difference between these two estimations is attributed to the existence of numerous surface defects in the case of experimental system. The release dynamics proceeds according to a simple 1D Fick’s mechanism, and either simulation or experimental data follow a very simple equation derived from the above assumption. That equation predicts that the release of simple molecules from carbon nanotubes should obey the second-order kinetic equation. The time scale of the release depends on the nanotube length, initial amount of drug, and diffusivity of drug molecules inside the nanotube. Simulations predict that, for the studied ideal architecture, the release completes in a few milliseconds. Experimental data show that that process is, due to surface defects, definitely slower; i.e., it needs about 3 h.

Resistance against anticancer drugs remains a serious obstacle in cancer treatment. Here we used novel strategies to target microsomal glutathione transferase 1 (MGST1) and glutathione transferase pi (GSTP) that are often overexpressed in tumors and confer resistance against a number of cytostatic drugs, including cisplatin and doxorubicin (DOX). By synthetically combining cisplatin with a GST inhibitor, ethacrynic acid, to form ethacraplatin, it was previously shown that cytosolic GST inhibition was improved and that cells became more sensitive to cisplatin. Here we show that ethacraplatin is easily taken up by the cells and can reverse cisplatin resistance in MGST1 overexpressing MCF7 cells. A second and novel strategy to overcome GST mediated resistance involves using GST releasable cytostatic drugs. Here we synthesized two derivatives of DOX, 2,4-dinitrobenzenesulfonyl doxorubicin (DNS-DOX) and 4-mononitrobenzenesulfonyl doxorubicin (MNS-DOX) and showed that they are substrates for MGST1 and GSTP (releasing DOX). MGST1 overexpressing cells are resistant to DOX. The resistance is partially reversed by DNS-DOX. Interestingly, the less reactive MNS-DOX was more cytotoxic to cells overexpressing MGST1 than control cells. It would appear that, by controlling the reactivity of the prodrug, and thereby the DOX release rate, selective toxicity to MGST1 overexpressing cells can be achieved. In the case of V79 cells, DOX resistance proportional to GSTP expression levels was noted. In this case, not only was drug resistance eliminated by DNS-DOX but a striking GSTP-dependent increase in toxicity was observed in the clonogenic assay. In summary, MGST1 and GSTP resistance to cytostatic drugs can be overcome and cytotoxicity can be enhanced in GST overexpressing cells.

Platinum‐based cancer drugs, such as cisplatin, are highly effective chemotherapeutic agents used extensively for the treatment of solid tumors. However, their effectiveness is limited by drug resistance, which, in some cancers, has been associated with an overexpression of pi class glutathione S‐transferase (GST P1‐1), an important enzyme in the mercapturic acid detoxification pathway. Ethacraplatin (EA‐CPT), a trans‐PtIVcarboxylate complex containing ethacrynate ligands, was designed as a platinum cancer metallodrug that could also target cytosolic GST enzymes. We previously reported that EA‐CPT was an excellent inhibitor of GST activity in live mammalian cells compared to either cisplatin or ethacrynic acid. In order to understand the nature of the drug–protein interactions between EA‐CPT and GST P1‐1, and to obtain mechanistic insights at a molecular level, structural and biochemical investigations were carried out, supported by molecular modeling analysis using quantum mechanical/molecular mechanical methods. The results suggest that EA‐CPT preferentially docks at the dimer interface at GST P1‐1 and subsequent interaction with the enzyme resulted in docking of the ethacrynate ligands at both active sites (in the H‐sites), with the Pt moiety remaining bound at the dimer interface. The activation of the inhibitor by its target enzyme and covalent binding accounts for the strong and irreversible inhibition of enzymatic activity by the platinum complex.

A series of fluorescent imidazolium‐based salts containing the cation [AnCH2MeIm]+(in which An=anthracene and Im=the imidazolium cation) with Cl−, BF4−, PF6−, SO3CF3−, [N(CN)2]−, [N(SO2CF3)2]−, or PhBF3−anions have been prepared and characterized. X‐ray diffraction analysis of four of the salts reveals a number of CH⋅⋅⋅X‐type (X=O, N, F) hydrogen bonds between the hydrogen atoms from the imidazolium ring and in some cases from the anthracene ring with the electronegative atoms of the anions. Additionally, CH⋅⋅⋅π interactions can be found in all the salts analyzed by X‐ray diffraction, whereas π–π stacking is observed only in the salt containing the phenyltrifluoroborate anion. Fluorescence emission analysis in acetonitrile shows that the fluorescence of these salts varies significantly according to the nature of the anion, and correlates to the extent of ion pairing present in solution. Photodimerization of these salts was observed, and in one case a dimer has been isolated and characterized by X‐ray crystallography.

A series of imidazolium dicarboxylic acids have been prepared from the reaction of the 1,3‐bis(carboxymethyl)imidazolium zwitterion with the Brønsted acids HX (X=F, Br, Cl, ClO4). The structures of these acids have been established in the solid state by single‐crystal X‐ray diffraction, which revealed that the cations and anions form strong hydrogen bonds through OH⋅⋅⋅X interactions, leading to the formation of dimeric and polymeric networks. These acids react with elemental zinc and cobalt to form stable polymeric coordination complexes, some of which have also been characterised by X‐ray diffraction.

Pathogenic microorganisms pose a serious threat to global public health due to their persistent adaptation and growing resistance to antibiotics. Alternative therapeutic strategies are required to address this growing threat. Bactericidal antibiotics that are routinely prescribed to treat infections rely on hydroxyl radical formation for their therapeutic efficacies. We developed a redox approach to target bacteria using organotransition metal complexes to mediate the reduction of cellular O2to H2O2, as a precursor for hydroxyl radicals via Fenton reaction. We prepared a library of 480 unique organoruthenium Schiff-base complexes using a coordination-driven three-component assembly strategy and identified the lead organoruthenium complex Ru1 capable of selectively invoking oxidative stress in Gram-positive bacteria, in particular methicillin-resistant Staphylococcus aureus, via transfer hydrogenation reaction and/or single electron transfer on O2. This strategy paves the way for a targeted antimicrobial approach leveraging on the redox chemistry of organotransition metal complexes to combat drug resistance.

Review: 93 refs.

The effectiveness…︁of platinum‐based cancer drugs are limited by drug resistance and pi class glutathione S‐transferase, a major detoxifying enzyme, plays a role in this resistance. X‐ray crystallography and molecular modeling have been used to visualize how a platinum cancer drug (shown in ball‐and‐stick) is recognized by the dimeric enzyme (protein backbone shown as pink ribbons). The ethacrynate ligands (orange spheres), potent inhibitors of the enzyme, dissociate from the metal‐bound enzyme complex, where they likely diffuse through a surface cavity (grey surface) a short distance to the active sites of each monomer leading to enzymatic inhibition. For more details see the Full Paper by M. W. Parker et al. on page 7806 ff.

A series of fluorescent…︁anthracene‐functionalized, imidazolium‐based salts containing the cation [AnCH2MeIm]+(An=anthracene and Im=the imidazolium cation) with Cl−, BF4−, PF6−, SO3CF3−, [N(CN)2]−, [N(SO2CF3)2]−, or PhBF3−have been prepared and characterized. In their Full Paper on page 6473 ff., P. J. Dyson et al. describe the single‐crystal X‐ray diffraction analysis of some of the salts and fluorescence emission analysis. Photodimerization of these salts was also observed. We thank Dr. Alexey Nazarov for providing the photo of the Matterhorn.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

The cover picture shows an organoruthenium antimetastasis compound, superimposed over a Sudoku puzzle, representing the challenge of discovering new anticancer drugs and elucidating their mechanisms of action. One needs to uncover pieces of information which are interrelated, and eventually, the complete ‘picture’ is revealed. In this review, we describe the extent to which the picture has been revealed for ruthenium-based drugs, which are currently growing in interest as a result of recent successes in clinical trials. The emphasis is directed towards classifying the vast array of ruthenium compounds already evaluated in vitro and in vivo against primary and secondary cancers within the context of their probable target. It is hoped that on the basis of the picture presented here more of this intriguing puzzle will be revealed soon. Details are presented in the Microreview by W. H. Ang and P. J. Dyson on p. 4003 ff.