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Tetrazole, a bioisostere of the carboxylic acid group, can replace the carboxyl group in drugs to increase the lipophilicity, bioavailability and reduce side effects. Tetrazole derivatives possess a broad-spectrum of biological properties including anti-tubercular and anti-malarial activities, and some tetrazole-based compounds have already been used in clinics for the treatment of various diseases. Therefore, tetrazole is an important pharmacophore in the development of new drugs. This review covers the recent advances of tetrazole derivatives as potential anti-tubercular and anti-malarial agents, and the structure-activity relationship is also discussed for the further rational design of tetrazole derivatives. Show less

A series of N-benzoylated mononuclear copper(II) complexes of the type [Cu(L1−6)Cl2] (1–6), where L1= ethyl 4-benzoyl-5-methyl-7-aryl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate, L2= ethyl 4-(4-nitrobenzoyl)-5-methyl-7-aryl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate, L3 = ethyl 4-benzoyl-5-methyl-7-(4-methoxyphenyl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate, L4 = ethyl 4-(4-nitrobenzoyl)-5-methyl-7-(4-methoxyphenyl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate, L5 = ethyl 4-benzoyl-5-methyl-7-(4-chlorophenyl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate and L6 = ethyl 4-(4-nitrobenzoyl)-5-methyl-7-(4-chlorophenyl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate have been synthesized and characterized by spectral methods. Electron paramagnetic resonance spectra of complexes show four lines, characteristic of square planar geometry. The binding studies of the complexes with calf thymus DNA (CT–DNA) revealed groove mode of binding, which were further supported by molecular docking studies. Gel electrophoresis experiments demonstrated the ability of the complexes to cleave plasmid DNA in the absence of activators. Further, the cytotoxicity activity of the complexes were examined on three cancerous cell lines (lung (A549), cervical (HeLa) and colon (HCT-15)), and on two normal cells (human embryonic kidney (HEK) and peripheral blood mononuclear cells (PBMC)) by MTT assay. Show less

Platinum-resistant cancer cells are sensitive to changes in the levels of reactive oxidative species (ROS). Herein, we design a biotin-modified Ru(ii) complex as a photosensitizer (denoted as Ru-Biotin). Ru-Biotin can selectively target cancer cells and produce vast amounts of singlet oxygen under two-photon excitation at 820 nm leading to cell apoptosis. Ru-Biotin is therefore an excellent candidate to overcome platinum resistance via two-photon photodynamic therapy. Show less

Emerging studies have shown that mitochondrial DNA (mtDNA) is a potential target for cancer therapy. Herein, six cyclometalated Ir(III) complexes Ir1-Ir6 containing a series of extended planar diimine ligands have been designed and assessed for their efficacy as anticancer agents. Ir1-Ir6 show much higher cytotoxicity than cisplatin and they can effectively localize to mitochondria. Among them, complexes Ir3 and Ir4 with dipyrido[3,2- a:2',3'- c]phenazine (dppz) ligands can bind to DNA tightly in vitro, intercalate to mtDNA in situ, and induce mtDNA damage. Ir3- and Ir4-impaired mitochondria exhibit decline of mitochondrial membrane potential, disability of adenosine triphosphate generation, disruption of mitochondrial energetic and metabolic status, which subsequently cause protective mitophagy, G₀/G₁ phase cell cycle arrest, and apoptosis. In vivo antitumor evaluations also show that Ir4 can inhibit tumor xenograft growth effectively. Overall, our work proves that targeting the mitochondrial genome may present an effective strategy to develop metal-based anticancer agents to overcome cisplatin resistance. Show less

The Warburg effect is a peculiar feature of cancer’s metabolism, which is an attractive therapeutic target that could aim tumor cells while sparing normal tissue. Matrine is an alkaloid extracted from the herb root of a traditional Chinese medicine, Sophora flavescens Ait. Matrine has been reported to have selective cytotoxicity towards cancer cells but with elusive mechanisms. Here, we reported that matrine was able to reverse the Warburg effect (inhibiting glucose uptake and lactate production) and suppress the growth of human colon cancer cells in vitro and in vivo. Mechanistically, we revealed that matrine significantly decreased the mRNA and protein expression of HIF-1α, a critical transcription factor in reprogramming cancer metabolism towards the Warburg effect. As a result, the expression levels of GLUT1, HK2, and LDHA, the downstream targets of HIF-1α in regulating glucose metabolism, were dramatically inhibited by matrine. Moreover, this inhibitory effect of matrine was significantly attenuated when HIF-1α was knocked down or exogenous overexpressed in colon cancer cells. Together, our results revealed that matrine inhibits colon cancer cell growth via suppression of HIF-1α expression and its downstream regulation of Warburg effect. Matrine could be further developed as an antitumor agent targeting the HIF-1α-mediated Warburg effect for colon cancer treatment. Show less

Third-generation aromatase inhibitors such as anastrozole (ATZ) and letrozole (LTZ) are widely used to treat estrogen receptor-positive ER+ breast cancers in postmenopausal women. Investigating their ability to coordinate metals could lead to the emergence of a new category of anticancer drug candidates with a broader spectrum of pharmacological activities. In this study, a series of ruthenium (II) arene complexes bearing the aromatase inhibitor anastrozole was synthesized and characterized. Among these complexes, [Ru(η ⁶ -C₆H₆)(PPh₃)(η ¹ -ATZ)Cl]BPh₄ (3) was found to be the most stable in cell culture media, to lead to the highest cellular uptake and in vitro cytotoxicity in two ER+ human breast cancer cell lines (MCF7 and T47D), and to induce a decrease in aromatase activity in H295R cells. Exposure of zebrafish embryos to complex 3 (12.5 μM) did not lead to noticeable signs of toxicity over 96 h, making it a suitable candidate for further in vivo investigations. Show less

Stable five-coordinated (16-electron) half-sandwich iridium(III) and ruthenium(II) complexes are rarely reported, and their biological evaluations have not been considered to date. Herein, in an experiment designed to synthesize six-coordinated half-sandwich iridium(III) and ruthenium(II) complexes containing N,N-chelated α-keto-β-diimine ligands, we observed the serendipitous formation of half-sandwich aminoimine iridium(III) and ruthenium(II) complexes via solvent-involved rearrangement reaction. These unsaturated 16-electron complexes had sufficient stability in DMSO-water solution. Moreover, no reaction with two-electron donors (CO and PPh₃) and nucleobase (9-MeA and 9-EtG) was observed. Most of the complexes show good anticancer activities toward A549, HeLa, and HepG2 cancer cells, which are higher than the clinical drug cisplatin. The investigation of mechanism by flow cytometry showed that the complexes exert their anticancer efficacy by inducing apoptosis or necrosis, and increasing the intracellular ROS level. In addition, fluorescence property of these complexes makes it possible to investigate the microscopic mechanism by confocal microscopy. Notably, the complexes Ir3 and Ru1 enter A549 cancer cells through an energy-independent pathway, and they are mainly located in mitochondria and lysosomes. Show less

Eight new organometallic Ru(II)-arene complexes of the type [RuCl₂(η⁶-arene)(η¹-S-aroylthiourea)] (arene = p-cymene or benzene) were synthesized in order to evaluate the effect of the arene moiety and the substituent of the aroylthiourea ligand on the cytotoxicity of the complexes. The ligands (L1 and L2) and complexes (1-8) were characterized using analytical and spectroscopic (UV-visible, infrared, ¹H NMR, ¹³C NMR, and mass) methods. The structure of the ligands (L1 and L2) and complexes (1 and 3-6) was obtained from single-crystal X-ray diffraction studies. The cytotoxicity of the complexes was evaluated against four different cancer cell lines: MCF-7 (breast), COLO 205 (colon), A549 (lung), and IMR-32 (neuroblastoma). All the complexes showed good cytotoxicity and the highest was in the IMR-32 cell line, which articulates the specificity of these complexes toward the IMR-32 cancer cell line. The complexes 5, 7, and 8 exhibited remarkable cytotoxicity in the entire cancer cell lines tested, which was comparable with the standard drug, cisplatin. The anticancer mechanism of the complexes 3 and 7 in IMR-32 cells was evaluated by bright-field microscopy, intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), DNA damage, and caspase-3 analyses. The cells treated with the complexes showed upregulated caspase-3 compared to the control, and it was found that ROS and MMP were dose-dependent on analysis. Also, bright-field microscopy and 4',6-diamidino-2-phenylindole (DAPI) staining have correspondingly shown cellular membrane blebbing and DNA damage, which were morphological hallmarks of apoptosis. The study concluded that the complexes promoted the oxidative stress-mediated apoptotic death of the cancer cells through the generation of intracellular ROS, depletion of MMP, and damage of the nuclear material. Show less

Acute myeloid leukemia (AML) is a devastating disease, with the majority of patients dying within a year of diagnosis. For patients with relapsed/refractory AML, the prognosis is particularly poor with currently available treatments. Although genetically heterogeneous, AML subtypes share a common differentiation arrest at hematopoietic progenitor stages. Overcoming this differentiation arrest has the potential to improve the long-term survival of patients, as is the case in acute promyelocytic leukemia (APL), which is characterized by a chromosomal translocation involving the retinoic acid receptor alpha gene. Treatment of APL with all-trans retinoic acid (ATRA) induces terminal differentiation and apoptosis of leukemic promyelocytes, resulting in cure rates of over 80%. Unfortunately, similarly efficacious differentiation therapies have, to date, been lacking outside of APL. Inhibition of dihydroorotate dehydrogenase (DHODH), a key enzyme in the de novo pyrimidine synthesis pathway, was recently reported to induce differentiation of diverse AML subtypes. In this report we describe the discovery and characterization of BAY 2402234 - a novel, potent, selective and orally bioavailable DHODH inhibitor that shows monotherapy efficacy and differentiation induction across multiple AML subtypes. Herein, we present the preclinical data that led to initiation of a phase I evaluation of this inhibitor in myeloid malignancies. Show less

Organoruthenium complexes are potent alternatives for platinum-based complexes because of their superior anticancer activity. In this investigation, a series of new Ru(II)-arene complexes with triarylamine-thiosemicarbazone hybrid ligands with higher anticancer activity than cisplatin are reported. The molecular structure of the ligands and complexes was confirmed spectroscopically and supported by single-crystal X-ray crystallography. These complexes adopted a three-leg piano stool geometry. All the Ru(II)-arene complexes were systematically investigated for their in vitro cytotoxicity against human cervical (HeLa S3), lung (A549) cancer, and human normal lung (IMR-90) cell lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Interestingly, a pyrrolidine-attached Ru(II)-benzene complex exhibited superior activity against cancer cells with low IC₅₀ values, and colony formation study showed complete inhibition at 5 and 10 μM concentration. Furthermore, morphological changes assessed by acridine orange and propidium iodide staining revealed that the cell death occurred by apoptosis. In addition, the interaction between synthesized Ru(II)-arene complexes and DNA/protein was explored by absorption and emission spectroscopy methods. These synthesized new organoruthenium complexes can be used for developing new metal-based anticancer drugs. Show less

The endoplasmic reticulum (ER) is an indispensable organelle that undertakes the synthesis and export of proteins and membrane lipids. Subtle interferences of the ER redox signaling pathway are very likely to cause ER-stress induced apoptosis. In view of this, we herein present a series of ER-targeted Ir(iii) complexes (Ir1-Ir3) as photodynamic therapy (PDT) photosensitizers with a gradually extended conjugation area in the main ligand, and study the correlation between the conjugation area and PDT performance. The results showed that all of these complexes can accumulate in the ER and effectively induce cell apoptosis after PDT therapeutics (405 nm, 6 J cm-2) by an ER stress mechanism, and both their singlet oxygen quantum yields and cytotoxicities increase as the conjugation area extends. All complexes showed PDT efficacy towards different cancer cell lines. Among them, Ir2 exhibited the highest PI value (94.3) against A549 cells with an IC50 down to 0.65 μM. In addition, the post PDT ER-stress induced apoptosis along with the efflux of Ca2+ from the ER system in A549 cells in a short period of time (45-90 min) with the pretreatment of Ir2 was demonstrated. All of these results indicate the promising potential of Ir2 as an effective PDT photosensitizer. Show less

Ru(ii) polypyridyl complexes, containing a morpholine moiety, and possessing two-photon absorption properties and pH dependent singlet oxygen production were used for stepwise lysosomes-to-mitochondria photodamage of cancer cells. Show less

AbstractMetal‐driven self‐assembly is one of the most effective approaches to lucidly design a large range of discrete 2D and 3D coordination architectures/complexes. Palladium(II)‐based self‐assembled coordination architectures are usually prepared by using suitable metal components, in either a partially protected form (PdL′) or typical form (Pd; charges are not shown), and designed ligand components. The self‐assembled molecules prepared by using a metal component and only one type of bi‐ or polydentate ligand (L) can be classified in the homoleptic series of complexes. On the other hand, the less explored heteroleptic series of complexes are obtained by using a metal component and at least two different types of non‐chelating bi‐ or polydentate ligands (such as La and Lb). Methods that allow the controlled generation of single, discrete heteroleptic complexes are less understood. A survey of palladium(II)‐based self‐assembled coordination cages that are heteroleptic has been made. This review article illustrates a systematic collection of such architectures and credible justification of their formation, along with reported functional aspects of the complexes. The collected heteroleptic assemblies are classified here into three sections: 1) [(PdL′)m(La)x(Lb)y]‐type complexes, in which the denticity of La and Lb is equal; 2) [(PdL′)m(La)x(Lb)y]‐type complexes, in which the denticity of La and Lb is different; and 3) [Pdm(La)x(Lb)y]‐type complexes, in which the denticity of La and Lb is equal. Representative examples of some important homoleptic architectures are also provided, wherever possible, to set a background for a better understanding of the related heteroleptic versions. The purpose of this review is to pave the way for the construction of several unique heteroleptic coordination assemblies that might exhibit emergent supramolecular functions. Show less

Transition metal complexes are of increasing interest as photosensitizers in photodynamic therapy (PDT) and, more recently, for photochemotherapy (PCT). In recent years, Ru(II) polypyridyl complexes have emerged as promising systems for both PDT and PCT. Their rich photochemical and photophysical properties derive from a variety of excited-state electronic configurations accessible with visible and near-infrared light, and these properties can be exploited for both energy- and electron-transfer processes that can yield highly potent oxygen-dependent and/or oxygen-independent photobiological activity. Selected examples highlight the use of rational design in coordination chemistry to control the lowest-energy triplet excited-state configurations for eliciting a particular type of photoreactivity for PDT and/or PCT effects. These principles are also discussed in the context of the development of TLD1433, the first Ru(II)-based photosensitizer for PDT to enter a human clinical trial. The design of TLD1433 arose from a tumor-centered approach, as part of a complete PDT package that includes the light component and the protocol for treating non-muscle invasive bladder cancer. Briefly, this review summarizes the challenges to bringing PDT into mainstream cancer therapy. It considers the chemical and photophysical solutions that transition metal complexes offer, and it puts into context the multidisciplinary effort needed to bring a new drug to clinical trial. Show less

We here review the extraordinary mineralogical properties of green rusts and their naturally occurring form, fougerite, and discuss the pertinence of these properties within the alkaline hydrothermal vent (AHV) hypothesis for life's emergence. We put forward an extended version of the AHV scenario which enhances the conformity between extant life and its earliest progenitor by extensively making use of fougerite's mechanistic and catalytic particularities. Show less

Among all molecules developed for anticancer therapies, photodynamic therapeutic agents have a unique profile. Their maximal activity is specifically triggered in tumors by light, and toxicity of even systemically delivered drug is prevented in nonilluminated parts of the body. Photosensitizers exert their therapeutic effect by producing reactive oxygen species via a light-activated reaction with molecular oxygen. Consequently, the lowering of pO₂ deep in solid tumors limits their treatment and makes essential the design of oxygen-independent sensitizers. In this perspective, we have recently developed Ir(III)-based molecules able to oxidize biomolecules by type I processes under oxygen-free conditions. We examine here their phototoxicity in relevant biological models. We show that drugs, which are mitochondria-accumulated, induce upon light irradiation a dramatic decrease of the cell viability, even under low oxygen conditions. Finally, assays on 3D tumor spheroids highlight the importance of the light-activation step and the oxygen consumption rate on the drug activity. Show less

Peroxidation of cardiolipin (CL) in the inner mitochondrial membrane plays a key role in the development of various pathologies and, probably, aging. The four fatty acid tails of CL are usually polyunsaturated, which makes CL particularly sensitive to peroxidation. Peroxidation of CL is involved in the initiation of apoptosis, as well as in some other important cellular signaling chains. However, the studies of CL peroxidation are strongly limited by the lack of methods for its tracing in living cells. We have synthesized a new mitochondria-targeted fluorescent probe sensitive to lipid peroxidation (dubbed MitoCLox), where the BODIPY fluorophore, carrying a diene-containing moiety (as in the C11-BODIPY (581/591) probe), is conjugated with a triphenylphosphonium cation (TPP + ) via a long flexible linker that contains two amide bonds. The oxidation of MitoCLox could be measured either as a decrease of absorbance at 588 nm or as an increase of fluorescence in the ratiometric mode at 520/590 nm (emission). In CL-containing liposomes, MitoCLox oxidation was induced by cytochrome c and developed in parallel with cardiolipin oxidation. TPP + -based mitochondria-targeted antioxidant SkQ1, in its reduced form, inhibited oxidation of MitoCLox concurrently with the peroxidation of cardiolipin. Molecular dynamic simulations of MitoCLox in a cardiolipin-containing membrane showed affinity of positively charged MitoCLox to negatively charged CL molecules; the oxidizable diene moiety of MitoCLox resided on the same depth as the cardiolipin lipid peroxides. We suggest that MitoCLox could be used for monitoring CL oxidation in vivo and, owing to its flexible linker, also serve as a platform for producing peroxidation sensors with affinity to particular lipids. Show less

Eukaryotic transcription-coupled nucleotide excision repair (TC-NER) is a pathway that removes DNA lesions capable of blocking RNA polymerase II (Pol II) transcription from the template strand. This process is initiated by lesion-arrested Pol II and the recruitment of Cockayne Syndrome B protein (CSB). In this review, we will focus on the lesion recognition steps of eukaryotic TC-NER and summarize the recent research progress toward understanding the structural basis of Pol II-mediated lesion recognition and Pol II-CSB interactions. We will discuss the roles of CSB in both TC-NER initiation and transcription elongation. Finally, we propose an updated model of tripartite lesion recognition and verification for TC-NER in which CSB ensures Pol II-mediated recognition of DNA lesions for TC-NER. Show less

While medicinal inorganic chemistry has been practised for over 5000 years, it was not until the late 1800s when Alfred Werner published his ground-breaking research on coordination chemistry that we began to truly understand the nature of the coordination bond and the structures and stereochemistries of metal complexes. We can now readily manipulate and fine-tune their properties. This had led to a multitude of complexes with wide-ranging biomedical applications. This review will focus on the use and potential of metal complexes as important therapeutic agents for the treatment of cancer. With major advances in technologies and a deeper understanding of the human genome, we are now in a strong position to more fully understand carcinogenesis at a molecular level. We can now also rationally design and develop drug molecules that can either selectively enhance or disrupt key biological processes and, in doing so, optimize their therapeutic potential. This has heralded a new era in drug design in which we are moving from a single- toward a multitargeted approach. This approach lies at the very heart of medicinal inorganic chemistry. In this review, we have endeavored to showcase how a "multitargeted" approach to drug design has led to new families of metallodrugs which may not only reduce systemic toxicities associated with modern day chemotherapeutics but also address resistance issues that are plaguing many chemotherapeutic regimens. We have focused our attention on metallodrugs incorporating platinum and ruthenium ions given that complexes containing these metal ions are already in clinical use or have advanced to clinical trials as anticancer agents. The "multitargeted" complexes described herein not only target DNA but also contain either vectors to enable them to target cancer cells selectively and/or moieties that target enzymes, peptides, and intracellular proteins. Multitargeted complexes which have been designed to target the mitochondria or complexes inspired by natural product activity are also described. A summary of advances in this field over the past decade or so will be provided. Show less