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. Compound 1, the most potent lactate transmembrane carrier, was studied in HeLa cells. The use of a monocarboxylate transporters (MCTs) inhibitor proved that 1 is an active lactate transporter in living cells, confirming the results obtained in phospholipid vesicles. Moreover, an additive effect of compound 1 with cisplatin was observed in HeLa cells. Identification of active lactate anionophores working in living cells opens up ways to exploit this class of compounds as molecular tools and drugs addressing dysregulated lactate metabolism.

A potent fluorescent transmembrane HCl transporter perturbs cellular pH and promotes cancer cell death.

A series of fluorescent coumarin bis-ureas 1-4 have been synthesised, and their anion transport properties studied. The compounds function as highly potent HCl co-transport agents in lipid bilayer membranes. Single crystal X-ray diffraction of compound 1 showed antiparallel stacking of the coumarin rings, stabilised by hydrogen bonds. Binding studies, using 1H-NMR titration, showed moderate chloride binding in DMSO-d6/0.5% with 1 : 1 binding mode (for transporter 1) and 1 : 2 binding mode (host: guest, for transporters 2-4). We examined the cytotoxicity of compounds 1-4 against three cancer cell lines, lung adenocarcinoma (A549), colon adenocarcinoma (SW620) and breast adenocarcinoma (MCF-7). The most lipophilic transporter, 4 showed a cytotoxic effect against all three cancer cell lines. Cellular fluorescence studies showed compound 4 crossed the plasma membrane and localised in the cytoplasm after a short time. Interestingly, compound 4, lacking any lysosome targeting groups, was co-localised with LysoTracker Red at 4 and 8 h in the lysosome. Cellular anion transport of compound 4 was assessed by measuring intracellular pH and showed a decrease in cellular pH, which may be due to the capacity of transporter 4 to co-transport HCl across biological membranes, as evidenced by the liposomal studies.

Aberrant immunoexpression of p53 tumour-suppressor and Bcl-2 family proteins (Bcl-2 and Bax) in ameloblastomas and odontogenic keratocysts.

Background: The growth of ameloblastomas (odontogenic tumours) and odontogenic keratocyst (OKC) (developmental cyst) is associated with the expression of proteins related to cell survival and apoptosis. Bcl-2-associated protein X (Bax) and the tumour suppressor protein p53 collectively promote p53-mediated apoptosis. This study aimed to assess the immunohistochemical expression of p53, Bcl-2 and Bax in conventional ameloblastoma (CA), unicystic ameloblastoma (UA) types, and OKC sporadic (OKC-NS/S) and syndromic (OKC-NBSCC). Material and Methods: Paraffinized blocks of CA (n=18), UA (n=15), OKC-NS/S (n=18) and OKC-NBSCC (n=15) fixed in 10% formalin were used. After diagnosis, tissue specimens were stained by immunohistochemistry for p53, Bcl-2 and Bax marker. Stained cells were randomly counted in five high power fields. The data analysis was performed via Shapiro-Wilk test, ANOVA with Tukey's multiple comparisons or Kruskal-Wallis with Dunn's multiple comparisons. Statistical significance was defined as p<0.05. Results: We did not observe differences between p53 expression in CA, mural UA (MUA), intraluminal/luminal UA (I/LUA), OKC-NS/S, and OKC-NBSCC (19.69%, 18.74%, 16.76%, 12.35% and 9.04%, respectively). Similar results were recognized for Bax expression in CA, MUA, I/LUA, OKC-NS/S, and OKC-NBSCC (33.72%, 34.95%, 22.94, 21.58% and 20.76%, respectively). However, we recognized significant differences between Bcl-2 expression in OKC-NS/S vs MUA, OKC-NS/S vs I/LUA, OKC-NS/S vs CA, OKC-NBSCC vs MUA, OKC-NBSCC vs I/LUA, and I/LUA vs CA. P53, Bcl-2 and Bax levels were higher in mural morphological areas versus intraluminal and luminal morphological areas in UA. Conclusions: There is a tendency for an increased expression of p53, Bcl-2, and Bax proteins in CA, and mural proliferation of UA, compared to lesions with a cystic morphology, which could be associated with a local aggressive behaviour. Key words:p53, Bcl-2, Bax protein, apoptosis, odontogenic tumour, odontogenic cyst.

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. In this regard, we designed a novel potent anionophore compound that specifically targets lysosomes, called LAI-1 (late-stage autophagy inhibitor-1), and evaluated its role in blocking autophagy and its potential anticancer effects in three lung cancer cell lines from different histological subtypes. Compared to other autophagy inhibitors, such as chloroquine and 3-Methyladenine, the LAI-1 treatment induced more potent anticancer effects in all tested cancer cells. LAI-1 was able to efficiently target and deacidify lysosomes, while acidifying cytoplasmic pH. Consequently, LAI-1 efficiently blocked autophagy, indicated by the increased LC3-II/I ratio and p62/SQSTM1 levels. Moreover, no colocalization was observed between autophagosomes, marked with LC3 or p62/SQSTM1, and lysosomes, stained with LAMP-1, after the LAI-1 treatment, indicating the blockage of autophagolysosome formation. Furthermore, LAI-1 induced cell death by activating apoptosis (enhancing the cleavage of caspase-3 and PARP) or necrosis, depending on the cancer cell line. Finally, LAI-1 sensitized cancer cells to the first-line chemotherapeutic agent cisplatin. Altogether, LAI-1 is a new late-stage autophagy inhibitor that causes lysosomal dysfunction and the blockage of autophagolysosome formation, as well as potently induces cancer cell death and sensitization to conventional treatments at lower concentrations than other known autophagy inhibitors, appearing as a potential new therapeutic approach to overcome cancer resistance.

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. Therefore, novel anticancer compounds with both effects need to be developed. In this work, we analyze the antimetastatic properties of prodigiosin and obatoclax (GX15-070), anticancer drugs of the Prodiginines (PGs) family. We studied PGs' effects on cellular adhesion and morphology in the human primary and metastatic melanoma cell lines, SK-MEL-28 and SK-MEL-5, and in the murine melanoma cell line, B16F10A. Cell adhesion sharply decreased in the treated cells, and this was accompanied by a reduction in filopodia protrusions and a significant decrease in the number of focal-adhesion structures. Moreover, cell migration was assessed through the wound-healing assay and cell motility was severely inhibited after 24 h of treatment. To elucidate the molecular mechanisms involved, changes in metastasis-related genes were analyzed through a gene-expression array. Key genes related to cellular invasion, migration and chemoresistance were significantly down-regulated. Finally, an in vivo model of melanoma-induced lung metastasis was established and significant differences in lung tumors were observed in the obatoclax-treated mice. Altogether, these results describe, in depth, PGs' cellular antimetastatic effects and identify in vivo antimetastatic properties of Obatoclax.

Cyclooxygenase-2 protein expression modulates cell proliferation and apoptosis in solid ameloblastoma and odontogenic keratocyst. An immunohistochemical study.

BACKGROUND: Cyclooxygenase-2 protein is a critically important mediator in inflammation that influences proliferation, apoptosis, angiogenesis and metastasis. Previous works showed a relationship between cyclooxygenase-2 and tumourigenesis in humans and animal models. In epithelial odontogenic tumours and cysts, increased cell proliferation and survival have been linked to its pathogenesis and tumour development. The aim of the present study was to analyse the immunohistochemical expression of cyclooxygenase-2 in solid ameloblastoma and odontogenic keratocyst and its association with proteins related to cell proliferation and apoptosis. METHODS: This study was conducted on 40 cases from the Pathological Anatomy Service, University of Chile. The cases were diagnosed as solid ameloblastoma (n = 21) and odontogenic keratocyst (n = 19) according to WHO 2017. Slides prepared from paraffin-embedded sections were immunohistochemically stained for cyclooxygenase-2, cyclin D1, Ki-67, p63 and Bcl-2. Statistical evaluation was performed by the Shapiro-Wilk test, ANOVA Mann-Whitney test and Spearman's correlation coefficient (p < 0.05). RESULTS: There were significant differences in the immunoexpression of cyclin D1, Ki-67 and Bcl-2 between solid ameloblastoma and odontogenic keratocyst. Likewise, there was a significant difference in the immunoexpression of p63 between follicular and plexiform histological types/subtypes of solid ameloblastoma. Lastly, there were statistical associations between cyclooxygenase-2 and Ki-67 for solid ameloblastoma and between cyclooxygenase-2 and p63 for odontogenic keratocyst. CONCLUSION: A high level of cyclooxygenase-2 is related to increased cell survival and proliferative activity in solid ameloblastoma and odontogenic keratocyst. This event might contribute to tumoural progression and local invasiveness in these lesions.

The Inflammatory Profile of the Tumor Microenvironment, Orchestrated by Cyclooxygenase-2, Promotes Epithelial-Mesenchymal Transition.

The tumor microenvironment (TME) corresponds to a complex and dynamic interconnection between the extracellular matrix and malignant cells and their surrounding stroma composed of immune and mesenchymal cells. The TME has constant cellular communication through cytokines that sustain an inflammatory profile, which favors tumor progression, angiogenesis, cell invasion, and metastasis. Although the epithelial-mesenchymal transition (EMT) represents a relevant metastasis-initiating event that promotes an invasive phenotype in malignant epithelial cells, its relationship with the inflammatory profile of the TME is poorly understood. Previous evidence strongly suggests that cyclooxygenase-2 (COX-2) overexpression, a pro-inflammatory enzyme related to chronic unresolved inflammation, is associated with common EMT-signaling pathways. This review article summarizes how COX-2 overexpression, within the context of the TME, orchestrates the EMT process and promotes initial metastatic-related events.

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. We have demonstrated that the anticancer drug used in this study, a hydrophobic anionophore named T21, increases its cytotoxic activity in acidic conditions when nanoencapsulated, which correlates with a more efficient cellular internalization. A biodistribution assay performed in mice has shown that the NCs are able to reach the tumor and the observed systemic toxicity of the free drug is significantly reduced in vivo when nanoencapsulated. Additionally, T21 antitumor activity is preserved, accompanied by tumor mass reduction compared to control mice. Altogether, this work shows these NCs as a potential drug delivery system able to reach the tumor microenvironment, reducing the undesired systemic toxic effects. Moreover, these nanosystems are prepared under scalable methodologies and straightforward process, and provide tumor selectivity through a smart mechanism independent of targeting ligands.

Piano-Stool Ruthenium(II) Complexes with Delayed Cytotoxic Activity: Origin of the Lag Time.

We have recently reported a series of piano-stool ruthenium(II) complexes of the general formula [RuCl2(η6-arene)(P(1-pyrenyl)R2R3)] showing excellent cytotoxic activities (particularly when R2 = R3 = methyl). In the present study, new members of this family of compounds have been prepared with the objective to investigate the effect of the steric hindrance of a bulky phosphane ligand, namely diisopropyl(1-pyrenyl)phosphane (L), on exchange reactions involving the coordinated halides (X = Cl, I). Two η6-arene rings were used, i.e. η6-methyl benzoate (mba) and η6-p-cymene (p-cym), and four complexes were synthesized, namely [RuCl2(mba)(L)] (1Cl2iPr), [RuI2(mba)(L)] (1I2iPr), [RuCl2(p-cym)(L)] (2Cl2iPr), and [RuI2(p-cym)(L)] (2I2iPr). Unexpectedly, all of the complexes exhibited poor cytotoxic activities after 24 h of incubation with cells, in contrast to the related compounds previously reported. However, it was observed that aged DMSO solutions of 2I2iPr (from 2 to 7 days) exhibited better activities in comparison to freshly prepared solutions and that the activity improved over "aging" time. Thorough studies were therefore performed to uncover the origin of this lag time in the cytotoxicity efficiency. The data achieved clearly demonstrated that compounds 2I2iPr and 2Cl2iPr were undergoing a series of transformation reactions in DMSO (with higher rates for the iodido complex 2I2iPr), ultimately generating cyclometalated species through a mechanism involving DMSO as a coordinated proton abstractor. The cyclometalated complexes detected in solution were subsequently prepared; hence, pure [RuCl(p-cym)(κ2C-diisopropyl(1-pyrenyl)phosphane)] (3CliPr), [RuI(p-cym)(κ2C-diisopropyl(1-pyrenyl)phosphane)] (3IiPr), and [Ru(p-cym)(κS-dmso)(κ2C-diisopropyl(1-pyrenyl)phosphane)]PF6 (3dmsoiPr) were synthesized and fully characterized. Remarkably, 3CliPr, 3IiPr, and 3dmsoiPr are all very efficient cytotoxic agents, exhibiting slightly better activities in comparison to the chlorido noncyclometalated complexes [RuCl2(η6-arene)(P(1-pyrenyl)R2R3)] described in an earlier report. For comparison purposes, the iodido compounds [RuI2(mba)(dimethyl(1-pyrenyl)phosphane)] (1I2Me) and [RuI2(p-cym)(dimethyl(1-pyrenyl)phosphane)] (2I2Me), bearing the less hindered dimethyl(1-pyrenyl)phosphane ligand, have also been prepared. The cytotoxic and chemical behaviors of 1I2Me and 1I2Me were comparable to those of their chlorido counterparts reported previously.

Lactate in the Tumor Microenvironment: An Essential Molecule in Cancer Progression and Treatment.

Cancer is a complex disease that includes the reprogramming of metabolic pathways by malignant proliferating cells, including those affecting the tumor microenvironment (TME). The "TME concept" was introduced in recognition of the roles played by factors other than tumor cells in cancer progression. In response to the hypoxic or semi-hypoxic characteristic of the TME, cancer cells generate a large amount of lactate via the metabolism of glucose and glutamine. Export of this newly generated lactate by the tumor cells together with H+ prevents intracellular acidification but acidifies the TME. In recent years, the importance of lactate and acidosis in carcinogenesis has gained increasing attention, including the role of lactate as a tumor-promoting metabolite. Here we review the existing literature on lactate metabolism in tumor cells and the ability of extracellular lactate to direct the metabolic reprogramming of those cells. Studies demonstrating the roles of lactate in biological processes that drive or sustain carcinogenesis (tumor promotion, angiogenesis, metastasis and tumor resistance) and lactate's role as an immunosuppressor that contributes to tumor evasion are also considered. Finally, we consider recent therapeutic efforts using available drugs directed at and interfering with lactate production and transport in cancer treatment.

Stimuli-Responsive Cycloaurated "OFF-ON" Switchable Anion Transporters.

Anion transporters have shown potential application as anti-cancer agents that function by disrupting homeostasis and triggering cell death. In this research article we report switchable anion transport by gold complexes of anion transporters that are "switched on" in situ in the presence of the reducing agent GSH by decomplexation of gold. GSH is found in higher concentrations in tumors than in healthy tissue and hence this approach offers a strategy to target these systems to tumors.

Click-tambjamines as efficient and tunable bioactive anion transporters.

A novel class of transmembrane anion carriers, the click-tambjamines, display remarkable anionophoric activities in model liposomes and living cells. The versatility of this building block for the generation of molecular diversity offers promise to develop future drugs based on this design.

Targeting Autophagy for Cancer Treatment and Tumor Chemosensitization.

Autophagy is a tightly regulated catabolic process that facilitates nutrient recycling from damaged organelles and other cellular components through lysosomal degradation. Deregulation of this process has been associated with the development of several pathophysiological processes, such as cancer and neurodegenerative diseases. In cancer, autophagy has opposing roles, being either cytoprotective or cytotoxic. Thus, deciphering the role of autophagy in each tumor context is crucial. Moreover, autophagy has been shown to contribute to chemoresistance in some patients. In this regard, autophagy modulation has recently emerged as a promising therapeutic strategy for the treatment and chemosensitization of tumors, and has already demonstrated positive clinical results in patients. In this review, the dual role of autophagy during carcinogenesis is discussed and current therapeutic strategies aimed at targeting autophagy for the treatment of cancer, both under preclinical and clinical development, are presented. The use of autophagy modulators in combination therapies, in order to overcome drug resistance during cancer treatment, is also discussed as well as the potential challenges and limitations for the use of these novel therapeutic strategies in the clinic.

The Natural-Based Antitumor Compound T21 Decreases Survivin Levels through Potent STAT3 Inhibition in Lung Cancer Models.

Lung cancer is the leading cause of cancer-related deaths worldwide; hence novel treatments for this malignancy are eagerly needed. Since natural-based compounds represent a rich source of novel chemical entities in drug discovery, we have focused our attention on tambjamines, natural compounds isolated from marine invertebrates that have shown diverse pharmacological activities. Based on these structures, we have recently identified the novel indole-based tambjamine analog 21 (T21) as a promising antitumor agent, which modulates the expression of apoptotic proteins such as survivin. This antiapoptotic protein plays an important role in carcinogenesis and chemoresistance. In this work, we have elucidated the molecular mechanism by which the anticancer compound T21 exerts survivin inhibition and have validated this protein as a therapeutic target in different lung cancer models. T21 was able to reduce survivin protein levels in vitro by repressing its gene expression through the blockade of Janus kinase/Signal Transducer and Activator of Transcription-3 (JAK/STAT3)/survivin signaling pathway. Interestingly, this occurred even when the pathway was overstimulated with its ligand interleukin 6 (IL-6), which is frequently overexpressed in lung cancer patients who show poor clinical outcomes. Altogether, these results show T21 as a potent anticancer compound that effectively decreases survivin levels through STAT3 inhibition in lung cancer, appearing as a promising therapeutic drug for cancer treatment.

DNA-binding and in vitro cytotoxic activity of platinum(II) complexes of curcumin and caffeine.

Three Pt(II) complexes containing the natural ligands curcumin and caffeine, namely [Pt(curc)(PPh3)2]Cl (1), [PtCl(curc)(DMSO)] (2) (curc = deprotonated curcumin) and trans-[Pt(caffeine)Cl2(DMSO)] (3), were synthesized and fully characterized. The data obtained suggest that, for both 1 and 2, the anion of curcumin is coordinated to the platinum ion via the oxygen atoms of the ß-diketonate moiety. Spectroscopic features reveal that in 2 and 3, a DMSO molecule is S-bonded to the metal centre. For 3, all data indicate a square-planar geometry formed by a 9-N bonded caffeine, two trans chloride anions and a DMSO. The three complexes undergo changes in solution upon incubation for 24 h; 1 and 2 release curcumin while 3 isomerizes from trans to cis configuration. The DNA-binding and cytotoxic properties of 1-3 were evaluated in vitro. Despite their structural similarity, curcuminate-containing 1 and 2 exhibit distinct DNA interactions. While 1 appears to intercalate between nucleobase pairs, inducing the oxidative degradation of the biomolecule, 2 behaves as a groove binder, by means of electrostatic forces. Caffeine-containing 3 exhibits a behaviour that is comparable to that of 2. Complexes 1 and 2 showed moderate to high cytotoxicity and selectivity against several cancer cell lines, while 3 is inactive. Compounds 1 and 2 can be further activated by visible-light irradiation.

Highly Cytotoxic Ruthenium(II)-Arene Complexes from Bulky 1-Pyrenylphosphane Ligands.

In the present study, the potential anti-neoplastic properties of a series of ruthenium half-sandwich complexes of formula [Ru(η6-arene)Cl2(PR1R2(1-pyrenyl))] (η6-arene = p-cymene and R1 = R2 = methyl for 1; η6-arene = methylbenzoate and R1 = R2 = methyl for 2; η6-arene = p-cymene and R1 = R2 = phenyl for 3; η6-arene = methylbenzoate and R1 = R2 = phenyl for 4; η6-arene = p-cymene, R1 = methyl and R2 = phenyl for 5; η6-arene = methylbenzoate, R1 = methyl and R2 = phenyl for 6) have been investigated. The six structurally related organoruthenium(II) compounds have been prepared in good yields and fully characterized; the X-ray structures of three of them, i.e., 1, 2, and 4, were determined. Although the piano-stool compounds contain a large polycyclic aromatic moiety, viz. a 1-pyrenyl group, they do not appear to interact with DNA. However, all the piano-stool complexes show significant cytotoxic properties against five human cell lines, namely, lung adenocarcinoma (A549), melanoma (A375), colorectal adenocarcinoma (SW620), breast adenocarcinoma (MCF7), and nontumorigenic epithelial breast (MCF10A), with IC50 values in the micromolar range for most of them. In addition, the most active compound, i.e., 2, induces a remarkable decrease of cell viability, that is in the nanomolar range, against two human neuroblastoma cell lines, namely, SK-N-BE(2) and CHLA-90. Complexes 1-6 are all capable of inducing apoptosis, but with various degrees of magnitude. Whereas 1, 3, 5, and 6 have no effect on the cell cycle of A375 cells, 2 and 4 can arrest it at the G2/M phase; furthermore, 2 (which is the most efficient compound of the series) also stops the cycle at the S phase, behaving as the well-known anticancer agent cisplatin. Finally, 2 is able to inhibit/reduce the cell migration of neuroblastoma SK-N-BE(2) cells.

Full elucidation of the transmembrane anion transport mechanism of squaramides using in silico investigations.

A comprehensive experimental and theoretical investigation of the transmembrane chloride transport promoted by four series of squaramide derivatives, with different degrees of fluorination, number of convergent N-H binding units and conformational shapes, is reported. The experimental chloride binding and transport abilities of these small synthetic molecules in liposomes were rationalised with quantum descriptors and molecular dynamics simulations in POPC bilayers. The tripodal tren-based compounds, with three squaramide binding motifs, have high chloride affinity, isolating the anion from water molecules within the membrane model and preventing its release to the aqueous phase, in agreement with the absence of experimental transport activity. In contrast, the symmetrical mono-squaramides, with moderate chloride binding affinity, are able to bind and release chloride either in the aqueous phase or at the membrane interface level, in line with experimentally observed high transport activity. The PMF profiles associated with the diffusion of these free transporters and their chloride complexes across phospholipid bilayers show that the assisted chloride translocation is thermodynamically favoured.

DNA interactions of non-chelating tinidazole-based coordination compounds and their structural, redox and cytotoxic properties.

Novel tinidazole (tnz) coordination compounds of different geometries were synthesised, whose respective solid-state packing appears to be driven by inter- and intramolecular lone pairπ interactions. The copper(ii) compounds exhibit interesting redox properties originating from both the tnz and the metal ions. These complexes interact with DNA through two distinct ways, namely via electrostatic interactions or/and groove binding, and they can mediate the generation of ROS that damage the biomolecule. Cytotoxic studies revealed an interesting activity of the dinuclear compound [Cu(tnz)2(µ-Cl)Cl]27, which is further more efficient towards cancer cells, compared with normal cells.

Photoactivation of the Cytotoxic Properties of Platinum(II) Complexes through Ligand Photoswitching.

The development of photoactivatable metal complexes with potential anticancer properties is a topical area of current investigation. Photoactivated chemotherapy using coordination compounds is typically based on photochemical processes occurring at the metal center. In the present study, an innovative approach is applied that takes advantage of the remarkable photochemical properties of diarylethenes. Following a proof-of-concept study with two complexes, namely, C1 and C2, a series of additional platinum(II) complexes from dithienylcyclopentene-based ligands was designed and prepared. Like C1 and C2, these new coordination compounds exhibit two thermally stable, interconvertible photoisomers that display distinct properties. The photochemical behavior of ligands L3-L7 has been analyzed by 1H NMR and UV-vis spectroscopies. Subsequently, the corresponding platinum(II) complexes C3-C7 were synthesized and fully characterized, including by single-crystal X-ray diffraction for some of them. Next, the interaction of each photoisomer (i.e., containing the open or closed ligand) of the metal complexes with DNA was examined thoroughly using various techniques, revealing their distinct DNA-binding modes and affinities, as observed for the earlier compounds C1 and C2. The antiproliferative activity of the two forms of the complexes was then assessed with five cancer cell lines and compared with that of C1 and C2, which supported the use of such diarylethene-based systems for the generation of a new class of potential photochemotherapeutic metallodrugs.

Small molecule anionophores promote transmembrane anion permeation matching CFTR activity.

Anion selective ionophores, anionophores, are small molecules capable of facilitating the transmembrane transport of anions. Inspired in the structure of natural product prodigiosin, four novel anionophores 1a-d, including a 1,2,3-triazole group, were prepared. These compounds proved highly efficient anion exchangers in model phospholipid liposomes. The changes in the hydrogen bond cleft modified the anion transport selectivity exhibited by these compounds compared to prodigiosin and suppressed the characteristic high toxicity of the natural product. Their activity as anionophores in living cells was studied and chloride efflux and iodine influx from living cells mediated by these derivatives was demonstrated. These compounds were shown to permeabilize cellular membranes to halides with efficiencies close to the natural anion channel CFTR at doses that do not compromise cellular viability. Remarkably, optimal transport efficiency was measured in the presence of pH gradients mimicking those found in the airway epithelia of Cystic Fibrosis patients. These results support the viability of developing small molecule anionophores as anion channel protein surrogates with potential applications in the treatment of conditions such as Cystic Fibrosis derived from the malfunction of natural anion transport mechanisms.