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Benzylic systems such as 9H-xanthenes, 9H-thioxanthenes and 9,10-dihydroacridines can be easily oxidized to the corresponding xanthones, thioxanthones or acridones, respectively, in deep eutectic solvents by a visible blue light-promoted photooxidation procedure carried out using ambient air as oxidant in the presence of riboflavin tetraacetate as a metal-free photocatalyst. The obtained yields are high or almost quantitative, and the reaction media can be recovered and reused. The environmental friendliness of the protocol is demonstrated based on several green metrics.

Systemic fungal infections caused by filamentous fungi, particularly in the immunocompromised population, represent a serious threat to public health. The increase in resistant strains to classic antifungal drugs, especially azoles, is a global health problem, with some infections becoming almost impossible to treat. Furthermore, the emergence of new multidrug-resistant fungal species, such as Scedosporium spp. and Fusarium spp., as etiological agents, poses a challenge in treatment. On the other hand, superficial fungal infections caused by dermatophytes have a high incidence rate, affecting approximately 20 to 30% of the healthy human population. Therefore, the discovery and development of new broad-spectrum antifungal compounds able to modulate and/or eradicate antifungal resistance have become an essential and urgent task. Taking into account that thioxanthones are privileged structures and bioisosteres of xanthones, three thioxanthones were synthesized and, subsequently, their activity as potential agents against filamentous fungi was evaluated. A minimum inhibitory concentration and minimum lethal concentration was tested against clinically relevant species using the broth microdilution method. The derivatives were synthesized through aromatic nucleophilic substitution reactions using a chlorinated thioxanthone and a primary amine as the building blocks. This showed interesting results against most of the isolates tested, including intrinsically resistant strains or those that acquired resistance to fluconazole or other azoles; among the tested compounds, one of the thioxanthone showed more promising activity. These findings highlight the potential value of thioxanthone derivatives as new models for antifungal agents for the treatment of systemic and superficial fungal infections.

Thioxanthone and its analogues, 2‐ or 4‐isopropylthioxanthone, 2‐chlorothioxanthone, 2,4‐diethylthioxanthone (DETX) and xanthone, are used as photoinitiators of ultraviolet (UV) light‐initiated curable inks. As these photoinitiators were found in numerous food/beverage products packaged in cartons printed with UV‐cured inks, the cytotoxic effects and mechanisms of these compounds were studied in freshly isolated rat hepatocytes. The toxicity of DETX was greater than that of other compounds. DETX elicited not only concentration (0–2.0 mm)‐ and time (0–3 hours)‐dependent cell death accompanied by the depletion of cellular adenosine triphosphate (ATP), and reduced glutathione (GSH) and protein thiol levels, but also the accumulation of GSH disulfide and malondialdehyde. Pretreatment of hepatocytes with either fructose at a concentration of 10 mm or N‐acetyl‐l‐cysteine (NAC) at a concentration of 5.0 mm ameliorated DETX (1 mm)‐induced cytotoxicity. Further, the exposure of hepatocytes to DETX resulted in the induction of reactive oxygen species (ROS) and loss of mitochondrial membrane potential, both of which were partially prevented by the addition of NAC. These results indicate that: (1) DETX‐induced cytotoxicity is linked to mitochondrial failure and depletion of cellular GSH; (2) insufficient cellular ATP levels derived from mitochondrial dysfunction were, at least in part, ameliorated by the addition of fructose; and (3) GSH loss and/or ROS formation was prevented by NAC. Taken collectively, these results suggest that the onset of toxic effects caused by DETX may be partially attributable to cellular energy stress as well as oxidative stress. The exposure of rat hepatocytes to thioxanthone photoinitiators, especially 2,4‐diethylthioxanthone (DETX), caused cell death accompanied by the depletion of intracellular ATP and glutathione, and the induction of glutathione disulfide, all of which were partially prevented by the preincubation with N‐acetyl‐L‐cysteine (NAC) or fructose. DETX‐induced cytotoxicity was also associated by mitochondrial dysfunction and reactive oxygen species formation, which could be prevented by NAC. These results suggest that DETX‐induced cytotoxicity may be attributable to cellular energy stress and/or oxidative stress. [ABSTRACT FROM AUTHOR]

The overexpression of efflux pumps is one of the causes of multidrug resistance, which leads to the inefficacy of drugs. This plays a pivotal role in antimicrobial resistance, and the most notable pumps are the AcrAB-TolC system (AcrB belongs to the resistance-nodulation-division family) and the NorA, from the major facilitator superfamily. In bacteria, these structures can also favor virulence and adaptation mechanisms, such as quorum-sensing and the formation of biofilm. In this study, the design and synthesis of a library of thioxanthones as potential efflux pump inhibitors are described. The thioxanthone derivatives were investigated for their antibacterial activity and inhibition of efflux pumps, biofilm formation, and quorum-sensing. The compounds were also studied for their potential to interact with P-glycoprotein (P-gp, ABCB1), an efflux pump present in mammalian cells, and for their cytotoxicity in both mouse fibroblasts and human Caco-2 cells. The results concerning the real-time ethidium bromide accumulation may suggest a potential bacterial efflux pump inhibition, which has not yet been reported for thioxanthones. Moreover, in vitro studies in human cells demonstrated a lack of cytotoxicity for concentrations up to 20 µM in Caco-2 cells, with some derivatives also showing potential for P-gp modulation.

Bright lanthanide based probes for optical bioimaging must rely on the antenna principle, where the lanthanide‐centred excited state is formed by a complex sensitization process. Efficient sensitization of lanthanide‐centred emission occurs via triplet states centred on the sensitizing chromophore. Here, the triplet state of thioxanthone chromophores is modulated by extending the π‐system. Three thioxanthone chromophores‐thioxanthone, benzo[c]thioxanthone, and naphtho[2,3‐c]thioxanthone were synthesised and characterised. The triplet state energies and lifetimes is found to change as expected, and two dyes are found to be suitable sensitizers for europium(iii) luminescence. Reactive derivatives of thioxanthone and benzo[c]thioxanthone were prepared and coupled to a 1,4,7,10‐tetraazacyclododecane‐1,4,7‐triacetic acid (DO3A) lanthanide binding pocket. The photophysics and the performance in optical bioimaging of the resulting europium(iii) complexes were investigated. It is concluded that while the energetics favour efficient sensitization, the solution structure does not. While it was found that the complexes are too lipophilic to be efficient luminescent probes for optical bioimaging, we successfully demonstrated bioimaging using europium(iii) luminescence following 405 nm excitation. [ABSTRACT FROM AUTHOR]

9H-Xanthenes, 9H-thioxanthenes and 9,10-dihydroacridines can be easily oxidized to the corresponding xanthones, thioxanthones and acridones, respectively, by a simple photo-oxidation procedure carried out using molecular oxygen as oxidant under the irradiation of visible blue light and in the presence of riboflavin tetraacetate as a metal-free photocatalyst. The obtained yields are high or quantitative.

This work reviews the contributions of the corresponding author (M.M.M.P.) and her research group to Medicinal Chemistry concerning the isolation from plant and marine sources of xanthone derivatives as well as their synthesis, biological/pharmacological activities, formulation and analytical applications. Although her group activity has been spread over several chemical families with relevance in Medicinal Chemistry, the main focus of the investigation and research has been in the xanthone family. Xanthone derivatives have a variety of activities with great potential for therapeutic applications due to their versatile framework. The group has contributed with several libraries of xanthones derivatives, with a variety of activities such as antitumor, anticoagulant, antiplatelet, anti-inflammatory, antimalarial, antimicrobial, hepatoprotective, antioxidant, and multidrug resistance reversal effects. Besides therapeutic applications, our group has also developed xanthone derivatives with analytical applications as chiral selectors for liquid chromatography and for maritime application as antifouling agents for marine paints. Chemically, it has been challenging to afford green chemistry methods and achieve enantiomeric purity of chiral derivatives. In this review, the structures of the most significant compounds will be presented.

Thioxanthones – being readily available in one step from thiosalicylic acid and arenes – were used in ruthenium-catalyzed C–H-activation reaction to produce 1-mono- or 1,8-disubstituted thioxanthones in good to excellent yields. Scope and limitation of this reaction are presented.

Recently, thioxanthone derivatives were found to protect cells against toxic P-glycoprotein (P-gp) substrates, acting as potent inducers/activators of this efflux pump. The study of new P-gp chiral modulators produced from thioxanthone derivatives could clarify the enantioselectivity of this ABC transporter towards this new class of modulators. The aim of this study was to evaluate the P-gp modulatory ability of four enantiomeric pairs of new synthesized chiral aminated thioxanthones (ATxs) 1–8, studying the influence of the stereochemistry on P-gp induction/ activation in cultured Caco-2 cells. The data displayed that all the tested compounds (at 20 μM) significantly decreased the intracellular accumulation of a P-gp fluorescent substrate (rhodamine 123) when incubated simultaneously for 60 min, demonstrating an increased activity of the efflux, when compared to control cells. Additionally, all of them except ATx 3 (+), caused similar results when the accumulation of the P-gp fluorescent substrate was evaluated after pre-incubating cells with the test compounds for 24 h, significantly reducing the rhodamine 123 intracellular accumulation as a result of a significant increase in P-gp activity. However, ATx 2 (−) was the only derivative that, after 24 h of incubation, significantly increased P-gp expression. These results demonstrated a significantly increased P-gp activity, even without an increase in P-gp expression. Therefore, ATxs 1–8 were shown to behave as P-gp activators. Furthermore, no significant differences were detected in the activity of the protein when comparing the enantiomeric pairs. Nevertheless, ATx 2 (−) modulates P-gp expression differently from its enantiomer, ATx 1 (+). These results disclosed new activators and inducers of P-gp and highlight the existence of enantioselectivity in the induction mechanism. [ABSTRACT FROM AUTHOR]

A simple, rapid and economical method was developed and validated for the analysis and quantification of 1-(propan-2-ylamino)-4-propoxy-9 H-thioxanthen-9-one (TX5), a P-glycoprotein inducer/activator, in biological samples, using reverse-phase high-performance liquid chromatography (HPLC). A C18 column and a mobile phase composed of methanol-water (90/10, v/v) with 1% (v/v) triethylamine, at a flow rate of 1 mL/min, were used for chromatographic separation. TX5 standards (0.5-150 μ m) were prepared in human serum. Methanol was used for TX5 extraction and serum protein precipitation. After filtration, samples were injected into the HPLC apparatus and TX5 was quantified by a conventional UV detector at 255 nm. The TX5 retention time was 13 min in this isocratic system. The method was validated according to ICH guidelines for specificity/selectivity, linearity, accuracy, precision, limits of detection and quantification (LOD and LOQ) and recovery. The method was proved to be selective, as there were no interferences of endogenous compounds with the same retention time of TX5. Also, the developed method was linear ( r 2 ≥ 0.99) for TX5 concentrations between 0.5 and 150 μ m and the LOD and LOQ were 0.08 and 0.23 μ m, respectively. The results indicated that the reported method could meet the requirements for TX5 analysis in the trace amounts expected to be present in biological samples. [ABSTRACT FROM AUTHOR]

The search for novel anticancer small molecules and strategies remains a challenge. Our previous studies have identified TXA1 (1-{[2-(diethylamino)ethyl]amino}-4-propoxy-9H- thioxanthen-9-one) as a hit compound, with in vitro antitumor potential by modulating autophagy and apoptosis in human tumor cell lines. In the present study, the mechanism of action and antitumor potential of the soluble salt of this molecule (TXA1.HCl) was further investigated using in vitro and mouse xenograft tumor models of NSCLC. Our results showed that TXA1.HCl affected steroid biosynthesis, increased RagD expression, and caused abnormal cellular cholesterol localization. In addition, TXA1.HCl treatment presented no toxicity to nude mice and significantly reduced the growth of human NSCLC cells xenografts in mice. Overall, this work provides new insights into the mechanism of action of TXA1, which may be relevant for the development of anticancer therapeutic strategies, which target cholesterol transport.

Recently, thioxanthone derivatives were found to protect cells against toxic P-glycoprotein (P-gp) substrates, acting as potent inducers/activators of this efflux pump. The study of new P-gp chiral modulators produced from thioxanthone derivatives could clarify the enantioselectivity of this ABC transporter towards this new class of modulators. The aim of this study was to evaluate the P-gp modulatory ability of four enantiomeric pairs of new synthesized chiral aminated thioxanthones (ATxs) 1–8, studying the influence of the stereochemistry on P-gp induction/ activation in cultured Caco-2 cells. The data displayed that all the tested compounds (at 20 μM) significantly decreased the intracellular accumulation of a P-gp fluorescent substrate (rhodamine 123) when incubated simultaneously for 60 min, demonstrating an increased activity of the efflux, when compared to control cells. Additionally, all of them except ATx 3 (+), caused similar results when the accumulation of the P-gp fluorescent substrate was evaluated after pre-incubating cells with the test compounds for 24 h, significantly reducing the rhodamine 123 intracellular accumulation as a result of a significant increase in P-gp activity. However, ATx 2 (−) was the only derivative that, after 24 h of incubation, significantly increased P-gp expression. These results demonstrated a significantly increased P-gp activity, even without an increase in P-gp expression. Therefore, ATxs 1–8 were shown to behave as P-gp activators. Furthermore, no significant differences were detected in the activity of the protein when comparing the enantiomeric pairs. Nevertheless, ATx 2 (−) modulates P-gp expression differently from its enantiomer, ATx 1 (+). These results disclosed new activators and inducers of P-gp and highlight the existence of enantioselectivity in the induction mechanism.

(1) Background: Our previous studies unveiled the hit thioxanthone TXA1 as an inhibitor of P-glycoprotein (drug efflux pump) and of human tumor cells growth, namely of melanoma cells. Since TXA1 is structurally similar to lucanthone (an autophagy inhibitor and apoptosis inducer) and to N10-substituted phenoxazines (isosteres of thioxanthones, and autophagy inducers), this study aimed at further assessing its cytotoxic mechanism and evaluating its potential as an autophagy modulator in A375-C5 melanoma cells; (2) Methods: Flow cytometry with propidium iodide (PI) for cell cycle profile analysis; Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, flow cytometry with Annexin V/PI labeling and Western blot for apoptosis analysis were conducted. A pharmacophore approach was used for mapping TXA1 onto pharmacophores for autophagy induction. Autophagy analyses included transmission electron microscopy for visualization of autophagic structures, fluorescence microscopy for observation of monodansylcadaverine (MDC) staining, pattern of LC3 expression in the cells and acridine orange staining, and Western blot for autophagic proteins expression; (3) Results: TXA1 induced autophagy of melanoma cells at the GI50 concentration (3.6 μM) and apoptosis at twice that concentration. Following treatment with TXA1, autophagic structures were observed, together with the accumulation of autophagosomes and the formation of autophagolysosomes. An increase in LC3-II levels was also observed, which was reverted by 3-methyladenine (3-MA) (an early stage autophagy-inhibitor) but further increased by E-64d/pepstatin (late-stage autophagy inhibitors). Finally, 3-MA also reverted the effect of TXA1 in cellular viability; (4) Conclusion: TXA1 decreases the viability of melanoma cells by modulation of autophagy and may, therefore, serve as a lead compound for the development of autophagy modulators with antitumor activity. [ABSTRACT FROM AUTHOR]

Thioxanthone (TX) and its derivatives, which are widely used as photoinitiators in UV curing technology, hold promising research interest in biological applications. In particular, the use of TXs as anticancer agent has recently been manifested as an outstanding additional property of this class of molecules. Incorporation of TX molecules into specially designed polymers widens their practical use in such applications. In this study, two water-soluble, biocompatible, and stable polymers, namely poly(vinyl alcohol) and poly(ethylene glycol), possessing TX moieties at the side chains and chain ends, respectively, are prepared and used as anticancer and radiotherapy agents. The findings confirm that both polymers are potential candidates for therapeutic agents as they possess useful features including water-solubility, radiosensitizer effect, and anticancer activity in a polymeric scaffold. [ABSTRACT FROM AUTHOR]

Our previous work has described a library of thioxanthones designed to have dual activity as P-glycoprotein modulators and antitumor agents. Some of these compounds had shown a significant cell growth inhibitory activity towards leukemia cell lines, without affecting the growth of non-tumor human fibroblasts. However, their effect in cell lines derived from solid tumors has not been previously studied. The present work aimed at: (i) screening this small series of compounds from an in-house library, for their in vitro cell growth inhibitory activity in human tumor cell lines derived from solid tumors; and (ii) initiate a study of the effect of the most potent compound on apoptosis. The tumor cell growth inhibitory effect of 27 compounds was first analysed in different human tumor cell lines, allowing the identification of a hit compound, TXA1. Its hydrochloride salt TXA1- HCl was then synthesized, to improve solubility and bioavailability. Both TXA1 and TXA1- HCl inhibited the growth of MCF-7, NCI-H460, A375-C5, HeLa, 786-O, Caki-2 and AGS cell lines. The effect of TXA1- HCl in MCF-7 cells was found to be irreversible and was associated, at least in part, with an increase in cellular apoptosis. [ABSTRACT FROM AUTHOR]

The induction of P-glycoprotein (P-gp), an ATP-dependent efflux pump, has been proposed as a strategy against the toxicity induced by P-gp substrates such as the herbicide paraquat (PQ). The aim of this study was to screen five newly synthetized thioxanthonic derivatives, a group known to interact with P-gp, as potential inducers of the pump's expression and/or activity and to evaluate whether they would afford protection against PQ-induced toxicity in Caco-2 cells. All five thioxanthones (20 µM) caused a significant increase in both P-gp expression and activity as evaluated by flow cytometry using the UIC2 antibody and rhodamine 123, respectively. Additionally, it was demonstrated that the tested compounds, when present only during the efflux of rhodamine 123, rapidly induced an activation of P-gp. The tested compounds also increased P-gp ATPase activity in MDR1-Sf9 membrane vesicles, indicating that all derivatives acted as P-gp substrates. PQ cytotoxicity was significantly reduced in the presence of four thioxanthone derivatives, and this protective effect was reversed upon incubation with a specific P-gp inhibitor. In silico studies showed that all the tested thioxanthones fitted onto a previously described three-feature P-gp induction pharmacophore. Moreover, in silico interactions between thioxanthones and P-gp in the presence of PQ suggested that a co-transport mechanism may be operating. Based on the in vitro activation results, a pharmacophore model for P-gp activation was built, which will be of further use in the screening for new P-gp activators. In conclusion, the study demonstrated the potential of the tested thioxanthonic compounds in protecting against toxic effects induced by P-gp substrates through P-gp induction and activation. Graphical Abstract: [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

The series of mercaptoalkoxy-thioxanthones, new group of photoinitiators for free radical polymerization, are synthesized and characterized. The kinetics of free radical polymerization was studied using a polymerization solution composed of either monomer (2-ethyl-2-(hydroxymethyl)-1,3-propanediol triacrylate (TMPTA)) and initiator (synthesized thioxanthone derivatives) for one-component photoinitiating system or monomer, initiator and co-initiator ( N-phenyl-glycine (NPG)) for two-component photoinitiating system. These compounds effectively initiate a acrylate polymerization. Based on the mechanism on the electron-transfer process and nanosecond laser flash photolysis experiments, we proposed sequence of reactions leading to the formation of radical species capable of initiating the chain reaction. [ABSTRACT FROM AUTHOR]

In the search of voltage stabilizers for high voltage underground cables the chemical synthesis and electrical tree inhibiting effect of a series of thioxanthone derivatives in cross-linked low-density polyethylene (XLPE) is reported. The strongest increase in electrical tree initiation field under high-voltage alternating current (HVAC) conditions was 55% compared to reference XLPE after the addition of 0.3 wt% 9-oxo-9H-thioxanthen-2-yl methacrylate. Thermal analysis, small angle X-ray scattering and gel content measurements showed that the addition of the stabilizers did not significantly influence the microstructure and gel fraction of XLPE. A comparison between the stabilizing effects of the thioxanthone derivatives and previously reported photophysical properties revealed that a short lifetime of the triplet excited state can be related to a good voltage-stabilizing effect. [ABSTRACT FROM AUTHOR]

(1) Background: Our previous studies unveiled the hit thioxanthone TXA1 as an inhibitor of P-glycoprotein (drug efflux pump) and of human tumor cells growth, namely of melanoma cells. Since TXA1 is structurally similar to lucanthone (an autophagy inhibitor and apoptosis inducer) and to N10-substituted phenoxazines (isosteres of thioxanthones, and autophagy inducers), this study aimed at further assessing its cytotoxic mechanism and evaluating its potential as an autophagy modulator in A375-C5 melanoma cells; (2) Methods: Flow cytometry with propidium iodide (PI) for cell cycle profile analysis; Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, flow cytometry with Annexin V/PI labeling and Western blot for apoptosis analysis were conducted. A pharmacophore approach was used for mapping TXA1 onto pharmacophores for autophagy induction. Autophagy analyses included transmission electron microscopy for visualization of autophagic structures, fluorescence microscopy for observation of monodansylcadaverine (MDC) staining, pattern of LC3 expression in the cells and acridine orange staining, and Western blot for autophagic proteins expression; (3) Results: TXA1 induced autophagy of melanoma cells at the GI50 concentration (3.6 μM) and apoptosis at twice that concentration. Following treatment with TXA1, autophagic structures were observed, together with the accumulation of autophagosomes and the formation of autophagolysosomes. An increase in LC3-II levels was also observed, which was reverted by 3-methyladenine (3-MA) (an early stage autophagy-inhibitor) but further increased by E-64d/pepstatin (late-stage autophagy inhibitors). Finally, 3-MA also reverted the effect of TXA1 in cellular viability; (4) Conclusion: TXA1 decreases the viability of melanoma cells by modulation of autophagy and may, therefore, serve as a lead compound for the development of autophagy modulators with antitumor activity.

Our previous work has described a library of thioxanthones designed to have dual activity as P-glycoprotein modulators and antitumor agents. Some of these compounds had shown a significant cell growth inhibitory activity towards leukemia cell lines, without affecting the growth of non-tumor human fibroblasts. However, their effect in cell lines derived from solid tumors has not been previously studied. The present work aimed at: (i) screening this small series of compounds from an in-house library, for their in vitro cell growth inhibitory activity in human tumor cell lines derived from solid tumors; and (ii) initiate a study of the effect of the most potent compound on apoptosis. The tumor cell growth inhibitory effect of 27 compounds was first analysed in different human tumor cell lines, allowing the identification of a hit compound, TXA1. Its hydrochloride salt TXA1·HCl was then synthesized, to improve solubility and bioavailability. Both TXA1 and TXA1·HCl inhibited the growth of MCF-7, NCI-H460, A375-C5, HeLa, 786-O, Caki-2 and AGS cell lines. The effect of TXA1·HCl in MCF-7 cells was found to be irreversible and was associated, at least in part, with an increase in cellular apoptosis.

Abstract: The palladium(0)-catalyzed Suzuki cross-coupling reactions of the bis(triflates) of 1,3- and 1,4-dihydroxythioxanthone afforded various aryl-substituted thioxanthones. While the Suzuki reactions of the bis(triflate) derived from 1,3-dihydroxythioxanthone proceeded by site-selective attack in favor of position 3, the reactions of the bis(triflate) of 1,4-dihydroxythioxanthone proceeded in favor of position 1. The site-selectivity is controlled by steric and electronic parameters. [Copyright &y& Elsevier]

Abstract: For many pathologies, there is a crescent effort to design multiple ligands that interact with a wide variety of targets. 1-Aminated thioxanthone derivatives were synthesized and assayed for their in vitro dual activity as antitumor agents and P-glycoprotein (P-gp) inhibitors. The approach was based on molecular hybridization of a thioxanthone scaffold, present in known antitumor drugs, and an amine, described as an important pharmacophoric feature for P-gp inhibition. A rational approach using homology modeling and docking was used, to select the molecules to be synthesized by conventional or microwave-assisted Ullmann C–N cross-coupling reaction. The obtained aminated thioxanthones were highly effective at inhibiting P-gp and/or causing growth inhibition in a chronic myelogenous leukemia cell line, K562. Six of the aminated thioxanthones had GI50 values in the K562 cell line below 10μM and 1-{[2-(diethylamino)ethyl]amino}-4-propoxy-9H-thioxanthen-9-one (37) had a GI50 concentration (1.90μM) 6-fold lower than doxorubicin (11.89μM) in the K562Dox cell line. The best P-gp inhibitor found was 1-[2-(1H-benzimidazol-2-yl)ethanamine]-4-propoxy-9H-thioxanthen-9-one (45), which caused an accumulation rate of rhodamine-123 similar to that caused by verapamil in the K562Dox resistant cell line, and a decrease in ATP consumption by P-gp. At a concentration of 10μM, compound 45 caused a decrease of 12.5-fold in the GI50 value of doxorubicin in the K562Dox cell line, being 2-fold more potent than verapamil. From the overall results, the aminated thioxanthones represent a new class of P-gp inhibitors with improved efficacy in sensitizing a resistant P-gp overexpressing cell line (K562Dox) to doxorubicin. [Copyright &y& Elsevier]

Abstract: The palladium(0)-catalyzed Suzuki cross-coupling reaction of the bis(triflate) of 1,3-dihydroxythioxanthone afforded various aryl-substituted thioxanthones. The reactions proceeded with very good site-selectivity in favour of position 3, due to steric reasons. [Copyright &y& Elsevier]

Thioxanthones are aromatic hydrocarbons with cytotoxic activity against several tumor models. Potential mechanisms of action may include DNA intercalation, inhibition of nucleic acid biosynthesis, and topoisomerase inhibition, as well as formation of intracellular DNA single strand breaks. Such a broad spectrum of expected antitumor activity makes this class of compounds particularly interesting and worth pursuing in clinical studies. SW 33377 (Win 33377, SR 233377) was so promising in vitro that it was taken into Phase I clinical trials for further evaluation. The compound had undesirable cardiac effects, so new analogs were sought that would have similar antitumor effects without the undesirable side effects. In the present study, two new analogs SW 68210 (WIN 68210), and SW 71425 (WIN 71425) are compared to the antiproliferative action of SW 33377 against a variety of freshly explanted human tumor specimens using an in vitro soft agar cloning system. All compounds were more effective with continuous exposure than 1 hour exposure and a concentration-response effect was evident with all compounds. SW 68210 with continuous exposure showed similar activity to SW 33377 at all concentrations. SW 71425 with continuous exposure was less effective at the lower concentrations but was nearly as effective at 10 μg/ml as the other two compounds and was highly effective at 50 μg/ml. At the 10 μg/ml concentration all compounds were similarly effective against breast, colon, non-small cell lung, and ovarian tumors. The two new analogs, SW 68210 and SW 71425 have activity similar to SW 33377 and are both likely candidates for further development. [ABSTRACT FROM AUTHOR]

The overexpression of efflux pumps is one of the causes of multidrug resistance, which leads to the inefficacy of drugs. This plays a pivotal role in antimicrobial resistance, and the most notable pumps are the AcrAB-TolC system (AcrB belongs to the resistance-nodulation-division family) and the NorA, from the major facilitator superfamily. In bacteria, these structures can also favor virulence and adaptation mechanisms, such as quorum-sensing and the formation of biofilm. In this study, the design and synthesis of a library of thioxanthones as potential efflux pump inhibitors are described. The thioxanthone derivatives were investigated for their antibacterial activity and inhibition of efflux pumps, biofilm formation, and quorum-sensing. The compounds were also studied for their potential to interact with P-glycoprotein (P-gp, ABCB1), an efflux pump present in mammalian cells, and for their cytotoxicity in both mouse fibroblasts and human Caco-2 cells. The results concerning the real-time ethidium bromide accumulation may suggest a potential bacterial efflux pump inhibition, which has not yet been reported for thioxanthones. Moreover, in vitro studies in human cells demonstrated a lack of cytotoxicity for concentrations up to 20 µM in Caco-2 cells, with some derivatives also showing potential for P-gp modulation. [ABSTRACT FROM AUTHOR]

9H-Xanthenes, 9H-thioxanthenes and 9,10-dihydroacridines can be easily oxidized to the corresponding xanthones, thioxanthones and acridones, respectively, by a simple photo-oxidation procedure carried out using molecular oxygen as oxidant under the irradiation of visible blue light and in the presence of riboflavin tetraacetate as a metal-free photocatalyst. The obtained yields are high or quantitative. [ABSTRACT FROM AUTHOR]

This work reviews the contributions of the corresponding author (M.M.M.P.) and her research group to Medicinal Chemistry concerning the isolation from plant and marine sources of xanthone derivatives as well as their synthesis, biological/pharmacological activities, formulation and analytical applications. Although her group activity has been spread over several chemical families with relevance in Medicinal Chemistry, the main focus of the investigation and research has been in the xanthone family. Xanthone derivatives have a variety of activities with great potential for therapeutic applications due to their versatile framework. The group has contributed with several libraries of xanthones derivatives, with a variety of activities such as antitumor, anticoagulant, antiplatelet, anti-inflammatory, antimalarial, antimicrobial, hepatoprotective, antioxidant, and multidrug resistance reversal effects. Besides therapeutic applications, our group has also developed xanthone derivatives with analytical applications as chiral selectors for liquid chromatography and for maritime application as antifouling agents for marine paints. Chemically, it has been challenging to afford green chemistry methods and achieve enantiomeric purity of chiral derivatives. In this review, the structures of the most significant compounds will be presented. [ABSTRACT FROM AUTHOR]

In vitro studies showed that 1-(propan-2-ylamino)-4-propoxy-9 H -thioxanthen-9-one (TX5) increases P-glycoprotein (P-gp) expression and activity in Caco-2 cells, preventing xenobiotic toxicity. The present study aimed at investigating TX5 effects on P-gp expression/activity using Wistar Han rats: a) in vivo , evaluating intestinal P-gp activity; b) ex vivo , evaluating P-gp expression in ileum brush border membranes (BBM) and P-gp activity in everted intestinal sacs; c) ex vivo, evaluating P-gp activity in everted intestinal sacs of the distal and proximal ileum. TX5 (30 mg/kg, b.w.), gavage, activated P-gp in vivo , given the significant decrease in the AUC of digoxin (0.25 mg/kg, b.w.). The efflux of rhodamine 123 (300 μM), a P-gp fluorescent substrate, significantly increased in TX5-treated everted sacs from the distal portion of the rat ileum, when P-gp activity was evaluated in the presence of TX5 (20 μM), an effect abolished by the P-gp inhibitor verapamil (100 μM). No increases on P-gp expression or activity were found in TX5-treated BBM of the distal ileum and everted distal sacs, respectively, 24 h after TX5 (10 mg/kg, b.w.) administration. In vivo , no differences were found on digoxin portal concentration between control (digoxin 0.025 mg/kg, b.w., intraduodenal) and TX5-treated (digoxin+TX5 20 μM, intraduodenal) rats. The observed discrepancies in digoxin results can be related to differences in TX5 dose administered and used methodologies. Thus, the results show that TX5 activates P-gp at the distal portion of the rat ileum, and, at the higher dose tested (30 mg/kg, b.w.), seems to modulate in vivo the AUC of P-gp substrates. Unlabelled Image • P-glycoprotein (P-gp) is a carrier efflux protein. • TX5 activates P-gp ex vivo , only at the distal portion of the rat ileum. • TX5 seems to modulate, in vivo, the AUC of P-gp substrates. [ABSTRACT FROM AUTHOR]

Front Cover: -Expanded Thioxanthones - Engineering the Triplet Level of Thioxanthone Sensitizers for Lanthanide-Based Luminescent Probes with Visible Excitation (ChemPlusChem 12/2019) Keywords: lanthanides; luminescence; molecular probes; thioxanthones; triplet sensitizers Lanthanides, luminescence, molecular probes, thioxanthones, triplet sensitizers. [Extracted from the article]

P-glycoprotein (P-gp) is an ATP-binding cassette transporter involved in the efflux of numerous compounds that influences the pharmacokinetics of xenobiotics. It reduces intestinal absorption and exposure of target cells to toxicity. Thioxanthones are compounds able to induce and/or activate P-gp in vitro . Particularly, 1-(propan-2-ylamino)-4-propoxy-9 H -thioxanthen-9-one (TX5) behaves as a P-gp inducer and activator in vitro . The aims of this study were: i) to perform a histological characterization, by testing a single high dose of TX5 [30 mg/kg, body weight (b.w.), gavage], administered to Wistar Han rats, 24 hours after administration; and ii) to perform both a complete histological characterization and a preliminary safety evaluation, in distinct target organs, 24 hours after administration of a single lower dose of TX5 (10 mg/kg, b.w., gavage) to Wistar Han rats. The results showed a relevant histological toxicity for the higher dose of TX5 administered (30 mg/kg, b.w.), manifested by extensive hepatic necrosis and splenic toxicity (parenchyma with hyperemia, increased volume of both white and red pulp, increased follicles marginal zone). Moreover, in the kidneys, a slight hyperemia and tubular edema were observed in TX5-treated animals, as well as an inflammation of the small intestine. On the contrary, for the lower tested dose (10 mg/kg, b.w.), we did not observe any relevant histological toxicity in the evaluated organs. Additionally, no significant differences were found in the ATP levels between TX5-exposed and control animals in any of the evaluated organs, with the exception of the intestine, where ATP levels were significantly higher in TX5-treated rats. Similarly, TX5 caused a significant increase in the ratio GSH/GSSG only in the lungs. TX5 (10 mg/kg, b.w.) did not induce any change in any of the hematological and biochemical circulating evaluated parameters. However, TX5 was able to significantly reduce the activated partial thromboplastin time, without affecting the prothrombin time. The urine biochemical analysis revealed a TX5-mediated increase in both creatinine and sodium. Taken together, our results show that TX5, at a dose of 10 mg/kg, does not induce considerable toxicity in the biological matrices studied. Given this adequate safety profile, TX5 becomes a particularly interesting compound for ex vivo and in vivo studies, regarding the potential for induction and activation of P-gp at the intestinal barrier., (Copyright © 2019 Rocha-Pereira et al.)

The search for novel anticancer small molecules and strategies remains a challenge. Our previous studies have identified TXA1 (1-{[2-(diethylamino)ethyl]amino}-4-propoxy-9H- thioxanthen-9-one) as a hit compound, with in vitro antitumor potential by modulating autophagy and apoptosis in human tumor cell lines. In the present study, the mechanism of action and antitumor potential of the soluble salt of this molecule (TXA1.HCl) was further investigated using in vitro and mouse xenograft tumor models of NSCLC. Our results showed that TXA1.HCl affected steroid biosynthesis, increased RagD expression, and caused abnormal cellular cholesterol localization. In addition, TXA1.HCl treatment presented no toxicity to nude mice and significantly reduced the growth of human NSCLC cells xenografts in mice. Overall, this work provides new insights into the mechanism of action of TXA1, which may be relevant for the development of anticancer therapeutic strategies, which target cholesterol transport. [ABSTRACT FROM AUTHOR]

A simple, rapid and economical method was developed and validated for the analysis and quantification of 1-(propan-2-ylamino)-4-propoxy-9H-thioxanthen-9-one (TX5), a P-glycoprotein inducer/activator, in biological samples, using reverse-phase high-performance liquid chromatography (HPLC). A C 18 column and a mobile phase composed of methanol-water (90/10, v/v) with 1% (v/v) triethylamine, at a flow rate of 1 mL/min, were used for chromatographic separation. TX5 standards (0.5-150 μm) were prepared in human serum. Methanol was used for TX5 extraction and serum protein precipitation. After filtration, samples were injected into the HPLC apparatus and TX5 was quantified by a conventional UV detector at 255 nm. The TX5 retention time was 13 min in this isocratic system. The method was validated according to ICH guidelines for specificity/selectivity, linearity, accuracy, precision, limits of detection and quantification (LOD and LOQ) and recovery. The method was proved to be selective, as there were no interferences of endogenous compounds with the same retention time of TX5. Also, the developed method was linear (r 2  ≥ 0.99) for TX5 concentrations between 0.5 and 150 μm and the LOD and LOQ were 0.08 and 0.23 μm, respectively. The results indicated that the reported method could meet the requirements for TX5 analysis in the trace amounts expected to be present in biological samples., (Copyright © 2016 John Wiley & Sons, Ltd.)

Thioxanthones - being readily available in one step from thiosalicylic acid and arenes - were used in ruthenium-catalyzed C-H-activation reaction to produce 1-mono- or 1,8-disubstituted thioxanthones in good to excellent yields. Scope and limitation of this reaction are presented.