Synthesis of Xanthones, Thioxanthones and Acridones by a Metal-Free Photocatalytic Oxidation Using Visible Light and Molecular Oxygen.

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.

Polymeric Thioxanthones as Potential Anticancer and Radiotherapy Agents.

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.

Preparation of 1-fluoro-4-methyl-9H-[carbonyl-(14) C]thioxanthen-9-one and amine derivatives.

9H-Thioxanthen-9-ones are an important class of compound and are a common heterocyclic scaffold in biologically active and medicinally significant compounds. In this paper the synthesis of 1-fluoro-4-methyl-9H-thioxanthen-9-one and some amine derivatives labeled with carboxyl-14 is described.

Screening a Small Library of Xanthones for Antitumor Activity and Identification of a Hit Compound which Induces Apoptosis.

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.

Novel 2-Thioxanthine and Dipyrimidopyridine Derivatives: Synthesis and Antimicrobial Activity.

Several fused imidazolopyrimidines were synthesized starting from 6-amino-1-methyl-2-thiouracil (1) followed by nitrosation, reduction and condensation with different aromatic aldehydes to give Schiff's base. The dehydrocyclization of Schiff's bases using iodine/DMF gave Compounds 5a-g. The methylation of 5a-g using a simple alkylating agent as dimethyl sulfate ((CH3)2SO4) gave either monoalkylated imidazolopyrimidine 6a-g at room temperature or dialkylated derivatives 7a-g on heating 6a-g with ((CH3)2SO4). On the other hand, treatment of 1 with different aromatic aldehydes in absolute ethanol in the presence of conc. hydrochloric acid at room temperature and/or reflux with acetic acid afforded bis-5,5́-diuracylmethylene 8a-e, which cyclized on heating with a mixture of acetic acid/HCl (1:1) to give 9a-e. Compounds 9a-e can be obtained directly by refluxing of Compound 1 with a mixture of acetic acid/HCl. The synthesized new compounds were screened for antimicrobial activity, and the MIC was measured.

Highly sensitive determination of low-level water content in organic solvents using novel solvatochromic dyes based on thioxanthone.

Two thioxanthone-based fluorescent probes exhibited prominent solvatofluorochromism, and they were further found to be useful as fluorescence indicators for the qualitative and quantitative detection of low-level water content in various solvent media.

A century of thioxanthones: through synthesis and biological applications.

The interest in the synthesis and applications of thioxanthones, dibenzo-gamma-thiopyrones, started in the beginning of the 20th century. Thioxanthones are traditionally synthesized via benzophenone, diarylthioether or diarylthioester intermediates. In recent years, more efficient and cleaner synthetic methodologies are being applied to obtain thioxanthone derivatives, especially for photochemical applications. Considering biological activities, the first thioxanthone introduced in therapy in 1945 was Miracil D, as an antischistosomal agent. Since then, the variety of studies of biological/ pharmacological activities of thioxanthones led to the discovery of new agents and to the disclosure of their mechanisms of action. Moreover, the ability to sensitize cancer cells suggested new and promising applications in chemotherapy. New antitumor derivatives are being developed by molecular modifications such as isosterism (aza-thioxanthones and aminoethylthioxanthones) or hybridation (psorospermine and acronycin analogues). The last generation of antitumor thioxanthones rendered a derivative, SR271425, with an excellent preclinical antitumor efficacy. The last decade has been excited in the research of thioxanthones with important achievements in both synthesis and biochemical applications, especially in order to dissociate the antitumor activity from the toxicity of drug candidates. Recently, thioxanthones emerged as dual inhibitors of P-glycoprotein and tumor cell growth. It is expected that in the following years new analogues with the thioxanthone scaffold emerge in the field of anticancer therapy, with enhanced antitumor activity and without serious side effects.

Synthesis of fluorinated benzophenones, xanthones, acridones, and thioxanthones by iterative nucleophilic aromatic substitution.

Fluorination of fluorophores can substantially enhance their photostability and improve spectroscopic properties. To facilitate access to fluorinated fluorophores, bis(2,4,5-trifluorophenyl)methanone was synthesized by treatment of 2,4,5-trifluorobenzaldehyde with a Grignard reagent derived from 1-bromo-2,4,5-trifluorobenzene, followed by oxidation of the resulting benzyl alcohol. This hexafluorobenzophenone was subjected to sequential nucleophilic aromatic substitution reactions, first at one or both of the more reactive 4,4'-fluorines, and second by cyclization through substitution of the less reactive 2,2'-fluorines, using a variety of oxygen, nitrogen, and sulfur nucleophiles, including hydroxide, methoxide, amines, and sulfide. This method yields symmetrical and asymmetrical fluorinated benzophenones, xanthones, acridones, and thioxanthones and provides scalable access to known and novel precursors to fluorinated analogues of fluorescein, rhodamine, and other derivatives. Spectroscopic studies revealed that several of these precursors are highly fluorescent, with tunable absorption and emission spectra, depending on the substituents. This approach should allow access to a wide variety of novel fluorinated fluorophores and related compounds.

Novel highly potent and selective nonsteroidal aromatase inhibitors: synthesis, biological evaluation and structure-activity relationships investigation.

In further pursuing our search for potent and selective aromatase inhibitors, a new series of molecules was designed and synthesized, exploring possible structural modifications of a previously identified xanthone scaffold. Among them, highly potent compounds, with inhibitory activity in the low nanomolar range, were found. In particular, substitution of the heterocyclic oxygen atom in the xanthone core by a sulfur atom and/or increase in structure flexibility seemed to be favorable for the interaction with the enzyme.

A facile regioselective synthesis of novel spiro-thioxanthene and spiro-xanthene-9',2-[1,3,4]thiadiazole derivatives as potential analgesic and anti-inflammatory agents.

The 1,3-dipolar cycloaddition of nitrile imines to 9H-thioxanthone-9-thione and 9H-xanthone-9-thione afforded novel spiro-thioxanthene-9',2-[1,3,4]thiadiazoles 6a-g and spiro-xanthene-9',2-[1,3,4]thiadiazoles 7a-g in good yields. Some of the newly synthesized compounds were tested for anti-inflammatory and analgesic activities comparable to ibuprofen. Compounds 6a,d,e and 7a,d,e showed significant activity compared to standard drug. The toxicity studies revealed that neither death nor other behavioral or toxicological changes were observed on rats up to a dose as high as 200 mg/kg.

Synthesis of xanthones, thioxanthones, and acridones by the coupling of arynes and substituted benzoates.

The reaction of silylaryl triflates, CsF, and ortho-heteroatom-substituted benzoates affords a general and efficient way to prepare biologically interesting xanthones, thioxanthones, and acridones. This chemistry presumably proceeds by a tandem intermolecular nucleophilic coupling of the benzoate with an aryne and a subsequent intramolecular electrophilic cyclization.

New approach to biomimetic transamination using bifunctional [1,3]-proton transfer catalysis in thioxanthenyl dioxide imines.

A pyridoxamine equivalent, 9-aminothioxanthene 10,10-dioxide, has been designed that is capable of affording transamination in good to excellent yields of natural as well as artificial amino acids. Amidines and guanidines in catalytic amounts were capable of performing [1,3]-proton transfer in the imines under mild conditions, whereas various simple amines failed. The use of chiral catalysts resulted in modest asymmetric induction (ee < or = 45%). The electronic dependence in para-substituted phenyl glyoxylate imines, isotope effects, and computational studies support a stepwise, bifunctional mechanism for amidine and guanidine catalysts. Attempts toward an autocatalytic model system are described.

Synthesis and antitumor activity of 4-aminomethylthioxanthenone and 5-aminomethylbenzothiopyranoindazole derivatives.

Two new series of antitumor agents, 4-aminomethylthioxanthenones (6-50) and 5-aminomethylbenzothiopyranoindazoles (51-61), are described and compared. Nearly all members of both series display excellent in vivo activity versus murine pancreatic adenocarcinoma 03 (Panc03) although there is little to distinguish the two series from each other. In both series there is no discernible relationship between structure and in vivo efficacy. Selected analogues were evaluated in vitro; all were observed to have moderate to strong DNA binding via intercalation. However, varying degrees of in vitro P388 cytotoxicity and topoisomerase II inhibition were seen. In general, those molecules which exhibited strong topoisomerase II inhibition were significantly more cytotoxic than those which did not. In both series, those derivatives (48-50, 60, and 61) having a phenolic hydroxy substitution exhibited the most potent P388 cytotoxicity and topoisomerase II inhibition.

Reactions with thiaxanthen-9-ol: new thiaxanthene derivatives with molluscicidal and nematocidal activity.

Thiaxanthen-9-ol (1) was condensed with nitriles 2a-e to yield the thiaxanthen-9-yl-acetonitriles 3a-e. With the thiols 7a-d, 1 yielded the thioethers 8a-d.

Synthesis of N-(9H-xanthen-9-yl)aminoalkanamide and N-(9H-thioxanthen-9-yl)aminoalkanamide derivatives and their in vitro evaluation as potential intercalators and antitumor drugs.

A series of new N-(9H-xanthen-9-yl)aminoalkanamide and N-(9H-thioxanthen-9-yl)aminoalkanamide derivatives was synthesized and evaluated as potential intercalators by measuring their DNA binding affinity. They were also tested for cytotoxic activity against L1210. The results suggest that the cytotoxicity of these molecules was not due to an intercalating mechanism.

Synthesis and antileukemic activity of 1-[(quinolizidinylalkyl)amino]4/7-R-thioxanthen-9-ones.

Fifteen 1-(quinolizidinylalkyl)amino derivatives of thioxanthenone bearing different substituents on position 4 and 7 were prepared and tested in mice against lymphocytic leukemia P 388. These compounds were inactive or displayed only borderline activity (compounds 1, 10, 15).

Acylthioxanthenes: agents which selectively reduce decerebrate rigidity in the cat.

A series of 2-acylthioxanthene-delta 9 (gamma)-propylamines was synthesized, and their effect of reducing the intercollicular decerebrate rigidity in the cat was evaluated. The compound exhibiting the greatest separation between the dosage that reduced rigidity and that which caused sedation was (Z)-2-propionyl-9-[3-(dimethylamino)propylidene]thioxanthene. The separation of Z and E isomers was monitored by 1H NMR spectroscopy, using an europium shift reagent.