Tetracyclic Thioxanthene Derivatives: Studies on Fluorescence and Antitumor Activity

Abstract

Thioxanthones are bioisosteres of the naturally occurring xanthones. They have been described for multiple activities, including antitumor. As such, the synthesis of a library of thioxanthones was pursued, but unexpectedly, four tetracyclic thioxanthenes with a quinazoline–chromene scaffold were obtained. These compounds were studied for their human tumor cell growth inhibition activity, in the cell lines A375-C5, MCF-7 and NCI-H460. Photophysical studies were also performed. Two of the compounds displayed GI50 values below 10 µM for the three tested cell lines, and structure–activity relationship studies were established. Three compounds presented similar wavelengths of absorption and emission, characteristic of dyes with a push-pull character. The structures of two compounds were elucidated by X-ray crystallography. Two tetracyclic thioxanthenes emerged as hit compounds. One of the two compounds accumulated intracellularly as a bright fluorescent dye in the green channel, as analyzed by both fluorescence microscopy and flow cytometry, making it a promising theranostic cancer drug candidate.

Antimicrobial Activity of a Library of Thioxanthones and Their Potential as Efflux Pump Inhibitors

“…A remarkable increase in the intracellular fluorescence of cells exposed to compounds 10-13 and 15-17 was observed, making it impossible to assess the effect of these thioxanthone derivatives on P-gp expression. In fact, compounds 15-17 had previously been reported as fluorescent compounds [15] and this characteristic limited some of the studies reported herein. Only compounds 9 and 14 were tested further for their potential to modulate P-gp expression.…”

“…Four tetracyclic thioxanthenes (15-18, Table 1) were also synthesized under the same conditions as compounds 8-13. These were obtained from guanidine or urea derivatives leading to a quinazoline-thiochromene scaffold, as previously described [15]. material for the coupling with sulfamides, which were less reactive (procedure b).…”

“…The syntheses of compounds 2-7 [11] and 15-18 [15] have been previously reported. Compounds 8-13 were synthesized in the same way as 15-18, through a copper-catalyzed Ullmann-type C-N coupling, starting from compound 1 or 14.…”

Intramolecular Friedel–Crafts Reaction with Trifluoroacetic Acid: Synthesizing Some New Functionalized 9-Aryl/Alkyl Thioxanthenes

“…The synthesis of xanthenes, especially thioxanthenes, has increased remarkably in recent years due to their wide range of biological and pharmacological properties. As an example of its biological and pharmacological properties, anticancer, − antitumor, − antiviral, antimicrobial, − antibacterial, − and anti-inflammatory activities can be cited. Moreover, some types are also used as materials in dye technology, , sensor, , and organic light-emitting diodes (OLEDs) − due to the conjugation and heteroring in their structures, ensuring optical and electrochemical properties.…”