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

Abstract

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.

Synthesis of a Small Library of Nature-Inspired Xanthones and Study of Their Antimicrobial Activity

“…Using several straightforward transformations, it was possible to synthetize a series of structurally diverse xanthones (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15) and evaluate their antimicrobial activity, along with a series of 19 in-house 3,4-dioxygenated xanthones 16-33. The results of antimicrobial screening revealed the potential of some of the obtained compounds either as new antibacterial (7, 8, 12, 20, 26 and 27) or antifungal (3, 26 and 27) agents, with compound 3 exhibiting a potent inhibitory effect on the growth of dermatophyte clinical strains (T. rubrum FF5, M. canis FF1 and E. floccosum FF9), with a MIC of 16 µg/mL for all the tested strains.…”

“…Although a myriad of substitution patterns can be found in natural xanthones, the presence of certain groups in specific positions imposed by their biosynthetic pathway is a known limitation that can be surpassed by the use of organic synthesis [11]. Therefore, this scaffold has been an interesting starting point for the discovery of new potential drug candidates due to its ability to display binding functionalities from a rigid dibenzo-gamma-pyrone core [12][13][14][15][16][17][18]. In a recent work, our group described the synthesis of a series of novel nature-inspired chlorinated xanthones and their antimicrobial activity [19].…”

Xanthone and Flavone Derivatives as Dual Agents with Acetylcholinesterase Inhibition and Antioxidant Activity as Potential Anti-Alzheimer Agents

“…From this study, the Mannich base derivatives 3 and 14 emerged as dual agents with AChE inhibition and antioxidant activity. The synthesis of salt form of these amines to obtain bioactive water-soluble compounds will allow further investigating their potential as dual AChE inhibitors and antioxidants [64]. Figure 4: AChE active site (surface) bound to 2 (pink sticks) and 3 (purple sticks) (pdb ID: 4EY7) (a); residues involved in hydrogen interactions (yellow broken line), stacking interactions (yellow double arrow), and -cation interactions (orange double arrow) are displayed using a stick model.…”

The Design and Synthesis of N-Xanthone Benzenesulfonamides as Novel Phosphoglycerate Mutase 1 (PGAM1) Inhibitors

“…The inhibitory activities both on the enzymatic and cellular level of those xanthone derivatives were significantly improved compared to PGMI-004A [ 22 ]. Besides, the xanthone core as an important scaffold with diverse biologic activities, such as antitumor, antioxidant, anti-inflammation, etc., was of documented relevance to human diseases [ 23 , 24 , 25 , 26 , 27 ]. In this paper, maintaining the xanthone scaffold and considering that the ortho -dihydroxy phenol moiety might cause metabolic instability [ 28 ], we removed the C2-hydroxy group to design and synthesize a series of new N -xanthone benzenesulfonamides.…”