Chiral Derivatives of Xanthones: Investigation of the Effect of Enantioselectivity on Inhibition of Cyclooxygenases (COX-1 and COX-2) and Binding Interaction with Human Serum Albumin

Fernandes, Carla; Palmeira, Andreia; Ramos, Inês I.; Carneiro, Carlos; Afonso, Carlos; Tiritan, Maria Elizabeth; Cidade, Honorina; Pinto, Paula C.A.G.; Saraiva, M. Lúcia M.F.S.; Reis, Salette; Pinto, Madalena

doi:10.3390/ph10020050

Cited by 25 publications

(25 citation statements)

References 70 publications

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“…Herein, we investigated the potential modulatory effect on P-gp activity and expression of four newly synthetized pairs of enantiomers of aminated thioxanthones (ATxs 1 – 8 , Figure 1 ), to clarify the enantioselectivity of this efflux pump towards the ABC transporters class. Moreover, although some examples of biological enantioselectivity were reported in the literature for structurally related xanthones [ 56 , 57 , 58 ], for thioxanthones, and specifically for P-gp modulation, data is presented here for the first time.…”

Section: Introductionmentioning

confidence: 99%

Chiral Thioxanthones as Modulators of P-glycoprotein: Synthesis and Enantioselectivity Studies

et al. 2018

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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.

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Section: Introductionmentioning

confidence: 99%

Chiral Thioxanthones as Modulators of P-glycoprotein: Synthesis and Enantioselectivity Studies

et al. 2018

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“…It is important to emphasize that, in our group, carboxyxanthone derivative 169 has been used as a suitable building block for the synthesis of several chiral derivatives [167,169] with high enantiomeric purity [170,171,172]. Some chiral derivatives showed interesting growth inhibitory activity on A375-C5, MCF-7 and NCI-H460 human tumor cell lines [167], ability to block sciatic nerve transmission [169] and inhibit cyclooxygenases 1 and 2 enzymes [173]. Some of them were also promising chiral selectors in liquid chromatography enantioseparation [21,22].…”

Section: Synthetic Carboxyxanthone Derivativesmentioning

confidence: 99%

“…In our group, carboxyxanthone derivative 289 has been used as a building block to obtain diverse chiral derivatives with potential biological activities [167,169,173], as well as chiral selectors for analytical liquid chromatography application [21,22].…”

Section: Synthetic Carboxyxanthone Derivativesmentioning

confidence: 99%

Carboxyxanthones: Bioactive Agents and Molecular Scaffold for Synthesis of Analogues and Derivatives

et al. 2019

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Xanthones represent a structurally diverse group of compounds with a broad range of biological and pharmacological activities, depending on the nature and position of various substituents in the dibenzo-γ-pyrone scaffold. Among the large number of natural and synthetic xanthone derivatives, carboxyxanthones are very interesting bioactive compounds as well as important chemical substrates for molecular modifications to obtain new derivatives. A remarkable example is 5,6-dimethylxanthone-4-acetic acid (DMXAA), a simple carboxyxanthone derivative, originally developed as an anti-tumor agent and the first of its class to enter phase III clinical trials. From DMXAA new bioactive analogues and derivatives were also described. In this review, a literature survey covering the report on carboxyxanthone derivatives is presented, emphasizing their biological activities as well as their application as suitable building blocks to obtain new bioactive derivatives. The data assembled in this review intends to highlight the therapeutic potential of carboxyxanthone derivatives and guide the design for new bioactive xanthone derivatives.

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“…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.…”

Section: Figures Schemes and Tablesmentioning

confidence: 99%

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

et al. 2018

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Upregulation of phosphoglycerate mutase 1 (PGAM1) has been identified as one common phenomenon in a variety of cancers. Inhibition of PGAM1 provides a new promising therapeutic strategy for cancer treatment. Herein, based on our previous work, a series of new N-xanthone benzenesulfonamides were discovered as novel PGAM1 inhibitors. The representative molecule 15h, with an IC50 of 2.1 μM, showed an enhanced PGAM1 inhibitory activity and higher enzyme inhibitory specificity compared to PGMI-004A, as well as a slightly improved antiproliferative activity.

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Chiral Derivatives of Xanthones: Investigation of the Effect of Enantioselectivity on Inhibition of Cyclooxygenases (COX-1 and COX-2) and Binding Interaction with Human Serum Albumin

Cited by 25 publications

References 70 publications

Chiral Thioxanthones as Modulators of P-glycoprotein: Synthesis and Enantioselectivity Studies

Chiral Thioxanthones as Modulators of P-glycoprotein: Synthesis and Enantioselectivity Studies

Carboxyxanthones: Bioactive Agents and Molecular Scaffold for Synthesis of Analogues and Derivatives

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

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