Design, synthesis and biological evaluation of novel trimethylangelicin analogues targeting nuclear factor kB (NF-kB)

Marzaro, Giovanni; Lampronti, Ilaria; D’Aversa, Elisabetta; Sacchetti, Gianni; Miolo, Giorgia; Vaccarin, Christian; Cabrini, Giulio; Dechecchi, Maria Cristina; Gambari, Roberto; Chilin, Adriana

doi:10.1016/j.ejmech.2018.03.080

Cited by 12 publications

(10 citation statements)

References 37 publications

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“…lumacaftor and ivacaftor were obtained by Selleckchem (United States), TMA and TMA analogs were partly synthesized as previously described ( Guiotto et al, 1984 , 1995 ; Marzaro et al, 2018 ) and partly belong to the collection of the Organic Synthesis Lab (Department of Pharmaceutical Sciences, University of Padova). DMA was newly synthesized as described in the Supplementary Material.…”

Section: Methodsmentioning

confidence: 99%

“…A second series was designed and synthesized, in an effort to abolish or minimize these side effects ( Marzaro et al, 2018 ). Three additional non-mutagenic compounds were subsequently be identified: 4-isopropyl-6-ethyl-4′-methylangelicin (IPEMA), 4-propyl-6-ethyl-4′-methylangelicin (PEMA) and 4-isopropyl-6,4′-dimethylangelicin (IPDMA) (Supplementary Figure S1 ).…”

Section: Introductionmentioning

confidence: 99%

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Molecular Mechanism of Action of Trimethylangelicin Derivatives as CFTR Modulators

et al. 2018

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The psoralen-related compound, 4,6,4′-trimethylangelicin (TMA) potentiates the cAMP/PKA-dependent activation of WT-CFTR and rescues F508del-CFTR-dependent chloride secretion in both primary and secondary airway cells homozygous for the F508del mutation. We recently demonstrated that TMA, like lumacaftor (VX-809), stabilizes the first membrane-spanning domain (MSD1) and enhances the interface between NBD1 and ICL4 (MSD2). TMA also demonstrated anti-inflammatory properties, via reduction of IL-8 expression, thus making TMA a promising agent for treatment of cystic fibrosis. Unfortunately, TMA was also found to display potential phototoxicity and mutagenicity, despite the fact that photo-reactivity is absent when the compound is not directly irradiated with UVA light. Due to concerns about these toxic effects, new TMA analogs, characterized by identical or better activity profiles and minimized or reduced side effects, were synthesized by modifying specific structural features on the TMA scaffold, thus generating compounds with no mutagenicity and phototoxicity. Among these compounds, we found TMA analogs which maintained the potentiation activity of CFTR in FRT-YFP-G551D cells. Nanomolar concentrations of these analogs significantly rescued F508del CFTR-dependent chloride efflux in FRT-YFP-F508del, HEK-293 and CF bronchial epithelial cells. We then investigated the ability of TMA analogs to enhance the stable expression of varying CFTR truncation mutants in HEK-293 cells, with the aim of studying the mechanism of their corrector activity. Not surprisingly, MSD1 was the smallest domain stabilized by TMA analogs, as previously observed for TMA. Moreover, we found that TMA analogs were not effective on F508del-CFTR protein which was already stabilized by a second-site mutation at the NBD1-ICL4 interface. Altogether, our findings demonstrate that these TMA analogs mediate correction by modifying MSD1 and indirectly stabilizing the interface between NBD1 and CL4.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular Mechanism of Action of Trimethylangelicin Derivatives as CFTR Modulators

et al. 2018

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“…The data obtained ( Figure 6 ) demonstrated that compound 5 inhibited the interactions between NF-κB and a 32 P-labelled target oligonucleotide mimicking the NF-κB binding sites. The activity of compound 5 was similar to that of a known NF-κB inhibitor, trimethylangelicin (TMA); see the representative example shown in Figure 6 B, upper part of the panel [ 25 , 26 , 27 ]. Moreover, when quantitative data obtained using compound 5 , TMA, and another validated NF-κB inhibitor (corilagin) [ 28 ] were compared, compound 5 was conclusively demonstrated to exert anti NF-κB activity leading to inhibition of the formation of NF-κB/DNA complexes with an efficiency similar to that of other NF-κB control inhibitors ( Figure 6 B, lower part of the panel).…”

Section: Resultsmentioning

confidence: 78%

“…The synthetic oligonucleotides used in this study were purchased from IDT (Integrated DNA Technologies, Leuven, Belgium).Control NF-κB inhibitors were trimethylangelicin (TMA) and β-1- O -galloyl-3,6-( R )-hexahydroxydiphenoyl- d -glucose (corilagin). Synthesis of TMA has been reported elsewhere [ 25 , 26 , 27 ]; corilagin was obtained from the China National Institute for the Control of Pharmaceutical and Biological Products. For quantitative analyses, the autoradiographs were scanned through a Gel-Doc Instrument (Biorad, Hercules, CA, USA) using the QuantityOne software (Version 4, Biorad, Hercules, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

Targeting DNA Binding for NF-κB as an Anticancer Approach in Hepatocellular Carcinoma

Chung

Lam

Zhou

et al. 2018

Cells

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Quinoline core has been shown to possess a promising role in the development of anticancer agents. However, the correlation between its broad spectrum of bioactivity and the underlying mechanism of actions is poorly understood. The present study, with the use of bioinformatics approaches, reported a series of designed molecules which integrated quinoline core and sulfonyl moiety, with the objective of evaluating the substituent and linker effects on anticancer activities and associated mechanistic targets. We identified potent compounds (1h, 2h, 5 and 8) exhibiting significant anticancer effects towards liver cancer cells (Hep3B) with the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) relative values of cytotoxicity below 0.40, a value in the range of doxorubicin positive control with the value of 0.12. Bulky substituents and the presence of bromine atom, as well as the presence of sulfonamide linkage, are likely the favorable structural components for molecules exerting a strong anticancer effect. To the best of our knowledge, our findings obtained from chemical synthesis, in vitro cytotoxicity, bioinformatics-based molecular docking analysis (similarity ensemble approach, SEA),and electrophoretic mobility shift assay provided the first evidence in correlation to the anticancer activities of the selected compound 5 with the modulation on the binding of transcription factor NF-κB to its target DNA. Accordingly, compound 5 represented a lead structure for the development of quinoline-based NF-κB inhibitors and this work added novel information on the understanding of the mechanism of action for bioactive sulfonyl-containing quinoline compounds against hepatocellular carcinoma.

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“…In previous work, we defined some structural determinants of the angelicin scaffold to maintain biological activities and eliminate side effects, thus identifying 4-isopropyl-6-ethyl-4′-methylangelicin (IPEMA) ( Figure 1 ) as a promising candidate with TMA-like inhibitory activity on NF-kB/DNA interactions but lacking mutagenicity and DNA damaging properties [ 11 ]. Further investigations revealed that IPEMA significantly rescued F508del CFTR-dependent chloride efflux at nanomolar concentrations and maintained the potentiation activity of CFTR in FRT-YFP-G551D cells, acting by the same mechanism of TMA [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Improved Trimethylangelicin Analogs for Cystic Fibrosis: Design, Synthesis and Preliminary Screening

Vaccarin

Gabbia

Franceschinis

et al. 2022

IJMS

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A small library of new angelicin derivatives was designed and synthesized with the aim of bypassing the side effects of trimethylangelicin (TMA), a promising agent for the treatment of cystic fibrosis. To prevent photoreactions with DNA, hindered substituents were inserted at the 4 and/or 6 positions. Unlike the parent TMA, none of the new derivatives exhibited significant cytotoxicity or mutagenic effects. Among the synthesized compounds, the 4-phenylderivative 12 and the 6-phenylderivative 25 exerted a promising F508del CFTR rescue ability. On these compounds, preliminary in vivo pharmacokinetic (PK) studies were carried out, evidencing a favorable PK profile per se or after incorporation into lipid formulations. Therefore, the selected compounds are good candidates for future extensive investigation to evaluate and develop novel CFTR correctors based on the angelicin structure.

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Design, synthesis and biological evaluation of novel trimethylangelicin analogues targeting nuclear factor kB (NF-kB)

Cited by 12 publications

References 37 publications

Molecular Mechanism of Action of Trimethylangelicin Derivatives as CFTR Modulators

Molecular Mechanism of Action of Trimethylangelicin Derivatives as CFTR Modulators

Targeting DNA Binding for NF-κB as an Anticancer Approach in Hepatocellular Carcinoma

Improved Trimethylangelicin Analogs for Cystic Fibrosis: Design, Synthesis and Preliminary Screening

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