Synthesis, Crystallization Studies, and in vitro Characterization of Cinnamic Acid Derivatives as <i>Sm</i>HDAC8 Inhibitors for the Treatment of Schistosomiasis

Bayer, Theresa; Chakrabarti, Alokta; Lancelot, Julien; Shaik, T.B.; Hausmann, Kristin; Melesina, Jelena; Schmidtkunz, Karin; Marek, Martin; Erdmann, Frank; Schmidt, Matthias; Robaa, Dina; Romier, Christophe; Pierce, Raymond J.; Jung, Manfred; Sippl, Wolfgang

doi:10.1002/cmdc.201800238

Cited by 25 publications

(33 citation statements)

References 40 publications

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“…The 1 H-NMR and 13 C-NMR data confirm the proposed structures. According to the spectroscopic data the compounds present E- configuration [17,28,29], while characteristic C-NMR-peaks are present e.g., 1 H-NMR CH=C or e.g., 13 C-NMR C OOH 160–185 ppm. The carboxylic and phenolic protons are not recorded in the 1 H-NMR spectra when CDCl 3 [17,28] was used as a solvent.…”

Section: Resultsmentioning

confidence: 99%

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Multi-Target Cinnamic Acids for Oxidative Stress and Inflammation: Design, Synthesis, Biological Evaluation and Modeling Studies

Pontiki

Hadjipavlou‐Litina

2018

Molecules

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Inflammation is a complex phenomenon that results as a healing response of organisms to different factors, exerting immune signaling, excessive free radical activity and tissue destruction. Lipoxygenases and their metabolites e.g., LTB4, are associated with allergy, cell differentiation and carcinogenesis. Lipoxygenase 12/15 has been characterized as a mucosal-specific inhibitor of IgA and a contributor to the development of allergic sensitization and airway inflammation. Development of drugs that interfere with the formation or effects of these metabolites would be important for the treatment of various diseases like asthma, psoriasis, ulcerative colitis, rheumatoid arthritis, atherosclerosis, cancer and blood vessel disorders. In this study we extended our previous research synthesizing a series of multi-target cinnamic acids from the corresponding aldehydes with suitable 4-OH/Br substituted phenyl acetic acid by Knoevenagel condensation. The final products 1i, 3i, 3ii, 4i, 6i, 6ii, and 7i were obtained in high yields (52–98%) Their structures were verified spectrometrically, while their experimentally lipophilicity was determined as RM values. The novel derivatives were evaluated for their antioxidant activity using DPPH, hydroxyl radical, superoxide anion and ABTS+•, anti-lipid peroxidation and soybean lipoxygenase inhibition assays. The compounds presented medium interaction with DPPH (30–48% at 100 µM). In contrast all the synthesized derivatives strongly scavenge OH radicals (72–100% at 100 µM), ABTS+• (24–83% at 100 µM) and presented remarkable inhibition (87–100% at 100 µM) in linoleic acid peroxidation (AAPH). The topological polar surface of the compounds seems to govern the superoxide anion scavenging activity. Molecular docking studies were carried out on cinnamic acid derivative 3i and found to be in accordance with experimental biological results. All acids presented interesting lipoxygenase inhibition (IC50 = 7.4–100 µM) with compound 3i being the most potent LOX inhibitor with IC50 = 7.4 µM combining antioxidant activities. The antioxidant results support the LOX inhibitory activities. The recorded in vitro results highlight compound 3i as a lead compound for the design of new potent lipoxygenase inhibitors for the treatment of asthma, psoriasis, ulcerative colitis, rheumatoid arthritis, atherosclerosis, cancer and blood vessel disorders.

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Section: Resultsmentioning

confidence: 99%

“…This is commonly happens and referred in the literature. These protons are shown when DMSO [29] is used although this is not always happen due to the presence of water in DMSO.…”

Section: Resultsmentioning

confidence: 99%

Multi-Target Cinnamic Acids for Oxidative Stress and Inflammation: Design, Synthesis, Biological Evaluation and Modeling Studies

Pontiki

Hadjipavlou‐Litina

2018

Molecules

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“…In recent years, targeting the Schistosoma mansoni 99 epigenome has emerged as a new and promising strategy to control schistosomiasis. The 100 study of histone acetylation in S. mansoni biology and the effect of inhibitors of histone 101 deacetylases (HDACs and SIRTs) or histone acetyltransferases (HATs) on parasite 102 development and survival have demonstrated the importance of these enzymes as potential 103 therapeutic targets (8)(9)(10)(11)(12). 104…”

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confidence: 99%

Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni

Carneiro

Silva

Amaral

et al. 2019

Preprint

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Treatment and control of schistosomiasis still rely on only one effective drug, praziquantel (PZQ), and due to mass treatment, the increasing risk of selecting for schistosome strains that are resistant to PZQ has alerted investigators to the urgent need to develop novel therapeutic strategies. The histone-modifying enzymes (HMEs) represent promising targets for the development of epigenetic drugs against Schistosoma mansoni. In the present study, we targeted the S. mansoni lysine-specific demethylase 1 (SmLSD1), a transcriptional corepressor, using a novel and selective synthetic inhibitor, MC3935. We synthesized a novel and potent LSD1 inhibitor, MC3935, which was used to treat schistosomula or adult worms in vitro. By using cell viability assays and optical and electron microscopy, we showed that treatment with MC3935 affected parasite motility, egg-laying, tegument, and cellular organelle structures, culminating in the death of schistosomula and adult worms. In silico molecular modeling and docking analysis suggested that MC3935 binds to the catalytic pocket of SmLSD1. Western blot analysis revealed that MC3935 inhibited SmLSD1 demethylation activity of H3K4me1/2. Knockdown of SmLSD1 by RNAi recapitulated MC3935 phenotypes in adult worms. RNA-seq analysis of MC3935-treated parasites revealed significant differences in gene expression related to critical biological processes. Collectively, our findings show that SmLSD1 is a promising drug target for the treatment of schistosomiasis and strongly support the further development and in vivo testing of selective schistosome LSD1 inhibitors.Author SummarySchistosomiasis mansoni is a chronic and debilitating tropical disease caused by the helminth Schistosoma mansoni. The control and treatment of the disease rely almost exclusively on praziquantel (PZQ). Thus, there is an urgent need to search for promising protein targets to develop new drugs. Drugs that inhibit enzymes that modify the chromatin structure have been developed for a number of diseases. We and others have shown that S. mansoni epigenetic enzymes are also potential therapeutic targets. Here we evaluated the potential of the S. mansoni histone demethylase LSD1 (SmLSD1) as a drug target. We reported the synthesis of a novel and potent LSD1 inhibitor, MC3935, and show that it selectively inhibited the enzymatic activity of SmLSD1. Treatment of juvenile or adult worms with MC3935 caused severe damage to the tegument of the parasites and compromised egg production. Importantly, MC3935 proved to be highly toxic to S. mansoni, culminating in the death of juvenile or adult worms within 96 h. Transcriptomic analysis of MC3935-treated parasites revealed changes in the gene expression of hundreds of genes involved in key biological processes. Importantly, SmLSD1 contains unique sequences within its polypeptide chain that could be explored to develop a S. mansoni selective drug.

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“…Eggs laid on the plates were quantified daily and plotted as the ratio of eggs laids per day normalized by the number of coupled worms observed. The compound concentration required to cause mortality in 50% of schistosomula in culture was determined using methods previously described [11]. Briefly, 2000 schistosomula were incubated with different concentrations of MC3935.…”

Section: Viability Assaymentioning

confidence: 99%

“…In recent years, targeting the Schistosoma mansoni epigenome has emerged as a new and promising strategy to control schistosomiasis. The study of histone acetylation in S. mansoni biology and the effect of inhibitors of histone deacetylases (HDACs and SIRTs) or histone acetyltransferases (HATs) on parasite development and survival have demonstrated the importance of these enzymes as potential therapeutic targets [8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni

et al. 2020

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Treatment and control of schistosomiasis still rely on only one effective drug, praziquantel (PZQ) and, due to mass treatment, the increasing risk of selecting for schistosome strains that are resistant to PZQ has alerted investigators to the urgent need to develop novel therapeutic strategies. The histone-modifying enzymes (HMEs) represent promising targets for the development of epigenetic drugs against Schistosoma mansoni. In the present study, we targeted the S. mansoni lysine-specific demethylase 1 (SmLSD1), a transcriptional corepressor, using a novel and selective synthetic inhibitor, MC3935, which was used to treat schistosomula and adult worms in vitro. By using cell viability assays and optical and electron microscopy, we showed that treatment with MC3935 affected parasite motility, egg-laying, tegument, and cellular organelle structures, culminating in the death of schistosomula and adult worms. In silico molecular modeling and docking analysis suggested that MC3935 PLOS NEGLECTED TROPICAL DISEASES

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Synthesis, Crystallization Studies, and in vitro Characterization of Cinnamic Acid Derivatives as SmHDAC8 Inhibitors for the Treatment of Schistosomiasis

Cited by 25 publications

References 40 publications

Multi-Target Cinnamic Acids for Oxidative Stress and Inflammation: Design, Synthesis, Biological Evaluation and Modeling Studies

Multi-Target Cinnamic Acids for Oxidative Stress and Inflammation: Design, Synthesis, Biological Evaluation and Modeling Studies

Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni

Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni

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