A click chemistry approach identifies target proteins of xanthohumol

Brodziak-Jarosz, Lidia; Fujikawa, Yuuta; Pastor-Flores, Daniel; Kasikci, Sonay; Jirásek, Petr; Pitzl, Sebastian; Owen, Robert W.; Klika, Karel D.; Gerhäuser, Clarissa; Amslinger, Sabine; Dick, Tobias P.

doi:10.1002/mnfr.201500613

Cited by 20 publications

(27 citation statements)

References 24 publications

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“…419–422 For the chalcone’s target identification, the design of the chalcone probes adopts one of the above strategies or a combination of them to obtain a multifunctional probe to identify their targets successfully. 25,101,289,374,423 For more information on the development of small-molecule probes, several recent reviews are available 374,399…”

Section: Target Identificationmentioning

confidence: 99%

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Chalcone: A Privileged Structure in Medicinal Chemistry

et al. 2017

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Privileged structures have been widely used as an effective template in medicinal chemistry for drug discovery. Chalcone is a common simple scaffold found in many naturally occurring compounds. Many chalcone derivatives have also been prepared due to their convenient synthesis. These natural products and synthetic compounds have shown numerous interesting biological activities with clinical potentials against various diseases. This review aims to highlight the recent evidence of chalcone as a privileged scaffold in medicinal chemistry. Multiple aspects of chalcone will be summarized herein, including the isolation of novel chalcone derivatives, the development of new synthetic methodologies, the evaluation of their biological properties, and the exploration of the mechanisms of action as well as target identification. This review is expected to be a comprehensive, authoritative, and critical review of the chalcone template to the chemistry community.

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Section: Target Identificationmentioning

confidence: 99%

“…289 Structurally, xanthohumol (Table 1, entry 17) is very similar to 4hydroxyderricin ( 142 ). Interestingly, this compound has attracted much attention due to its potential as a cancer chemopreventive agent.…”

Section: Target Identificationmentioning

confidence: 99%

Chalcone: A Privileged Structure in Medicinal Chemistry

et al. 2017

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“…Interestingly, the authors recorded that both the hydrogenation of 2 and Nrf2-knockdown in PC12 cells abolished its neuroprotective effect, indicating that the α,β-unsaturated ketone structure in 2 and the activation of Nrf2 are key determinants for the neuroprotection of 2 . More recently, Brodziak-Jarosz et al confirmed the ability of 2 to form a covalent bond with the sensor protein Keap1, an event that triggers Nrf2 activation, using a click chemistry approach and AREc32 cells [ 27 ]. They showed a weaker electrophilicity for 2 , suggesting its more selective interaction with the most nucleophilic thiols.…”

Section: Targeting the Nrf2 Pathway By Natural Chalconesmentioning

confidence: 99%

The Keap1/Nrf2-ARE Pathway as a Pharmacological Target for Chalcones

et al. 2018

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Chalcones have shown a broad spectrum of biological activities with clinical potential against various diseases. The biological activities are mainly attributed to the presence in the chalcones of the α,β-unsaturated carbonyl system, perceived as a potential Michael acceptor. Chalcones could activate the Kelch-like ECH-associated protein 1 (Keap1)/Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway through a Michael addition reaction with the cysteines of Keap1, which acts as a redox sensor and negative regulator of Nrf2. This modification allows the dissociation of Nrf2 from the cytoplasmic complex with Keap1 and its nuclear translocation. At this level, Nrf2 binds to the antioxidant response element (ARE) and activates the expression of several detoxification, antioxidant and anti-inflammatory genes as well as genes involved in the clearance of damaged proteins. In this regard, the Keap1/Nrf2–ARE pathway is a new potential pharmacological target for the treatment of many chronic diseases. In this review we summarize the current progress in the study of Keap1/Nrf2–ARE pathway activation by natural and synthetic chalcones and their potential pharmacological applications. Among the pharmacological activities highlighted, anti-inflammatory activity was more evident than others, suggesting a multi-target Michael acceptor mechanism for the chalcones involving key regulators of the Nrf2 and nuclear factor- κB (NF-κB) pathways.

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“…Further studies will be necessary to dissect the underlying molecular mode of action. Due to its electrophilic nature, 1 directly affects several cellular targets and signaling pathways 29 and modulates activity of kinases, such as Akt and AMPK, and of transcription factors, such as Nrf2, NF-kB, or STAT3. 19 , 30 , 31 All those signaling molecules may conceivably contribute to the reduced neointima formation.…”

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confidence: 99%

Xanthohumol Blocks Proliferation and Migration of Vascular Smooth Muscle Cellsin Vitroand Reduces Neointima Formationin Vivo

et al. 2017

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Xanthohumol (1) is a principal prenylated chalcone found in hops. The aim of this study was to examine its influence on platelet-derived growth factor (PDGF)-BB-triggered vascular smooth muscle cell (VSMC) proliferation and migration in vitro and on experimentally induced neointima formation in vivo. Quantification of resazurin conversion indicated that 1 can inhibit PDGF-BB-induced VSMC proliferation concentration-dependently (IC50 = 3.49 μM). Furthermore, in a wound-healing assay 1 potently suppresses PDGF-BB-induced VSMC migration at 15 μM. Tested in a mouse femoral artery cuff model, 1 significantly reduces neointima formation. Taken together, we show that 1 represses PDGF-BB-induced VSMC proliferation and migration in vitro as well as neointima formation in vivo. This novel activity suggests 1 as an interesting candidate for further studies addressing a possible therapeutic application to counteract vascular proliferative disease.

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A click chemistry approach identifies target proteins of xanthohumol

Abstract: We find support for the notion that XN modulates multiple pathways and processes by covalent modification of proteins with reactive cysteines.

Cited by 20 publications

References 24 publications

Chalcone: A Privileged Structure in Medicinal Chemistry

Chalcone: A Privileged Structure in Medicinal Chemistry

The Keap1/Nrf2-ARE Pathway as a Pharmacological Target for Chalcones

Xanthohumol Blocks Proliferation and Migration of Vascular Smooth Muscle Cellsin Vitroand Reduces Neointima Formationin Vivo

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