Extensive Structure Modification on Luteolin-Cinnamic Acid Conjugates Leading to BACE1 Inhibitors with Optimal Pharmacological Properties

Sun, Deyang; Cheng, Chen; Moschke, Katrin; Huang, Jian; Fang, Wei‐Shuo

doi:10.3390/molecules25010102

Cited by 6 publications

(6 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Among all of the examined flavanones, hesperidin demonstrated the best inhibition of BACE-1, AChE, and BChE, with IC 50 values of 10.02, 22.80, and 48.09 µM, respectively. Kinetic studies revealed that all the flavanones were noncompetitive inhibitors of BACE-1 and cholinesterase [ 101 , 102 ].…”

Section: Flavonoids Attenuate Human Diseases Via Direct Interactiomentioning

confidence: 99%

Flavonoids-Macromolecules Interactions in Human Diseases with Focus on Alzheimer, Atherosclerosis and Cancer

2021

View full text Add to dashboard Cite

Flavonoids, a class of polyphenols, consumed daily in our diet, are associated with a reduced risk for oxidative stress (OS)-related chronic diseases, such as cardiovascular disease, neurodegenerative diseases, cancer, and inflammation. The involvement of flavonoids with OS-related chronic diseases have been traditionally attributed to their antioxidant activity. However, evidence from recent studies indicate that flavonoids' beneficial impact may be assigned to their interaction with cellular macromolecules, rather than exerting a direct antioxidant effect. This review provides an overview of the recent evolving research on interactions between the flavonoids and lipoproteins, proteins, chromatin, DNA, and cell-signaling molecules that are involved in the OS-related chronic diseases; it focuses on the mechanisms by which flavonoids attenuate the development of the aforementioned chronic diseases via direct and indirect effects on gene expression and cellular functions. The current review summarizes data from the literature and from our recent research and then compares specific flavonoids’ interactions with their targets, focusing on flavonoid structure–activity relationships. In addition, the various methods of evaluating flavonoid–protein and flavonoid–DNA interactions are presented. Our aim is to shed light on flavonoids action in the body, beyond their well-established, direct antioxidant activity, and to provide insights into the mechanisms by which these small molecules, consumed daily, influence cellular functions.

show abstract

Section: Flavonoids Attenuate Human Diseases Via Direct Interactiomentioning

confidence: 99%

Flavonoids-Macromolecules Interactions in Human Diseases with Focus on Alzheimer, Atherosclerosis and Cancer

2021

View full text Add to dashboard Cite

show abstract

“…One bio-effective constituent is cinnamic acid, a BACE1 inhibitor. Sun et al [ 72 ] have coupled cinnamic acid ( p -hydroxy-cinnamic acid) with the phytochemical luteolin to develop BACE1 inhibitors with greater effectiveness. While each of them is a non-competitive inhibitor, they each bind to different regions of BACE1 [ 65 ].…”

Section: Bace1 As a Phytochemical Targetmentioning

confidence: 99%

“…While each of them is a non-competitive inhibitor, they each bind to different regions of BACE1 [ 65 ]. A series of constructs resulted in a single flavone-cinnamic acid hybrid referred to as 7c (IC 50 1.44 × 10 −6 M) that should be further examined as a potential therapy for AD [ 72 ]. This approach of developing phytochemical conjugates could possibly guide the discovery of BACE1 inhibitors that are specific for AβPP1 leading to reduced levels of Aβ, while leaving other essential substrates untouched.…”

Section: Bace1 As a Phytochemical Targetmentioning

confidence: 99%

Phytochemical Interactions with Calmodulin and Critical Calmodulin Binding Proteins Involved in Amyloidogenesis in Alzheimer’s Disease

O’Day

2023

Biomolecules

View full text Add to dashboard Cite

An increasing number of plant-based herbal treatments, dietary supplements, medical foods and nutraceuticals and their component phytochemicals are used as alternative treatments to prevent or slow the onset and progression of Alzheimer’s disease. Their appeal stems from the fact that no current pharmaceutical or medical treatment can accomplish this. While a handful of pharmaceuticals are approved to treat Alzheimer’s, none has been shown to prevent, significantly slow or stop the disease. As a result, many see the appeal of alternative plant-based treatments as an option. Here, we show that many phytochemicals proposed or used as Alzheimer’s treatments share a common theme: they work via a calmodulin-mediated mode of action. Some phytochemicals bind to and inhibit calmodulin directly while others bind to and regulate calmodulin-binding proteins, including Aβ monomers and BACE1. Phytochemical binding to Aβ monomers can prevent the formation of Aβ oligomers. A limited number of phytochemicals are also known to stimulate calmodulin gene expression. The significance of these interactions to amyloidogenesis in Alzheimer’s disease is reviewed.

show abstract

“…A later study found a linked conjugate of luteolin and p-hydroxy-cinnamic acid to be a highly potent, cellpermeable, and noncompetitive inhibitor of BACE1. 78 Further modification of this compound made it selective over other related enzymes such as BACE2 and rennin. Most of the initial BACE1 inhibitors were peptide-based and therefore cell impermeable and the challenge of generating one of the first natural scaffold-based cell-permeable inhibitors was addressed by Hwang et al They isolated lavandulyl flavanones from Sophora flavescens Aiton that show strong BACE1 inhibition in vitro as well as in human embryonic kidney cells.…”

Section: Flavonoids As Bace1 Inhibitorsmentioning

confidence: 99%

“…It was found that the flavonoid directly binds to BACE1 and also activates the estrogen receptor to reduce BACE1 transcription. A later study found a linked conjugate of luteolin and p -hydroxy-cinnamic acid to be a highly potent, cell-permeable, and noncompetitive inhibitor of BACE1 . Further modification of this compound made it selective over other related enzymes such as BACE2 and rennin.…”

Section: Flavonoids As Bace1 Inhibitorsmentioning

confidence: 99%

Scope of β-Secretase (BACE1)-Targeted Therapy in Alzheimer’s Disease: Emphasizing the Flavonoid Based Natural Scaffold for BACE1 Inhibition

Das

Sengupta

Chakraborty

2020

ACS Chem. Neurosci.

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common form of dementia in the world. Studies report the presence of extracellular amyloid plaques consisting of β-amyloid peptide and intracellular tangles consisting of hyperphosphorylated tau proteins as the histopathological indicators of AD. The process of β-amyloid peptide generation by sequential cleavage of amyloid precursor protein by β-secretase (BACE1) and γ-secretase, followed by its aggregation to form amyloid plaques, is the mechanistic basis of the amyloid hypothesis. Other popular hypotheses related to the pathogenesis of AD include the tau hypothesis and the oxidative stress hypothesis. Various targets of the amyloid cascade are now in prime focus to develop drugs for AD. Many BACE1 inhibitors, β-amyloid aggregation inhibitors, and Aβ clearance strategies using monoclonal antibodies are in various stages of clinical trials. This review provides an in-depth evaluation of the role of BACE1 in disease pathogenesis and also highlights the therapeutic approaches developed to find more potent but less toxic inhibitors for BACE1, particularly emphasizing the natural scaffold as a nontoxic lead for BACE1 inhibition. Cellular targets and signaling cascades involving BACE1 have been highlighted to understand the physiological role of BACE1. This knowledge is extremely crucial to understand the toxicity evaluations for BACE1-targeted therapy. We have particularly highlighted the scope of flavonoids as a new generation of nontoxic BACE1 inhibitory scaffolds. The structure–activity relationship of BACE1 inhibition for this group of compounds has been highlighted to provide a guideline to design more selective highly potent inhibitors. The review aims to provide a holistic overview of BACE1-targeted therapy for AD that paves the way for future drug development.

show abstract

Extensive Structure Modification on Luteolin-Cinnamic Acid Conjugates Leading to BACE1 Inhibitors with Optimal Pharmacological Properties

Cited by 6 publications

References 17 publications

Flavonoids-Macromolecules Interactions in Human Diseases with Focus on Alzheimer, Atherosclerosis and Cancer

Flavonoids-Macromolecules Interactions in Human Diseases with Focus on Alzheimer, Atherosclerosis and Cancer

Phytochemical Interactions with Calmodulin and Critical Calmodulin Binding Proteins Involved in Amyloidogenesis in Alzheimer’s Disease

Scope of β-Secretase (BACE1)-Targeted Therapy in Alzheimer’s Disease: Emphasizing the Flavonoid Based Natural Scaffold for BACE1 Inhibition

Contact Info

Product

Resources

About