Modified methylenedioxyphenol analogs lower LDL cholesterol through induction of LDL receptor expression

Zhao, Ying; Rajagopal, D.; Xu, Xiaohua; Maiseyeu, Andrei; Liu, Cuiqing; Sun, Qinghua; Ziouzenkova, Ouliana; Parthasarathy, S.; Rajagopalan, Sanjay

doi:10.1194/jlr.m022806

Cited by 8 publications

(6 citation statements)

References 31 publications

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“…LMDP contains the moieties of lipoic acid and methylenedioxyphenol that were shown to inhibit atherosclerotic progression in different animal models [ 13 , 16 , 20 ]. Notably, while lipoic acid and methylenedioxyphenol were shown to inhibit atherosclerotic progression at least partly through their effects on lipoprotein metabolism [ 13 , 22 ], the present study did not observe any significant effect of LMDP on plasma lipoproteins, suggesting that the anti-atherosclerotic mechanism of LMDP is different from that of lipoic acid and methylenedioxyphenol. Reinforcing this notion, treatment with LMDP did not have a significant effect on body weight, whereas treatment with lipoic acid has consistently been shown to decrease body weight [ 13 , 25 ].…”

Section: Discussioncontrasting

confidence: 71%

“…Plasma lipoproteins, in particular LDL and HDL, play a central role in the development of atherosclerosis, and we previously showed that another methylenedioxyphenol derive INV-403 lowers LDL cholesterol through induction of LDL receptor expression [ 22 ]. To test if LMDP inhibits atherosclerotic progression through change in lipoprotein levels, plasma of control and LMDP-treated animals were subjected to lipoprotein profiling.…”

Section: Resultsmentioning

confidence: 99%

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Lipoicmethylenedioxyphenol Reduces Experimental Atherosclerosis through Activation of Nrf2 Signaling

et al. 2016

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ObjectiveOxidative stress is implicated in the pathogenesis of atherosclerosis, and Nrf2 is the transcriptional factor central in cellular antioxidant responses. In the present study, we investigate the effect of a dihydrolipoic acid derivative lipoicmethylenedioxyphenol (LMDP) on the progression of atherosclerosis and test whether its effect on atherosclerosis is mediated by Nrf2.Methods and ResultsBoth magnetic resonance imaging (MRI) scanning and en face analysis reveal that 14 weeks of treatment with LMDP markedly reduced atherosclerotic burden in a rabbit balloon vascular injury model. Myograph analyses show decreased aortic contractile response to phenylephrine and increased aortic response to acetylcholine and insulin in LMDP-treated animals, suggesting that LMDP inhibits atherosclerosis through improving vascular function. A role of Nrf2 signaling in mediating the amelioration of vascular function by LMDP was supported by increased Nrf2 translocation into nuclear and increased expression of Nrf2 target genes. Furthermore, chemotaxis analysis with Boydem chamber shows that leukocytes isolated from LMDP-treated rabbits had reduced chemotaxis, and knock-down of Nrf2 significantly reduced the effect of LMDP on the chemotaxis of mouse macrophages.ConclusionOur results support that LMDP has an anti-atherosclerotic effect likely through activation of Nrf2 signaling and subsequent inhibition of macrophage chemotaxis.

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Section: Discussioncontrasting

confidence: 71%

Section: Resultsmentioning

confidence: 99%

Lipoicmethylenedioxyphenol Reduces Experimental Atherosclerosis through Activation of Nrf2 Signaling

et al. 2016

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“…The synthesis of 6-nitrobenzo[1,3]dioxol-5-ol 11c was accomplished in three steps, as depicted in Scheme 3. In detail, commercially available sesamol 14 was converted in its acetyl analogue 15, that was nitrated with HNO3/AcOH [49] to give the acetic acid 6-nitrobenzo[1,3]dioxol-5-yl ester 16.…”

Section: Chemistrymentioning

confidence: 99%

First dual AK/GSK-3β inhibitors endowed with antioxidant properties as multifunctional, potential neuroprotective agents

Brogi

Ramunno

Savi

et al. 2017

European Journal of Medicinal Chemistry

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“…All social groups are affected by the serious global health problem of CVD. A class of bioactive scaffolds known as substituted methylenedioxyphenyl (MDP) derivatives have been shown to possess antioxidant, antibacterial, antiobesity, antidiabetic, and anti-inflammatory properties. − The MDP pharmacophore remains of great interest to many research teams as it routinely provides encouraging results for the treatment of CVD. − A naturally occurring phytochemical derived from Piper nigrum (spice bell pepper), piperonylic acid, has MDP pharmacophore. The piperine in P.…”

Section: Introductionmentioning

confidence: 99%

“…This is probably due to nucleophilic oxygen in the diether group which readily donates electrons to the electrophilic center for interacting with protein residues within the active site to facilitate biological interactions. Also, the fifth and sixth positions of the MDP group are shown to influence the bioactivity of the molecule. ,− From the literature, MDP with nitro substitution at the sixth position is shown to offer better cardioprotective effects . Therefore, the nitro group at the sixth position is kept intact and further modification was done at the fifth position to get better bioactive derivatives.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Structural Elucidation, In Silico and In Vitro Studies of New Class of Methylenedioxyphenyl-Based Amide Derivatives as Potential Myeloperoxidase Inhibitors for Cardiovascular Protection

Rajan,

Karthikeyan,

Desikan

2024

ACS Omega

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Novel methylenedioxyphenyl-based amides, especially N-(4-methoxybenzyl)-6-nitrobenzo-[1,3]-dioxole-5-carboxamide (MDC) and N-(3-acetylphenyl)-6-nitrobenzo-[1,3]-dioxole-5-carboxamide (ADC), potential cardiovascular preventive agents, are successfully synthesized, and their chemical structures are verified by 1 H and 13 C NMR, Fourier transform infrared (FT-IR), high-resolution mass spectrometry (HRMS), and single-crystal Xray diffraction (SC-XRD) analyses. Data obtained from SC-XRD reveal that MDC and ADC are both monoclinic molecules with Z = 2 and 4, respectively. From density functional theory (DFT) calculations, 3.54 and 3.96 eV are the energy gaps of the optimized MDC and ADC structures, respectively. MDC and ADC exhibit an electrophilicity index value of more than 1.5 eV, suggesting that they can act as an electrophile, facilitating bond formation with biomolecules. Hirshfeld surface analysis demonstrates that more than 25% of atomic interactions in both MDC and ADC are from H•••H interactions. Based on pharmacokinetic predictions, MDC and ADC exhibit drug-like properties, and molecular docking simulations revealed favorable interactions with active site pockets. Both MDC and ADC achieved higher docking scores of −7.74 and −7.79 kcal/mol, respectively, with myeloperoxidase (MPO) protein. From docking results, MPO was found to be most favorable followed by dipeptidyl peptidase-4 (DPP-4) and α-glucosidase (α-GD). Antioxidant, anti-inflammatory, and in vitro enzymatic studies of MDC and ADC indicate that MDC is more selective toward MPO and more potent than ADC. The application of MDC to inhibit myeloperoxidase could be ascertained to reduce the cardiovascular risk factor. This can be supported from the results of computational docking (based on hydrogen bonding and docking score), in vitro antioxidant and anti-inflammatory properties, and MPO enzymatic inhibition (based on the percentage of inhibition and IC 50 values).

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Modified methylenedioxyphenol analogs lower LDL cholesterol through induction of LDL receptor expression

Cited by 8 publications

References 31 publications

Lipoicmethylenedioxyphenol Reduces Experimental Atherosclerosis through Activation of Nrf2 Signaling

Lipoicmethylenedioxyphenol Reduces Experimental Atherosclerosis through Activation of Nrf2 Signaling

First dual AK/GSK-3β inhibitors endowed with antioxidant properties as multifunctional, potential neuroprotective agents

Synthesis, Structural Elucidation, In Silico and In Vitro Studies of New Class of Methylenedioxyphenyl-Based Amide Derivatives as Potential Myeloperoxidase Inhibitors for Cardiovascular Protection

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