Elsevier

Phytochemistry Letters

Volume 26, August 2018, Pages 83-87
Phytochemistry Letters

O-Glucoside of natural cleomiscosin-A: An attenuator of pro-inflammatory cytokine production

https://doi.org/10.1016/j.phytol.2018.05.022Get rights and content

Highlights

  • O-glucoside of cleomiscosin-A (CAG) was synthesised from natural cleomiscosin-A (CA).

  • Inhibition effect of CAG and CA were tested against TNF-α, IL-6 and IL-1β using ELISA.

  • CAG significantly inhibited IL-6 and IL-1β (IC50 −7.94 and 45.76 μM, respectively).

  • Under mouse endotoxemia model CAG showed 5-fold rise in TNF-α inhibition than CA.

Abstract

The study was aimed to improve the hydrophilic property and pro-inflammatory cytokine inhibitory effect of cleomiscosin-A (CA), a naturally occurring coumarinolignan in plants. In view of this, O-, N- and S-glucosides of cleomiscosin-A was designed and docking studies were performed for TNF-α protein. All derivatives showed considerable docking scores in the range of −8.433 to −9.401 kcal/mol compared to a standard TNF-α inhibitor. The O-glucoside of cleomiscosin-A (CAG) was synthesized by reacting natural cleomiscosin-A (CA) with acetobromo-α-d-glucose and pyridine. The formed product was confirmed through APCI-MS and proton NMR analysis. Inhibition effect of CA and CAG against TNF-α, IL-6 and IL-1β secretions was determined on lipopolysaccharide-induced RAW 264.7 cells using ELISA kits. CAG was potentially inhibitory against IL-6 and IL-1β secretions exhibiting IC50 values of 7.94 and 45.76 μM, respectively. Also, in-vivo (mouse endotoxemia model) performance of CAG (oral administration) in inhibiting TNF-α expression was significant (52.03% and 29.23% at 50 and 25 mg/kg body weight, respectively), demonstrating five-fold increase in activity compared to CA. In addition, CAG reduced LPS-induced NO levels and was found to be weakly cytotoxic (IC50 > 150 μM). This is the first report of semi-synthesis and pro-inflammatory cytokine inhibition effect of a coumarinolignan glucoside.

Introduction

Cleomiscosin-A (CA) is a natural coumarinolignan isolated from various plant sources like Cleome viscosa, Hyoscyamus niger, Rhododendron collettianum, Acer nikoense, etc (Begum et al., 2010a). While CA has been screened for several biological activities (Begum et al., 2010a), it encompassed significant hepatoprotective (Yadav et al., 2010a, Yadav et al., 2010b) and anti-inflammatory potential (Begum et al., 2010b). CA is an oxidative coupled product of fraxetin and coniferyl alcohol, found to be insoluble in water and soluble only in a mixture of methanol and chloroform. In view of the cytokine inhibitory potential exhibited by cleomiscosin-A under in-vitro models (Sharma et al., 2012) and its poor solubility issue, polar derivatives were proposed to be synthesized and tested under cellular and animal models.

Section snippets

Results and discussions

As the study was aimed to improve the hydrophilic property, glycosides of CA were designed. So far no report on semisynthesis or synthesis of coumarinolignan glycosides has been published in the literature. However, isolation of a coumarinolignan glucoside i.e. Yinxiancaoside C (cleomiscosin C-4-O-β-d-glucopyranoside) from Chloranthus japonicus S., has been reported in the literature (Kuang et al., 2009). The designed glycoside molecules were first subjected for molecular docking in order to

General

Multi detection reader (Spectramax M4, California, USA), NMR (GSX 400, JEOL, USA), MS (LC–MS-2020, Shimadzu, Japan) instruments were used as per the requirements. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) was purchased from Himedia Laboratories Pvt. Ltd. Mumbai, India. Mouse macrophages cell line RAW 264.7 was obtained from the Cell Bank of National Center for Cell Sciences, Pune (Maharashtra, India). Silica gel (# 230–400 and 100–200), silica gel for TLC (G and GF254),

Conflict of interest

The authors do not have any conflict of interest.

Acknowledgements

Authors acknowledge Dr. A. Mallika, Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Hyderabad for docking study. This work was a part of an Extra Mural Grant sponsored by CSIR-New Delhi grant [02(0045)/12/EMR-II]. SK acknowledges BITS-Pilani and KH acknowledges CSIR, New Delhi for granting fellowship.

References (18)

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