Anti-Inflammatory Activity of Geldanamycin and Its Derivatives in LPS-Induced RAW 264.7 Cells

Thongchai Taechowisan,Watcharee Waratchareeyakul,Waya S Phutdhawong,Winyou Puckdee

doi:10.4236/aim.2019.94024

Abstract

Geldanamycin (1) had been isolated as a major compound from Streptomyces zerumbet W14; an endophyte of Zingiber zerumbet (L.) Smith. Two new geldanamycin derivatives; 17-(tryptamine)-17-demethoxygeldanamycin (2) and 17-(5’-methoxytryptamine)-17-demethoxygeldanamycin (3) were synthe- sized and their anti-inflammatory activity was evaluated in LPS-induced macrophage RAW 264.7 cells by investigating their effects on the inhibition of production of NO, PGE2, TNF-α, IL-1β, IL-6 and IL-10. The data obtained were consistent with the modulation of TNF-α, IL-1β, IL-6, IL-10 production by these derivatives at concentration of 1 to 5 μg/ml. A similar effect was also observed when LPS-induced NO release and PGE2 production were tested. The inhibitory effects were shown in concentration-dependent manners. From the obtained results, it was concluded that two new gelda- namycin derivatives possess anti-inflammatory activity on LPS-induced RAW 264.7 cells. They could be useful for the management of inflammatory diseases.

Highlights

IntroductionGeldanamycin had been isolated as a major compound from Streptomyces zerumbet W14; an endophyte of Zingiber zerumbet (L.) Smith
Tryptamine-gallic acid hybrid molecule have been synthesized as SEGA (3a), which prevented non-steroidal anti-inflammatory druginduced mitochondrial pathology, apoptosis, and gastropathy by blocking mitochondrial oxidative stress, chelating intramitochondrial free iron, and correcting mitochondrial pathology entering into mitochondria [12]
The experimental results showed that LPS could activate RAW 264.7 cells effectively, and induced expression of proinflammatory mediators (NO and PGE2) and cytokines (TNF-α, IL-1β, IL-6 and IL-10)

Summary

Introduction

Geldanamycin had been isolated as a major compound from Streptomyces zerumbet W14; an endophyte of Zingiber zerumbet (L.) Smith It had in vitro anti-inflammatory activity on LPS-induced RAW 264.7 cells by inhibition of mRNA expression and production of inducible NO synthase (iNOS), tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) [10]. Tryptamine-gallic acid hybrid molecule have been synthesized as SEGA (3a), which prevented non-steroidal anti-inflammatory druginduced mitochondrial pathology, apoptosis, and gastropathy by blocking mitochondrial oxidative stress, chelating intramitochondrial free iron, and correcting mitochondrial pathology entering into mitochondria [12]. According to this effect, the invention of tryptamine-geldanamycin hybrids has been designed and evaluated the in vitro anti-inflammatory activity. The C17 methoxyl of geldanamycin molecule could allow for the introduction of various nucleophiles, geldanamycin from the beginning had been apopular template for semisynthetic analogs [2]-[9]

Methods

Results

Conclusion