Isoquinolinequinone Derivatives from a Marine Sponge (Haliclona sp.) Regulate Inflammation in In Vitro System of Intestine

Yun Kim,Jung-Rae Rho,Na-Hyun Kim,Eun Jeong,Nguyen Van Tu,Yeong Ji

doi:10.3390/md19020090

Abstract

Using bio-guided fractionation and based on the inhibitory activities of nitric oxide (NO) and prostaglandin E2 (PGE2), eight isoquinolinequinone derivatives (1–8) were isolated from the marine sponge Haliclona sp. Among these, methyl O-demethylrenierate (1) is a noble ester, whereas compounds 2 and 3 are new O-demethyl derivatives of known isoquinolinequinones. Compound 8 was assigned as a new 21-dehydroxyrenieramycin F. Anti-inflammatory activities of the isolated compounds were tested in a co-culture system of human epithelial Caco-2 and THP-1 macrophages. The isolated derivatives showed variable activities. O-demethyl renierone (5) showed the highest activity, while 3 and 7 showed moderate activities. These bioactive isoquinolinequinones inhibited lipopolysaccharide and interferon gamma-induced production of NO and PGE2. Expression of inducible nitric oxide synthase, cyclooxygenase-2, and the phosphorylation of MAPKs were down-regulated in response to the inhibition of NF-κB nuclear translocation. In addition, nuclear translocation was markedly promoted with a subsequent increase in the expression of HO-1. Structure-activity relationship studies showed that the hydroxyl group in 3 and 5, and the N-formyl group in 7 may be key functional groups responsible for their anti-inflammatory activities. These findings suggest the potential use of Haliclona sp. and its metabolites as pharmaceuticals treating inflammation-related diseases including inflammatory bowel disease.

Highlights

Marine sponges are considered as prolific sources of novel compounds exhibiting diverse biological activities, which can be used for the treatment of human diseases [1,2,3]
The molecular formula of methyl O-demethylrenierate (1), a pale reddish amorphous powder in methanol, was deduced as C12H9NO5 based on the molecular ion peak at m/z 248.0554 [M + H]+ in the positive HRqTOF MS and the 13C NMR spectra
Compounds 2 and 3 were identified as derivatives formed by the replacement of the methoxy group with a methyl group at C-7 in renierol and 1,6-dimethyl-7-methoxy-5,8dihydroisoquinoline-5,8-dione, respectively

Summary

Introduction

Marine sponges are considered as prolific sources of novel compounds exhibiting diverse biological activities, which can be used for the treatment of human diseases [1,2,3]. Isoquinolinequinones, a class of metabolites derived from marine sponges, belonging to the genera Xesotospongia and Riniera, and to Petrosia sp., have been shown to possess a variety of biological activities, including cytotoxic, antimicrobial, antifungal, and antineoplastic effects [4,5,6]. During screening for in-house compounds isolated from various marine sponges with potent anti-inflammatory activities, some isoquinolinequinones isolated from the methanolic extract of Haliclona sp. In analysis of the 1H NMR spectrum of the methanolic extract of Haliclona sp., it was expected that various isoquinolinequinones derivatives were contained. Was reported in LPS-activated Raw 264.7 macrophages [7]. We focused on the identification of novel isoquinolinequinones from Haliclona sp., and the evaluation of their anti-inflammatory activities using an in vitro co-culture system resembling an intestine

Methods

Results

Conclusion