Cytotoxic Thiodiketopiperazine Derivatives from the Deep Sea-Derived Fungus Epicoccum nigrum SD-388.

Li Li,Bin-Gui Wang,Lu-Ping Chi,Xin Li,Xiao-Ming Li

doi:10.3390/md18030160

Abstract

Four new thiodiketopiperazine alkaloids, namely, 5’-hydroxy-6’-ene-epicoccin G (1), 7-methoxy-7’-hydroxyepicoccin G (2), 8’-acetoxyepicoccin D (3), and 7’-demethoxyrostratin C (4), as well as a pair of new enantiomeric diketopiperazines, (±)-5-hydroxydiphenylalazine A (5), along with five known analogues (6–10), were isolated and identified from the culture extract of Epicoccum nigrum SD-388, a fungus obtained from deep-sea sediments (−4500 m). Their structures were established on the basis of detailed interpretation of the NMR spectroscopic and mass spectrometric data. X-ray crystallographic analysis confirmed the structures and established the absolute configurations of compounds 1–3, while the absolute configurations for compounds 4 and 5 were determined by ECD calculations. Compounds 4 and 10 showed potent activity against Huh7.5 liver tumor cells, which were comparable to that of the positive control, sorafenib, and the disulfide bridge at C-2/C-2’ is likely essential for the activity.

Highlights

Natural products have historically been a rich source of new drugs or drug candidates
The TDKP derivatives are a family of diketopiperazines which have been isolated from several fungal sources, such as Epicoccum nigrum [3], Exserohilum rostratum [7], Penicillium brocae [8], and Penicillium adametzioides [9]
The fungal strain E. nigrum SD-388 was cultured on the rice solid medium, which was further

Summary

Introduction

Natural products have historically been a rich source of new drugs or drug candidates. Epicoccum nigrum is a chemically distinct fungal species with potential to produce structurally unique secondary metabolites including thiodiketopiperazines (TDKPs) [3,4], polyketides [5], and polysaccharides [6]. Some of these metabolites exhibited intriguing biological properties, such as antimicrobial [3], cytotoxic [4], and antioxidant activities [5,6]. A, an spiro-TDKP derivative, whose stereochemistry could not not be elucidated by conventional methods and was solved on residual chemical be elucidated by conventional.

Structure Elucidation of the New Compounds

Biological

General Experimental Procedures

Fungal Material

Fermentation

Extraction and Isolation

X-Ray Crystallographic Analysis

Computational Section

Cell Culture

Cell Proliferation Assay

Conclusions