Synthesis and Biological Evaluation of Epidithio-, Epitetrathio-, and bis-(Methylthio)diketopiperazines: Synthetic Methodology, Enantioselective Total Synthesis of Epicoccin G, 8,8′-epi-ent-Rostratin B, Gliotoxin, Gliotoxin G, Emethallicin E, and Haematocin and Discovery of New Antiviral and Antimalarial Agents

Abstract

An improved sulfenylation method for the preparation of epidithio-, epitetrathio- and bis-(methylthio)diketopiperazines from diketopiperazines has been developed. Employing NaHMDS and related bases and elemental sulfur or bis[bis(trimethylsilyl)amino]trisulfide (23) in THF, the developed method was applied to the synthesis of a series of natural and designed molecules, including epicoccin G (1), 8,8′-epi-ent-rostratin B (2), gliotoxin (3), gliotoxin G (4), emethallicin E (5) and haematocin (6). Biological screening of selected synthesized compounds led to the discovery of a number of nanomolar anti poliovirus agents (i.e. 46, 2,2′-epi-46 and 61, Table 5) and several low micromolar anti Plasmodium falciparum lead compounds (i.e. 46, 2,2′-epi-46, 58, 61 and 1, Table 5).

Susceptibilities of enterovirus D68, enterovirus 71, and rhinovirus 87 strains to various antiviral compounds

“…The work presented here has identified novel diketopiperazines (KCN-2,2’-epi-19, KCN-19, and KCN-21) that inhibit EV-D68. They have previously been reported by us to inhibit poliovirus (Nicolaou et al, 2012), thus these compounds deserve further investigation as anti-picornavirus agents. Many of the compounds studied here are not being pursued for further development but they should be.…”

“…3-deazaguanine and ribavirin were from the former ICN Pharmaceuticals (Costa Mesa, CA). Epidithiodiketopiperazine compounds KCN-2,2’-epi-19, KCN-19, and KCN-21 were prepared at The Scripps Research Institute (La Jolla, CA) as previously described (Nicolaou et al, 2012). Each compound was dissolved in DMSO or MEM then diluted in half-log 10 increments, and added to cells immediately prior to addition of virus-containing medium.…”

“…Guanidine HCl has been used to treat picornavirus infections in mice (Eggers, 1976; Herrmann et al, 1982). KCN-2,2’-epi-19, KCN-19, and KCN-21 are closely related compounds that we first reported as inhibitors of poliovirus replication (Nicolaou et al, 2012). Here we report their activities against EV-D68 and EV-71 for the first time.…”

A Nonribosomal Peptide Synthetase-Derived Iron(III) Complex from the Pathogenic FungusAspergillus fumigatus

“…2–5 LaeA is a global regulator of secondary metabolism in fungi and effects virulence, in part, by positive regulation of multiple small-molecule gene clusters. 3–6 For example, LaeA controls the biosynthesis of the epidithiodiketopiperazine gliotoxin, 7–10 which contributes to A. fumigatus’ success as a pathogen. 11 …”

New Design of a Disulfurating Reagent: Facile and Straightforward Pathway to Unsymmetrical Disulfanes by Copper‐Catalyzed Oxidative Cross‐Coupling

“…This vital motif plays a critical role in the formation of secondary and tertiary structures of proteins, and leads to a great impact on life code . Recently, abundant natural products containing S−S bonds have been demonstrated to possess various activities, such as anti‐bacterial (Lissoclibdin 5) and anti‐Polio virus (epidithiodiketopiperazines, ETPs) ,–. The disulfane moiety is also indispensable for pharmaceuticals, which are used in treatment of thrombi and alcohol addiction .…”