title: 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 antipoliovirus agents (i.e., 46, 2,2'-epi-46, and 61) and several low-micromolar anti- Plasmodium falciparum  lead compounds (i.e., 46, 2,2'-epi-46, 58, 61, and 1).
authors.affiliation: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. kcn@scripps.edu
authors.forename: K C
authors.initials: KC
authors.lastname: Nicolaou
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.forename: Sotirios
authors.initials: S
authors.lastname: Totokotsopoulos
authors.forename: Philipp
authors.initials: P
authors.lastname: Heretsch
authors.forename: Denis
authors.initials: D
authors.lastname: Giguère
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Sun
authors.forename: David
authors.initials: D
authors.lastname: Sarlah
authors.forename: Thu H
authors.initials: TH
authors.lastname: Nguyen
authors.forename: Ian C
authors.initials: IC
authors.lastname: Wolf
authors.forename: Donald F
authors.initials: DF
authors.lastname: Smee
authors.forename: Craig W
authors.initials: CW
authors.lastname: Day
authors.forename: Selina
authors.initials: S
authors.lastname: Bopp
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Winzeler
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054659:Diketopiperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D017955:Poliovirus / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D000998:Antiviral Agents; D054659:Diketopiperazines