Chloptosin, an Apoptosis-Inducing Dimeric Cyclohexapeptide Produced by Streptomyces

Abstract

In the course of screening for apoptosis-inducing agents, chloptosin (1) was isolated from the culture broth of Streptomyces. The dumbbell-type structure of the dimeric cyclohexapeptide consisting of D-valine, (3S)- and (3R)-piperazic acids, O-methyl-L-serine, D-threonine, and (2S,3aR,8aR)-6-chloro-3a-hydroxy-2,3,3a, 8a-hexahydropyrrolo[2,3-b]indole-2-carboxylic acid was elucidated by spectroscopic and chemical degradation studies. The amino acid components in each cyclohexapeptide domain were presented in alternating R and S configurations. Chloptosin (1) was found to induce apoptotic activity in apoptosis-resistant human pancreatic adenocarcinoma cell line AsPC-1 and showed a strong antimicrobial activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus.

Structure, Bioactivity and Synthesis of Natural Products with Hexahydropyrrolo[2,3‐b]indole

“…[85] Natural products with an HPIC integrated into the peptide chain include omphalotins B-I (D: 55), [86,87] phakellistatin 3 (56) and isophakellistatin 3; [88] himastatin (57), in which the HPIC is part of a depsipeptide-chain; [89,90] its structure and stereochemistry was revised after the total synthesis. [91,92] Other similar natural products are chloptosin (58); [93] NW-G01, an antibiotic isolated from Streptomyces alboflavus; [94] and kutznerides 1-9 (1: 59) [95,96] (Scheme 4). Most of these complex structures have only recently been isolated.…”

Identification and characterization of the biosynthetic gene cluster of polyoxypeptin A, a potent apoptosis inducer

“…Piperazic acid is an attractive building block of many complex secondary metabolites such as Antrimycin [52], Chloptosin [53], Himastatin [39], Luzopeptin [54], Quinoxapeptin [55], Lydiamycin [56], Piperazimycin [57] and Sanglifehrin [58]. The detailed biosynthetic mechanisms by which piperazic acid are formed are not well understood.…”

A new 16-membered tetraene macrolide JBIR-100 from a newly identified Streptomyces species

“…Monamycin, a series of antibiotics [16] , containing piperazic acids have been isolated from the culture broth of numerous Streptomyces spp. [375][376][377][378][379] and strains of the genus Actinomadura. [369,380] .…”