ABSTRACT
The tetra- and mono-thionated cyclic octadepsipeptides represent novel cyclic octadepsipeptide derivatives with broad-spectrum activity against parasitic nematodes in mice and sheep. Some of these show better activity than the potent natural anthelmintic cyclic octadepsipeptide PF1022A against Hymenolepis nana, Heterakis spumosa and Trichinella spiralis larvae in mice. In particular, they show improved efficacy against Haemonchus contortus and Trichostrongylus colubriformis in sheep compared with PF1022A. Here we report on two different and simple synthetic pathways for this new class of thionated cyclic octadepsipeptides.
Subject(s)
Anthelmintics/chemical synthesis , Depsipeptides , Helminths/drug effects , Peptides, Cyclic/chemical synthesis , Thioamides/chemical synthesis , Animals , Anthelmintics/metabolism , Anthelmintics/pharmacology , Helminthiasis, Animal/drug therapy , Magnetic Resonance Spectroscopy , Male , Mice , Mice, Inbred Strains , Molecular Structure , Peptides, Cyclic/metabolism , Peptides, Cyclic/pharmacology , Sheep , Structure-Activity Relationship , Thioamides/metabolism , Thioamides/pharmacologyABSTRACT
New cyclohexadepsipeptides of the enniatin type with potential anthelmintic properties were produced by two different strategies: 1. In vitro synthesis by use of the multienzyme enniatin synthetase, and 2. in vivo precursor feeding of enniatin producing strains Fusarium scirpi and Fusarium sambucinum. The compounds were analyzed by HPLC, various NMR measurements and mass spectrometry. The three N-methyl L-amino acid positions in the enniatin B molecule could be gradually replaced by other (N-methyl) L-amino acids, e.g. alanine, cysteine, threonine and serine. The latter two amino acids yield new enniatins with functional groups in the hydrophobic side chains. Similarly the three D-2-hydroxyisovalerate residues, present in all naturally occuring enniatins, could be substituted by D-2-hydroxybutyric acid and D-lactic acid. Despite its lower yield the in vitro synthesis has the advantage of a broader variety of products formed.
Subject(s)
Anthelmintics/metabolism , Anti-Bacterial Agents/biosynthesis , Depsipeptides , Fusarium/metabolism , Peptides , Anthelmintics/chemistry , Anti-Bacterial Agents/chemistry , Chromatography, High Pressure Liquid , Chromatography, Thin Layer , Culture Media , Fungal Proteins/biosynthesis , Fusarium/enzymology , Magnetic Resonance Spectroscopy , Mass Spectrometry , Peptide Synthases/metabolismABSTRACT
Protonated aromatic aldehydes and methyl ketones 1a-10a, carrying initially the proton at the carbonyl group, are prepared by electron impact-induced loss of a methyl radical from 1-arylethanols and 2-aryl-2-propanols, respectively. The aryl moiety of the ions corresponds to a benzene group, a naphthalene group, a phenanthrene group, a biphenyl group, and a terphenyl group. respectively, each substituted by a CH3OCH2 side-chain as remote from the acyl substituent as possible. The characteristic reactions of the metastable ions, studied by mass-analyzed ion kinetic energy spectrometry, are the elimination of methanol, the formation of CH3OCH 2 (+) ions, and the elimination of an ester RCOOCH3 (R = H and CH3) . The mechanisms of these fragmentations were studied by using D-labeled derivatives. Confirming earlier results, it is shown that the ester elimination, at least from the protonated aryl methyl ketones, has to proceed by an intermediate [acyl cation/arylmethyl methyl ether]-complex. The relative abundances of the elimination of methanol and of the ester decrease and increase, respectively, with the size of the aromatic system. Clearly, the fragmentation via intermediate ion-neutral complexes is favored for the larger ions. Furthermore, the acyl cation of these complexes can move unrestricted over quite large molecular distances to react with the remote CH3OCH2-side-chain, contrasting the restricted migration of a proton by 1,2-shifts ("ring walk") in these systems.
