ABSTRACT
Besides 24-membered cyclooctadepsipeptides (CODPs) with the most prominent member of this class emodepside, the structurally related 18-membered cyclohexadepsipeptides (CHDPs) were of interest with regard to their efficacy against the nematode H. contortus in sheep.The CHDPs prepared by a simple total synthesis represent enniatin derivatives with strong in vivo activity against H. contortus in sheep. The correlation between the nature of the CHDP major conformers and their anthelmintic activities was studied in detail. All CHDPs with strong in vivo activity exists in deuterochloroform solution as conformers with restricted flexibility which was found by 2D-NMR spectroscopic analysis. This reduced flexibility of the major conformer can be exemplified by CHDPs containing e.g.: (i) an unsymmetrically folded conformation with no cis-amide bound, (ii) an internal hydrogen bond or (iii) one cis-amide bond, respectively.The strong in vivo anthelmintic activity against H. contortus in sheep indicates that the stereochemistry in 2-position of CHDPs is less important for their high inding affinity. It may be assumed that the identified inflexible region of the major conformers might mimic the active conformation of these CHDPs, which could be helpful for rational design of anthelmintics with less complicated structures.
Subject(s)
Anthelmintics/pharmacology , Depsipeptides/pharmacology , Haemonchiasis/veterinary , Haemonchus/drug effects , Sheep Diseases/drug therapy , Animals , Depsipeptides/chemistry , Haemonchiasis/drug therapy , Models, Molecular , Molecular Structure , Sheep , Sheep Diseases/parasitology , Structure-Activity RelationshipABSTRACT
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
[2'-13C]Biotin was incorporated into avidin (egg white), glutaconyl-CoA decarboxylase (EC 4.1.1.70) from Acidaminococcus fermentans and the biotin carrier of transcarboxylase from Propionibacterium freudenreichii (EC 2.1.3.1). 13C-NMR measurements showed an upfield shift of the carbonyl carbon of 3.1 and 2.0 ppm for both enzymes, whereas binding to avidin induced no significant change of the chemical shift as compared to free biotin. The data indicate that the enzymes provide an electronic environment for the covalently bound biotin which favours carboxylation. In addition it was demonstrated by NMR-measurements that glutaconyl-CoA decarboxylase, from which the hydrophobic carboxy-lyase subunit (beta) was removed, could carboxylate free biotin.
Subject(s)
Biotin/chemistry , Avidin/chemistry , Carbon Isotopes , Carboxy-Lyases/chemistry , Carboxy-Lyases/metabolism , Decarboxylation , Magnetic Resonance Spectroscopy , Trypsin/pharmacologyABSTRACT
A systematic investigation of cancer detection by water-suppressed nuclear magnetic resonance (NMR) of plasma is reported. With additional suppression of lactate, a statistically significant difference between the linewidths of the methylene group signal of patients with untreated cancer (average linewidth 26.9 +/- 3.9 Hz) and normal controls (average linewidth 31.1 +/- 4.9 Hz) has been found. However, overlap was found between these two groups. It is shown that recognition of malignancy could be improved by consideration of the different relations of the linewidths on the content of serum triglycerides and the observation of a shoulder at the high field side of the methylene signal. Preliminary investigations on lipid fractions separated by ultracentrifugation (UC) indicate a connection of the appearance of the high field shoulder and the HDL lipoprotein.
