Influence of the cyclooctadepsipeptides PF1022A and PF1022E as natural products on the design of semi–synthetic anthelmintics such as emodepside

Abstract

The 24-membered cyclooctadepsipeptide (CODP) PF1022A, the active metabolite of the fungus imperfectus Mycelia sterilia (Rosellinia sp.) isolated from the plant Camellia japonica in Japan, is described as a powerful broad-spectrum anthelmintic natural product with low toxicity in animals. Further CODPs such as PF1022B, C, D and E have been isolated from the same culture and their structures have been established. Both PF1022A and PF1022E serve as valuable starting materials for the synthesis of semi-synthetic CODP derivatives with improved intrinsic anthelmintic potency and broad-spectrum activity. It was found that in most cases the di-substituted PF1022A derivatives showed a greater (or equal) activity by oral application against the gastrointestinal nematode Haemonchus contortus compared to the corresponding mono-substituted PF1022A analogues as exemplified by emodepside. In order to get additional information on the bioactive conformation, emodepside was transformed into its mono- and tetra-thionated derivatives by isosteric replacement. In the light of the increased efficacy of these derivatives against H. contortus or Trichostrongylus colubriformis, it has been suggested that the asymmetric conformation clearly influences the anthelmintic activity of CODPs. Although useful synthetic pathways are available today for the preparation of the semi-synthetic CODP emodepside, the fermentative production of its bis-para-nitro and bis-para-amino precursors could be the process used for its industrial-scale production in the future.

Segment Solid‐Phase Total Synthesis of the Anthelmintic Cyclooctadepsipeptides PF1022A and Emodepside

“…originally isolated from the leaves of Camellia japonica, has been established as a novel, resistance-breaking anthelmintic with low toxicity in animals ( Figure 1). [5,6] A semi-synthetic analogue of PF1022A, emodepside (2), has been introduced into the market recently for the treatment of parasitic helminth infections in companion animals ( Figure 1). [7] A prerequisite for the development of a PF1022A-based anthelmintic against human worm infections is an efficient procedure that allows the synthesis of a large number of PF1022 analogues for biological screening.…”

Progress and challenges in the discovery of macrofilaricidal drugs

“…Several pathways for total synthesis of PF1022A have been reported (for a review, see [46]), but it is not apparent that this route can be developed for the production of sufficient amounts of the drug at an acceptable cost-of-goods. However, much work on the generation of semi-synthetically modified derivatives of the prototype, which is isolated from fermentation of fungus in the genus Rosellinia, has been reported [46,49].…”

Fungal cyclooligomerdepsipeptides: From classical biochemistry to combinatorial biosynthesis

“…93 This 'Fungus imperfectus', classified later as Rosellinia sp., was isolated from the plant Camellia japonica in Japan. 94 Two sequences of putative CODSs are also available from GenBank, although the CODs that these synthetases produce have not been experimentally established. ADB27871 is derived from Fusarium oxysporum FB1501, a strain that produces both beauvericin and the enniatins H, I and MK 1688.…”