PF1022A and Related Cyclodepsipeptides - A Novel Class of Anthelmintics

Abstract

Parasitic nematodes are a major cause of morbidity and mortality in man and also cause widespread loss of food production by infection of livestock. A milestone in the chemotherapy of nematode infections, especially in animals, was the discovery of the avermectins and milbemycins during the 1970s. Since the discovery of these highly active macrolides, reports of potent new classes of anthelmintics have been scarce. One of the most outstanding recently reported anthelmintics is the cyclooctadepsipeptide PF1022A, the most active member of a novel class of anthelmintic agents. During the past years several total syntheses of PF1022A and manifold structure-activity relationships have been established. Additionally, the biosynthesis of PF1022A has been elucidated and intensive investigations into the mode of action of this novel anthelmintic are underway. Comprehensive studies including cyclodepsipeptides with smaller ring-sizes, such as the enniatins, proved the PF1022 family and related cyclodepsipeptides to be the most promising follow-up candidates for the avermectins and milbemycins, which suffer from increasing nematode resistance.

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.…”

“…Despite several published total syntheses in solution and an in vitro synthesis approach, only a limited number of PF1022A derivatives have become available. [5,[8][9][10] Remarkably, until now only a partial solid-phase synthesis of PF1022 analogues has been hydroxycarboxylic acids. We report herein an efficient synthesis of the anthelmintic PF1022A and its commercial analogue emodepside on Kaiser and Wang resins.…”

Identification of the nonribosomal peptide synthetase gene responsible for bassianolide synthesis in wood-decaying fungus Xylaria sp. BCC1067

“…Bassianolide belongs to a family of structurally related cyclodepsipeptide compounds, which have emerged as a broad family of compounds characterized by at least one ester linkage. Great interest in this class of natural products has stemmed from their diverse range of biological activities, as has been shown for cryptophycins, didemnins, dolastatins, PF1022, enniatin, destruxin, (Scherkenbeck et al, 2002;Sarabia et al, 2004).…”

In vitro Synthesis of New Cyclodepsipeptides of the PF1022‐Type: Probing the α‐D‐Hydroxy Acid Tolerance of PF1022 Synthetase

“…[6] In the course of a directed screening for anthelmintic properties Sasaki et al isolated the N-methylated cyclodepsipeptide PF1022A (Scheme 1), which is produced by the fungus Mycelia sterilia. [7,8] PF1022 belongs to a class of CDPs [9] that consist of an alternating arrangement of four N-methyl-l-leucines and a varying content of a-d-hydroxy acids, from four d-lactates (PF1022F) to four D-phenyllactates (PF1022B), respectively (Scheme 2). A semisynthetic derivative of PF1022, emodepside, is currently used as a highly effective drug against helminths.…”