Gerhard Bonse

Synthesis of a radiolabeled cyclodepsipeptide [3H-methyl]PF1022A

For receptor binding studies and the elucidation of the mode of action of the potent anthelmintic compound PF1022A a tritium labeled compound with very high specific activity was necessary. Tritium was introduced into the compound by methylation of the [bis-N-demethyl]precursor of PF1022A (PF1022-219). The identity of [bis-N-methyl- 3 H]PF1022A was determined by LC/MS. After synthesis and purification, 88.9 μg [bis-N-methyl- 3 H]PF1022A were available showing a specific activity of 162 Ci/mmol (5,99 TBq/mmol) determined by mass spectrometry. The total activity was 15 mCi (555 MBq). Radiolabeled PF1022A showed an efficient and specific binding to a membrane fraction from Ascaris suum. Displacement by unlabeled PF1022A was half-maximal at about 40 nM. At 100-fold higher concentrations the biologically much less effective optical antipodean (PF1022-001) competed for maximal 40% of the [ 3 H]PF1022A-binding in the Ascaris suum membrane preparation. In-vitro comparison of PF1022A with its optical antipodean revealed a more than 100-fold higher anthelmintic activity of PF1022A against Heterakis spumova, Nippostrongylus brasiliensis and Trichinella spiralis.

Chemistry of Anticestodal Agents

Historically, treatment of cestode infections has long been the domain of natural products. These herbal preparations are difficult to standardize and are but poorly tolerated. The first synthetic cestocide was dichlorophen. It was introduced into veterinary and human medicine in 1946 and 1956, respectively, and was at that time regarded as an important advance in the treatment of infections caused by adult cestodes. Typically, cestodes inhabit the intestinal lumen and thus can be easily reached by orally administered drugs. Whenever their ability to maintain their position in the intestine is impaired they are easily expelled from it. These two characteristics are probably the reason such a startling variety of natural products and synthetic compounds have been employed, or considered for use, as cestocides. Table I provides a list of these compounds, which is by no means complete and which has been compiled from several excellent reviews (de Carneri and Vita, 1973; Islip, 1973; Sharma et al., 1980; Vanden Bossche, 1980).