Synthesis and anthelmintic activity of isopelletierine and a series of side‐chain homologues

Abstract

The preparation and anthelmintic properties of isopelletierine and four side-chain homologues are described. The compounds were prepared from PI-piperideine and 3-0x0-acids at pH 4-5. PK'~-and Rf-values were determined.Anthelmintic activity as tested in v i m on the liver fluke, by three methods, was highest for 1 -(2'-piperidyl)butanone-2. The differences in anthelmintic properties of the compounds are discussed.

Tropane and Granatane Alkaloid Biosynthesis: A Systematic Analysis

“…Their results rendered the highest anthelminthic activity to the compound isopelletierine [26]. These findings were later scientifically supported in 1963 with newer and better chemical methods [27]. Fascioliasis, a disease caused by liver fluke Fasciola hepatica, is common in cattle.…”

“…Hypothesis I is based on the observation that P. granatum plants fed [1.5-14 C] and [1.5-14 C 3 H 2 ] cadaverine yields incorporation of the labels into N-methylpelletierine (7) and pseudopelletierine (6) [121]. In this pathway, lysine (25) is first decarboxylated to form cadaverine (26) which would subsequently be methylated to form N-methylcadaverine (27) [119]. N-methylcadaverine (27) would then be oxidized to form 5-methylaminopentanal (28) promoting a spontaneous cyclization to form the N-methyl-∆ 1 -piperidinium cation (29).…”

“…In this pathway, lysine (25) is first decarboxylated to form cadaverine (26) which would subsequently be methylated to form N-methylcadaverine (27) [119]. N-methylcadaverine (27) would then be oxidized to form 5-methylaminopentanal (28) promoting a spontaneous cyclization to form the N-methyl-∆ 1 -piperidinium cation (29). This product would then ultimately form N-methylpelletierine (7) or be converted to the corresponding oxobutanoate by the decarboxylative condensation of two malonyl-CoA which would then cyclize to form pseudopelletierine (6).…”

“…In this hypothesis, the first biosynthetic step is the methylation of lysine (25) which occurs at the ε-N position producing ε-N-methyl-lysine (32). This compound would then be decarboxylated to form N-methylcadaverine (27) which would undergo oxidation to form 5-methylaminopentanal (28), promoting a spontaneous cyclization to form the N-methyl-∆ 1 -piperidinium cation (29). As described in Hypothesis I, the N-methyl-∆ 1 -piperidinium cation (29) would ultimately form N-methylpelletierine (7) and pseudopelletierine (6).…”

“…The enzymes SPDS and PMT have been found to share substrate specificity, but PMT is dependent of the decarboxylated S-adenosylmethionine (dcSAM) as a co-substrate. The oxidation of N-methylcadaverine (27) in P. granatum and Sedum species could be performed with the aid of an enzyme similar to the methylputrescine oxygenase (MPO) present in the biosynthesis of nicotine in N. tabacum. While a copper dependent oxidase is used for tropane alkaloid biosynthesis, it is not possible to rule out alternative enzymes such as polyamine oxidases that require FAD as a cofactor [127].…”