Structural classification and biological activities of Stemona alkaloids

Stemona alkaloids represent a unique class of natural products exclusively known from the three genera Stemona, Stichoneuron, and Croomia of the monocotyledonous family Stemonaceae. Structurally they are characterized by a central pyrroloazepine core usually linked with two butyrolactone rings. The great diversity, comprising 215 derivatives, is created by the formation of additional C–C linkages and oxygen bridges together with ring cleavages and eliminations of the lactone rings. Based on biosynthetic considerations they can be grouped into three structural types represented by the croomine, stichoneurine, and protostemonine skeleton. Due to the formation of characteristic terminal lactone rings and the central pyrrolidine ring pandanamine and pandamarilactonine, isolated from Stichoneuron calcicola, were suggested to represent biogenetic precursors. The taxonomically complex S. tuberosa group can be clearly segregated by the formation of stichoneurines, while the other Stemona species are characterized by protostemonine derivatives. Croomine derivatives are more widespread found in both groups and in the genus Croomia. Of chemotaxonomic significance are the different transformations of protostemonine into stemofolines with a cage-type structure or into pyridoazepines characterized by a six-membered piperidine ring. Stimulated by the great interest in the antitussive activity of Stemona alkaloids, differences in transport mechanisms and potencies via different administrative routes were investigated. Follow-up studies on the significant insecticidal activities focused on the mode of action by using biochemical and electrophysiological approaches. Screening for acetylcholinesterase inhibitory properties revealed a much higher potency for stemofoline derivatives compared to pyridoazepines, but showed also significant activity for isomers of stenine with a stichoneurine skeleton. Evaluating synergistic growth inhibitory effects with cancer chemotherapeutic agents stemofoline exhibited the most potent effect in the reversal of permeability glycoprotein-mediated multidrug resistance. The anti-inflammatory activity of some derivatives was identified as an inhibition of the expression of inflammatory mediators. Comparing the diverse bioactivities of Stemona alkaloids stemofoline-type derivatives are the most versatile compounds representing promising lead structures for further development as commercial agents in agriculture and medicine.