Structural classification and biological activities of Stemona alkaloids

Abstract

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 CC 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.

Morphological and chemical variation of Stemona tuberosa from southern China – Evidence for heterogeneity of this medicinal plant species

“…In the case of S . tuberosa , the main compound tuberostemonine ( 1 ) seems to be sensitive against oxidation since numerous derivatives of this alkaloid are suspected to be artefacts (Greger ). Evaluation of the plant material used in previous reports indicates regular co‐occurrence of 3,4‐dehydro‐δ‐tocopherol ( 6 ) with tuberostemonine ( 1 ) and its derivatives, or with croomine‐type compounds (Brem et al .…”

“…These are structurally characterised by a pyrrolo‐ or pyrido [1,2‐α]‐azepine core. Greger () classified them into protostemonine, croomine and stichoneurine groups according to their core skeleton (Fig. ).…”

A Pharmacological Strategy Using Stemofoline for more Efficacious Chemotherapeutic Treatments Against Human Multidrug Resistant Leukemic Cells

“…This has generated the need to search for new effective MDR modulators that have been isolated from natural products and that do not produce adverse side effects. A previous study reported that Stemona curtisii root extract, which contains Stemona alkaloids (Greger, 2006), modulated P-gp activity in human cervical cancer cells and the KB-V1 cell line (high P-gp expression). However, this was not the case with Multidrug resistant related protein-1 (MRP-1) activity in the MRP1-HEK293 cell line (high MRP-1expression).…”

Enantioselective total syntheses of (+)-stemofoline and three congeners based on a biogenetic hypothesis

“…The Stemona alkaloids are a class of structurally diverse natural products that act as the principle active constituents in Stemona plants (Stemonaceae) 15 – 20 . Known as “Bai Bu” in traditional Chinese medicine, Stemona plants have been used in East Asia for thousands of years as insecticides and anti-cough agents 15 , 16 , 19 , 20 . To date, more than 215 Stemona alkaloids have been isolated 15 , classified by Pilli 19 , 20 into eight structural groups (see Supplementary Fig.…”

“…1 ). The attractive bioactivities 15 , 16 and unique polycyclic structures of these alkaloids have led to intense phytochemical, synthetic, and biomedical investigations, and many innovative total syntheses have been achieved 16 , 18 – 24 .…”