Structural classification and biological activities of Stemona alkaloids

Harald Greger

doi:10.1007/s11101-019-09602-6

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 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.

Highlights

In the framework of UNESCOs program ‘‘Man and the Biosphere’’ (MAB) broad-based phytochemical investigations within tropical plant families were carried out in our laboratory to find a replenishing source of naturally occurring insecticides or fungicides
Besides highly active sulfur-containing amides from the genus Glycosmis of the Rutaceae (Greger et al 1996; Hofer and Greger 2000) and flavaglines from Aglaia of the Meliaceae (Brader et al 1998; Bacher et al 1999) we found very promising biological activities in the genus Stemona of the small monocotyledonous family Stemonaceae (Brem et al 2002; Pacher et al 2002)
As reviewed previously the high insecticidal activity could be attributed to family-specific Stemona alkaloids (Greger 2006), whereas the antifungal property was caused by different groups of stilbenoids (Greger 2012)

Summary

Introduction

In the framework of UNESCOs program ‘‘Man and the Biosphere’’ (MAB) broad-based phytochemical investigations within tropical plant families were carried out in our laboratory to find a replenishing source of naturally occurring insecticides or fungicides. Apart from sporadic reports on iminosugars (Asano et al 2005) and chlorogenic acid derivatives (Ge et al 2007) continuative investigations mainly focused on Stemona alkaloids due to their unique molecular structures and wide range of bioactivities Synthetic approaches to their intricate structures were summarized in a microreview by Alibes and Figueredo (2009) and more recent advances were reviewed by Liu and Wang (2015). As shown in the structural overview (Tables 1, 2, 3) they can be derived from three basic skeletons differing in the substitution at C-9 (Fig. 1) This classification was supported by broad-based chemotaxonomic studies within the genus Stemona indicating two clear-cut trends either towards derivatives with a stichoneurine or protostemonine skeleton (Jiang et al 2006b; Schinnerl et al 2007; Li et al 2007a; Kongkiatpaiboon et al 2011).

C OO croomine skeleton

Findings

13 OMe cochinchistemonine elimination of lactone ring C O