Beauty of the beast: anticholinergic tropane alkaloids in therapeutics

Tropane alkaloids(TAs)are among the most valued chemical compounds known since pre-historic times.Poisonous plants from Solanaceae family(Hyoscyamus niger,Datura,Atropa belladonna,Scopolia lurida,Mandragora officinarum,Duboisia)and Erythroxylaceae(Erythroxylum coca)are rich sources of tropane alkaloids.These compounds possess the anticholinergic properties as they could block the neurotransmitter acetylcholine action in the central and peripheral nervous system by binding at either muscarinic and/or nicotinic receptors.Hence,they are of great clinical impor-tance and are used as antiemetics,anesthetics,antispasmodics,bronchodilator and mydriatics.They also serve as the lead compounds to generate more effective drugs.Due to the important pharmacological action they are listed in the WHO list of essential medicines and are available in market with FDA approval.However,being anticholinergic in action,TA medication are under the suspicion of causing dementia and cognitive decline like other medications with anticholinergic action,interestingly which is incorrect.There are published reviews on chemistry,biosynthesis,phar-macology,safety concerns,biotechnological aspects of TAs but the detailed information on anticholinergic mecha-nism of action,clinical pharmacology,FDA approval and anticholinergic burden is lacking.Hence the present review tries to fill this lacuna by critically summarizing and discussing the above mentioned aspects.

A chromosome-level genome assembly of anesthetic drug–producing Anisodus acutangulus provides insights into its evolution and the biosynthesis of tropane alkaloids

Tropane alkaloids(TAs),which are anticholinergic agents,are an essential class of natural compounds,and there is a growing demand for TAs with anesthetic,analgesic,and spasmolytic effects.Anisodus acutan-gulus(Solanaceae)is a TA-producing plant that was used as an anesthetic in ancient China.In this study,we assembled a high-quality,chromosome-scale genome of A.acutangulus with a contig N50 of 7.4 Mb.A recent whole-genome duplication occurred in A.acutangulus after its divergence from other Solanaceae species,which resulted in the duplication of ADC1 and UGT genes involved in TA biosynthesis.The catalytic activities of H6H enzymes were determined for three Solanaceae plants.On the basis of evolution and co-expressed genes,AaWRKY11 was selected for further analyses,which revealed that its encoded tran-scription factor promotes TA biosynthesis by activating AaH6H1 expression.Thesefindings provide useful insights into genome evolution related to TA biosynthesis and have potential implications for genetic manipulation of TA-producing plants.

Emerging tropane alkaloids:Global development and potential health threats

Tropane alkaloids(TAs)are a kind of plant secondary metabolite that mainly originate from Solanaceae.They have potent anticholinergic activity,and are well-known anticholinergic drugs,but have also been reported as plant toxins.Many studies have been conducted on TAs,but no scientometric research has been performed.This study aimed to expound the knowledge network and development of the feld of TAs and predict the emerging development topics based on bibliometrics.In particular,this research combined VOSviewer and CiteSpace for visualization and covered 1,298 related scientifc publications(1953–2022).The research on TAs is rapidly developing,with the participation of 86 countries,1,129 research institutions,and 4,087 researchers.China,the University of Geneva,and P.Christen are the most productive country,institution,and researcher,respectively.Currently,the main research topics on TAs include biosynthesis,in vitro synthesis,chemical synthesis,and determination methods.Since 2018,the monitoring of TAs in food related to human health has shown citation burst characteristics,which is considered an emerging development trend in the future.The fndings of this study will enable researchers to quickly tap into the knowledge background/structure of TAs from massive data to provide a reference for further research.

A novel and versatile method for the enantioselective syntheses of tropane alkaloids

A full account of the novel and flexible approach to hydroxylated 8-azabicyclo[3,2,1]octan-3-ones and 9-azabicyclo[3,3,1] nonan-3-ones is presented. Using keto-lactams as the starting materials, this two-step method consists of silyl enol ether for mation with TBDMSOTf, lactam activation with Tf20/DTBMP, and halide-promoted cyclization. Radical dechlorination of the resulting 1-halotropan-3-ones led to the corresponding hydroxylated tropan-3-ones, which can be hydrogenated to yield 3ct,613-dihydroxytropanes. Starting from optically active keto-lactams, the method has been applied to the enantioselective syntheses of （＋）-（1S,3S,5R,6S）-pervilleine C （6）, （＋）-（1S,3R,5S,6R）-valeroidine （3）, （＋）-（1S,3S,5R,6S）-dibenzoyloxytropane （8） and （＋）-（1S,3S,5R,6S）-merredissine （9）.

Metabolic Engineering of Tropane Alkaloid Biosynthesis in Plants

Abstract: Over the past decade, the evolving commercial importance of so-called plant secondary metabolites has resulted in a great interest in secondary metabolism and, particularly, in the possibilities to enhance the yield of fine metabolites by means of genetic engineering. Plant alkaloids, which constitute one of the largest groups of natural products, provide many pharmacologically active compounds. Several genes in the tropane alkaloids biosynthesis pathways have been cloned, making the metabolic engineering of these alkaloids possible. The content of the target chemical scopolamine could be significantly increased by various approaches, such as introducing genes encoding the key biosynthetic enzymes or genes encoding regulatory proteins to overcome the specific rate-limiting steps. In addition, antisense genes have been used to block competitive pathways. These investigations have opened up new, promising perspectives for increased production in plants or plant cell culture. Recent achievements have been made in the metabolic engineering of plant tropane alkaloids and some new powerful strategies are reviewed in the present paper.

Highly stereoselective construction of polycyclic benzofused tropane scaffolds and their latent bioactivities: bifunctional phosphonium salt-enabled cyclodearomatization process

Structurally fused heterocycles encompassing a centerpiece of benzotropane are significant scaffolds with a plethora of promising biological activities,but such molecular architectures pose a long-standing daunting synthetic challenge.Herein,we reported a highly efficient asymmetric cyclodearomatization of 2-nitrobenzofurans with cyclic azomethine ylides by employing bifunctional phosphonium salts as phase-transfer catalysts.Under optimized reaction conditions,a diverse array of polycyclic benzofused tropane derivatives with four contiguous 4°/3°stereocenters were readily synthesized in both high yields and diastereoselectivities with up to>99%ee.The practicality and utility of this protocol were further demonstrated by the scaled-up reaction and facile elaborations.Moreover,preliminary investigations into their antitumor activities were also presented.

NMR Studies on the Configuration of 6-Chloro Nitrile Epimers of Tropane Derivatives

Baogongteng A is a tropane alkaloid with cholinergic activity. It has been used clinically for the treatment of glaucoma, and its pharmacological activity on heart function has also been reported.In the synthesis of baogongteng A, the cycloadducts of Katritzky cycloaddition of 1-benzyl-3-oxidepyridinium with a-chloroacrylonitrile were ketalized with ethylene glycol in benzene by azeotropic distillation. After recrystallization from ethanol, two compounds（A, prisms, m.p.127—129℃; B, needles, m.p.75—77℃） were obtaines.Their MS, IR spectral data and elemental analysis were consistent with the proposed structures. They were assigned as C6-chloro nitrile epimers by 1H-1H