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.

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.

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.

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