**Kathrin Laura Kohnen-Johannsen and Oliver Kayser \***

Technical Biochemistry, Department of Biochemical and Chemical Engineering, Technical University Dortmund, D-44227 Dortmund, Germany; Laura.Kohnen@tu-dortmund.de

**\*** Correspondence: Oliver.Kayser@tu-dortmund.de; Tel.: +49-231-755-7487

Received: 15 January 2019; Accepted: 18 February 2019; Published: 22 February 2019

**Abstract:** Tropane alkaloids (TA) are valuable secondary plant metabolites which are mostly found in high concentrations in the Solanaceae and Erythroxylaceae families. The TAs, which are characterized by their unique bicyclic tropane ring system, can be divided into three major groups: hyoscyamine and scopolamine, cocaine and calystegines. Although all TAs have the same basic structure, they differ immensely in their biological, chemical and pharmacological properties. Scopolamine, also known as hyoscine, has the largest legitimate market as a pharmacological agent due to its treatment of nausea, vomiting, motion sickness, as well as smooth muscle spasms while cocaine is the 2nd most frequently consumed illicit drug globally. This review provides a comprehensive overview of TAs, highlighting their structural diversity, use in pharmaceutical therapy from both historical and modern perspectives, natural biosynthesis *in planta* and emerging production possibilities using tissue culture and microbial biosynthesis of these compounds.

**Keywords:** tropane alkaloids; scopolamine; cocaine; calystegine; chemistry; pharmacology; biosynthesis; biotechnological production

## **1. Introduction**

Alkaloids are naturally occurring compounds containing one or more nitrogen atoms. The name is derived from the basic nature of many members of this group, alkaloids from "alkaline-like". The definition of alkaloids is complex as many nitrogen-containing molecules do not necessarily belong to this group. Biogenic amines or amino sugars, for example, are natural plant products and *N*-containing but not defined as alkaloids. Tropane alkaloids (TAs) are a specific class of alkaloid and can be more specifically defined as all molecules that possess a tropane ring system (Figure 1 Structure of the tropane skeleton (green box) and the three major groups of TAs derived from, green box) [1].

TAs are either esters of 3α-tropanole (tropine) or, to a lesser extent, 3β-tropanole (pseudotropine) and can be distinguished into three groups: TAs from Solanaceae plants like hyoscyamine and scopolamine, coca alkaloids like cocaine from *Erythoxylum coca* and the recently discovered calystegines group, which are polyhydroxylated nortropane alkaloids (NTAs) mainly occurring in Convolvulaceae, Solanaceae, Moraceae, Erythrocylaceae and Brassicaceae (Figure 1 Structure of the tropane skeleton (green box) and the three major groups of TAs derived from) [2]. In total, ~200 different TAs have been described [3].

Biosynthesis of the tropane ring system is homologous in organisms which produce these three TA classes. TA biosynthesis begins with the amino acids ornithine or arginine and their intermediate putrescine, continuing to the common *N*-methyl-Δ1-pyrrolinium cation precursor of all TAs. This is the branch point of cocaine, hyoscyamine/scopolamine and calystegine as well as nicotine biosynthesis [4].

Although all TAs have a high degree of structural similarity due to their tropane ring, the pharmacological effects of these compounds differ significantly. Cocaine and hyoscyamine/scopolamine are able to pass the blood-brain barrier and commit dose-dependent hallucination and psychoactive effects. Calystegines do not cause these effects due to their polarity as well as hydrophilicity and consequent inability to pass this barrier.

**Figure 1.** Structure of the tropane skeleton (green box) and the three major groups of TAs derived from this skeleton.

The cultivation of coca plants, the extraction of cocaine and production of other cocaine-containing drugs as well as their trade, with a few exceptions, is illegal and cocaine is the 2nd most frequently consumed illicit drug globally [5]. Due its legal designation, research has only been conducted on pathway elucidation in order to understand cocaine biosynthesis, however, research of large-scale commercial production has not been conducted (legally). As the calystegines are a newly discovered group of TAs without any pharmaceutical, medicinal or economic interest, little research has thus far been performed on this group of TAs. In contrast, the cultivation and production of scopolamine is of major economic interest due to its miscellaneous pharmaceutical applications. Indeed, global demand for this compound is increasing. Moreover, scopolamine is one of the Essential Medicines of the World Health Organization (WHO) [6]. Hyoscyamine and scopolamine are extracted from the *Duboisia* plants being cultivated on large plantations in Queensland, Australia [1]. Climate change and resulting new biotic and abiotic factors challenge the pharmaceutical industry to produce consistently high volumes of scopolamine. To overcome this issue, alternative production methods have been also tested.

This review seeks to provide a comprehensive overview of current knowledge on medicinal and pharmaceutical applications of TAs, a comparative analysis of TA biosynthesis and future strategies for elucidation of biosynthetic pathways, with special focus placed on the production of scopolamine as well as derivatives and enhancement of their production.
