molecules Review Alkaloids of the Genus Datura: Review of a Rich Resource for Natural Product Discovery Maris A. Cinelli * and A. Daniel Jones * Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA * Correspondence: [email protected] or [email protected] (M.A.C.); [email protected] (A.D.J.); Tel.: +1-906-360-8177 (M.A.C.); +1-517-432-7126 (A.D.J.) Abstract: The genus Datura (Solanaceae) contains nine species of medicinal plants that have held both curative utility and cultural significance throughout history. This genus’ particular bioactivity results from the enormous diversity of alkaloids it contains, making it a valuable study organism for many disciplines. Although Datura contains mostly tropane alkaloids (such as hyoscyamine and scopolamine), indole, beta-carboline, and pyrrolidine alkaloids have also been identified. The tools available to explore specialized metabolism in plants have undergone remarkable advances over the past couple of decades and provide renewed opportunities for discoveries of new compounds and the genetic basis for their biosynthesis. This review provides a comprehensive overview of studies on the alkaloids of Datura that focuses on three questions: How do we find and identify alkaloids? Where do alkaloids come from? What factors affect their presence and abundance? We also address pitfalls and relevant questions applicable to natural products and metabolomics researchers. With both careful perspectives and new advances in instrumentation, the pace of alkaloid discovery—from not just Datura—has the potential to accelerate dramatically in the near future. Citation: Cinelli, M.A.; Jones, A.D. Alkaloids of the Genus Datura: Keywords: alkaloid; Solanaceae; tropane; indole; pyrrolidine; Datura Review of a Rich Resource for Natural Product Discovery. Molecules 2021, 26, 2629. https://doi.org/ 10.3390/molecules26092629 1. Introduction Perhaps no plants on Earth have been more famous—and infamous—throughout Academic Editors: Young Hae Choi, history than those in the genus Datura. Naturalized throughout the temperate regions of Young Pyo Jang, Yuntao Dai and Luis the world, Datura plants, like their other relatives in the family Solanaceae, are a rich source Francisco Salomé-Abarca of bioactive phytochemicals. Although phenolics, steroids, acylsugars, amides, and other compounds from these plants have been isolated and characterized, it is the alkaloids found Received: 27 March 2021 in Datura that have cemented these plants’ role in the remedies, religions, history, and lore Accepted: 25 April 2021 of different cultures in all corners of the world. Published: 30 April 2021 As some of the tropanes, pyrrolidines, indoles, and other alkaloids present in the plant yield both medicinal use and insidious toxicity, Datura has also been the subject Publisher’s Note: MDPI stays neutral of fairly intensive study. For over a century, a complex, multidisciplinary effort with with regard to jurisdictional claims in published maps and institutional affil- contributions from drug discovery and pharmacology, plant breeding and bioengineering, iations. evolutionary biology, analytical chemistry, and ethnobotany has sought to elucidate the peculiar and powerful properties of these plants and the substances within that cause them. This comprehensive review covers the alkaloids of Datura, the tools used to detect and identify them, the factors affecting their content and composition, and challenges facing the plant natural products field as a whole. This information could aid anyone Copyright: © 2021 by the authors. interested in discovering novel alkaloids or studying plant breeding or engineering systems Licensee MDPI, Basel, Switzerland. for alkaloid production. This article is an open access article distributed under the terms and 2. History and Taxonomy conditions of the Creative Commons 2.1. Medicine and Culture Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ The historical significance of Datura is both medicinal and cultural. Datura plant parts, 4.0/). extracts, and preparations have been used as medicines by humans for millennia. Although Molecules 2021, 26, 2629. https://doi.org/10.3390/molecules26092629 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 37 2. History and Taxonomy 2.1. Medicine and Culture The historical significance of Datura is both medicinal and cultural. Datura plant parts, extracts, and preparations have been used as medicines by humans for millennia. Although comprehensive analysis of the medicinal uses of Datura is beyond the scope of Molecules 2021, 26, 2629 this article, the reviews of Maheshwari [1], Benitez [2], and Batool [3]2 offer of 38 additional in- sights on this topic. Datura is described in ancient Chinese, traditional African, and Ayur- vedic medicine. These plants were also used medicinally by indigenous Americans, and comprehensive analysis of the medicinal uses of Datura is beyond the scope of this article, thetheir reviews properties of Maheshwari were also [1], Benitezdescribed [2], andin Medieval Batool [3] offer European additional texts. insights Datura on this was a remedy for topic.manyDatura conditionsis described including in ancient pain, Chinese, bruises, traditional wound African, infections, and Ayurvedic swellings medicine. and boils, rheuma- Thesetism, plantsand toothaches, were also used and medicinally Datura cigarettes by indigenous were Americans, smoked and to alleviate their properties asthma and breath- wereing problems also described [1,2]. in Medieval Extracts European and compounds texts. Datura was(both a remedy alkaloids for many and conditions other components) de- includingrived from pain, Datura bruises, have wound also infections, been investigated swellings and boils,for, am rheumatism,ong others, and toothaches,anticancer, antibacterial, and Datura cigarettes were smoked to alleviate asthma and breathing problems [1,2]. Extractsantiviral, and and compounds antifungal (both activities alkaloids and [1,3]. other components) derived from Datura have also beenThe investigated genus’ most for, among famous others, alkaloidal anticancer, constituents antibacterial, antiviral,are the andtropane antifungal alkaloids atropine activities(racemic [1 ,13,]. or hyoscyamine, (S)-1), see below for clarification) and scopolamine (2, or hy- oscine),The genus’which most are famous shown alkaloidal in Figure constituents 1. Tropan aree the alkaloids tropane alkaloids(bicyclic atropine [3.2.1] alkaloids) are (racemic 1, or hyoscyamine, (S)-1), see below for clarification) and scopolamine (2, or hyoscine),known across which aremany shown plant in Figure genera1. Tropanebeyond alkaloids Datura (bicyclic, and it [3.2.1]is worth alkaloids) noting are that the primary knowncommercial across manysources plant of genera atropine beyond andDatura scopolamine, and it is worth are noting usually that thethe primary genus Duboisia (and commercialsometimes sources Brugmansia of atropine), and and not scopolamine Datura are[4]. usually Alkaloid the genus 2 is aDuboisia muscarinic(and some- antagonist used to timestreat Brugmansianausea, vomiting,), and not Datura and motion[4]. Alkaloid sickness,2 is a muscarinic whereas antagonistatropine used(1) is to a treat similar anticholin- nausea,ergic agent, vomiting, and and is motionused in sickness, the treatment whereas atropineof certain (1) ispoisonings a similar anticholinergic and heart conditions, and agent, and is used in the treatment of certain poisonings and heart conditions, and to dilate theto dilate pupils inthe ophthalmology. pupils in ophthalmology. Both of these drugs Both are listedof these on the drugs World are Health listed Organiza- on the World Health tion’sOrganization’s Model List of Model Essential List Medicines of Essential [5], and Medici syntheticnes or semisynthetic[5], and synthetic derivatives or semisynthetic of de- theserivatives drugs of are these also used. drugs are also used. FigureFigure 1. 1.Hyoscyamine Hyoscyamine [(S)-1, [(S the)-1, Sthe-enantiomer S-enantiomer of atropine, of atropine, (1) and scopolamine (1) and scopolamine (2), the most (2), the most well-knownwell-known alkaloids alkaloids of the of genus the genusDatura. Datura. As Datura contains high levels of these potent alkaloids (and many others whose bioactivityAs Datura is ill-defined), contains all parts high of levels the plants of these are considered potent toxic,alkaloids and can (and easily many poison others whose bi- bothoactivity humans is andill-defined), livestock animals all parts if accidentallyof the plants or deliberately are considered ingested toxic, [6,7]. andDatura can easily poison poisoningboth humans in humans and causes livestock dilated animals pupils, increased if accidentally heart rate, or blood deliberately pressure, and ingested body [6,7]. Datura temperature,poisoning in dry humans mucous membranes,causes dilated confusion, pupils, depression, increased and heart incoherence rate, [blood8,9]. Severe pressure, and body symptomstemperature, can cause dry heartmucous arrhythmias, membranes, coma [8confusion,], respiratory depression depression,, andand death. incoherence In [8,9]. Se- one 26-year period in the United States, Datura species were responsible for 20% of fatal plantvere poisoningssymptoms in can humans, cause despite heart arrhythmias, their consumption coma being [8], uncommon respiratory [7]. depression,Datura and death. poisoningIn one 26-year also causes period characteristic