Alkaloids of the Cactaceae ― The Classics Bruce K. Cassels Department of Chemistry, Faculty of Sciences, University of Chile, Santiago 7800003, Chile bcassels@uchile.cl Received: October 16 th , 2018; Accepted: November 10 th , 2018 Alkaloids of the Cactaceae have been studied for the last 120 years. The first half of that period provided the “classic” compounds, after which a large number of usually very similar analogs were isolated or determined with modern methods. Although some unusual synthetic approaches have been developed, their preparation is generally quite straightforward. Their biosynthesis has been studied but, particularly in the case of the isoquinoline compounds, important aspects have not been addressed. Due to its striking effects, the pharmacology of mescaline has been studied more intensely than that of the other phenethylamines present in cacti, followed only by hordenine. The many 1,2,3,4-tetrahydroisoquinoline alkaloids have attracted much less interest and have often been considered practically inactive. Nevertheless, some recorded activities of this group of compounds suggests a need for additional studies, especially in connection with their co-administration with mescaline, as in dried cacti and in beverages prepared from them. Keywords: Cactaceae, Alkaloids, Phenethylamines, 1,2,3,4-Tetrahydroisoquinolines, Structures, Synthesis, Pharmacology. The Cactaceae are exclusively native to the Americas, growing from southern Canada to Patagonia, although Rhipsalis baccifera (J.S.Muell) Stearn is also found growing wild in tropical Africa, Madagascar and Sri Lanka and is believed to have been introduced from Brazil or the Caribbean basin, possibly in historical times [1- 4]. Four subfamilies are generally recognized: the relatively primitive Pereskioideae, the very small, specialized Maihuenioideae (only two species), and the very numerous Opuntioideae and Cactoideae. Alkaloids (if simple phenethylamines are considered as such) have been found most frequently in the Cactoideae, but there are a few recorded examples from the Opuntioideae and Pereskioideae. The present review will focus on the “classic” cactus alkaloids, discovered up to the middle of the 20 th century. The very numerous compounds isolated since then are almost exclusively either simple amines (e.g. phenethylamine, tyramine, dopamine) or commonplace variations on the previous structures. Although valuable reviews on the original compounds were published from 1950 to 1954 by Ladislao Reti [5], modern pharmacology and biochemistry have opened up new vistas, not necessarily connected to the remarkable psychedelic effects of “peyote” (Lophophora williamsii (Lem. ex Salm-Dyck) J.M.Coult). This paper attempts to put such knowledge up to date and is a homage to Reti’s pioneering work. The history of Cactaceous alkaloid chemistry begins with Louis Lewin’s 1888 study of “peyote”, which was then viewed as close to the previously described “Anhalonium williamsii” and was designated “A. lewinii” in his honor. From this cactus, growing in Northeast Mexico and spreading into Southeast Texas, Lewin, working in Berlin, crystallized a crude sample of anhalonine, the first cactus alkaloid, and showed that it was not responsible for the remarkable psychotropic effects of peyote tops or “mescal buttons” [6(a)]. Up to 1894 he continued studies on cacti that were then classified as “A. jourdanianum” and “A. williamsii” (now all grouped as Lophophora williamsii), as well as four or five Mammillaria species and a Rhipsalis, but without any clear chemical results [6(b)]. More fruitful early studies were carried out by Arthur Heffter, who isolated and characterized “anhaline” (now known as hordenine) from “Anhalonium fissuratum” or “Mammillaria fissurata” (now Ariocarpus fissuratus (Engelm.) K.Schum.) and pellotine from a “pellote” described as “Anhalonium williamsii”, plus a small amount of what he later characterized as mescaline from “A. lewinii” [7(a)]. In subsequent papers Heffter characterized his pellotine and mescaline more completely, isolated anhalonidine and lophophorine and improved on Lewin’s description of anhalonine, all from “A. lewinii” [7(b,c)]. In one of his 1898 papers [7(c)] he also demonstrated that mescaline was responsible for peyote’s psychedelic properties, while anhalonine and anhalonidine at similar doses were devoid of any effects worthy of note. In contrast, he found that pellotine only made him sleepy, leading to subsequent testing in humans for this purpose. Heffter demonstrated the presence of alkaloids in several other cactus species, but did not describe any chemical details. Shortly thereafter E. Kauder isolated one more alkaloid, anhalamine, from peyote [8]. Stimulated by Heffter and Kauder’s work, Georg Heyl published a paper describing the isolation of pilocereine (actually a mixture of alkaloids) from “Pilocereus sargentianus” (now Pachycereus schottii (Engelm.) D.R.Hunt), and “pectenine” from “Cereus pecten-aboriginum” (now Pachycereus pecten-aboriginum (Engelm. ex Watson) Britton & Rose) [9]. Many years later Heyl isolated carnegine from Carnegeia gigantea (Engelm.) Britton & Rose [10]. This early work included the preparation of various salts of the alkaloids (usually containing metals such as mercury, gold or platinum), elementary analyses and some other chemical tests based on oxidations and the Zeisel quantification of methoxyl groups [11(a,b)], but no convincing structure was determined until 1919, when a young Ernst Späth in the University of Vienna demonstrated the identity of “anhaline” with hordenine and proved the structure of mescaline [12(a)]. In the following decade Späth and his students, particularly Friedrich Becke and Johann Bruck, carried out a number of studies showing the structures of anhalonine and lophophorine [12(b)], carnegine, found to be the same as the “pectenine” of Pachycereus species [12(c,d)], pellotine and anhalonidine [12(e)], anhalamine [12(f)], and then of a succession of “new” peyote alkaloids: anhalinine [12(g)], anhalidine [12(h)], N-methylmescaline [12(i)], the first non-basic cactus alkaloid N-acetylmescaline [12(j)], and O-methylanhalonidine [12(k)]. NPC Natural Product Communications 2019 Vol. 14 No. 1 85 - 90