Alkaloids

A Treasury of Poisons and Medicines

Shinji Funayama, Geoffrey A. Cordell

• Publisher: Academic Press
• Year: 2014
• ISBN:
  9780124173149
• Topic: Sciences physiques
• Subtopic: Chimie organique

Alkaloids are a large group of structurally complex natural products displaying a wide range of biological activities. The purpose of Alkaloids: A Treasury of Poisons and Medicines is to classify, for the first time, the alkaloids isolated from the natural sources until now. The book classifies all of the alkaloids by their biosynthetic origins. Of interest to the organic chemistry and medicinal chemistry communities involved in drug discovery and development, this book describes many alkaloids isolated from the medicinal plants, including those used in Japanese Kampo medicine.

• Classifies and lists alkaloids from natural sources
• Occurrence and biosynthetic pathways of alkaloids
• Indicates key uses and bioactivity of alkaloids

Chapter 1

Alkaloids Derived from Phenylalanine and Tyrosine

Abstract

This chapter introduces those alkaloids derived from phenylalanine and tyrosine.

Keywords

Aristolochic acid; Berberine; Chelidonine; Coclaurine; Colchicine; d-tubocurarine; Dopamine; Emetine; Galanthamine; L-DOPA; Lycorine; Morphine; Phenylethylamine; Thyroxine

The thousands of alkaloids derived from phenylalanine and tyrosine possess a wide range of important biological activities, and several of them are pharmaceutical agents, present in various traditional medicines in various systems, or serve as biological tools. In this chapter, those alkaloids are discussed, from the simplest alkaloids to those that represent more complex chemical structures. The coclaurine-type alkaloids are one of the simplest of these alkaloids, and are described in Section 1.4. Among them, reticuline, in its antipodal forms, is an important biosynthetic precursor of various alkaloids, including such alkaloids as berberine and morphine. Some of the alkaloids of this type are derived through highly complicated, and incompletely understood, biosynthetic pathways. For example, it is very difficult to elucidate the original amino acid derivations of colchicine (Section 1.11) and lycorine (Section 1.13) from a superficial examination of their chemical structures.

Both phenylalanine and tyrosine are derived from chorismic acid, which is itself derived from shikimic acid-3-phosphate through the shikimic acid pathway. In this sequence, chorismic acid is first transformed into prephenic acid by chorismate mutase. If prephenic acid is converted into phenylpyruvic acid by the action of prephenate dehydratase and a transaminase, phenylalanine is formed. On the other hand, if it is transformed into 4-hydroxyphenylpyruvic acid by the action of prephenate dehydrogenase, followed by a transaminase reaction, then tyrosine is formed.

1.1

Phenylethylamines (Phenethylamines)

Peyote (Lophophora williamsii, syn. Anhalonium williamisii) is a cactus and member of the family Cactaceae, and grows wild in the deserts of Mexico and the southern United States [1]. The cactus is also cultivated in Japan as a decorative plant and known as “Ubatama.”

This cactus is an important source of the so-called phenylethylamine (phenethylamine) alkaloids with a C₆C₂N skeleton. The main component of the alkaloid mixture is mescaline. The name mescaline is derived from the name of the cactus, which is also known as “mescal buttons.” Mescaline is known to possess hallucinatory effects and a number of undesirable side effects. With respect to the biosynthesis of mescaline, it was shown that L-tyrosine is oxidized to give L-DOPA (L-3,4-dihydroxyphenylalanine), which is transformed to the biosynthetic precursor dopamine (3,4-dihydroxyphenethylamine) [2], which is selectively O-methylated to afford 3-O-methyldopamine, a key biosynthetic precursor of the alkaloid. The direct biosynthetic precursor of mescaline was determined to be 3,5-dimethoxy-4-hydroxyphenethylamine, because 3,4,5-trihydroxy phenethylamine and 3,4-dimethoxy-5-hydroxyphenethylamine were not incorporated into the biosynthetic pathway to mescaline [2].

Hordenine and N-methyltyramine are isolates from the young roots of Hordeum vulgare var. hexastichon (Poaceae), and are simple phenylethylamine-type alkaloids. The biosynthetic precursor of these alkaloids is considered to be tyramine, derived from tyrosine. dl-[2-¹⁴C]-Tyrosine was fed to H. vulgare var. hexastichon 4 days after germination, and hordenine and N-methyltyramine were isolated after 11 days from the roots. Both alkaloids possessed ¹⁴C label at the α-carbon. It was also found that dl-[2-¹⁴C]-tyrosine was more effectively incorporated into N-methyltyramine than into hordenine, and no tyramine was detected in the extract. So, the incorporated tyrosine was converted into tyramine and methylated immediately to give N-methyltyramine. Subsequent steps form hordenine by the methylation of N-methyltyramine [3].

On the other hand, it was clarified by the incorporation of labeled methionine that the methyl groups incorporated during the biosynthesis of N-methyltyramine and hordenine were derived from methionine. The yield of N-methyltyramine in these experiments is less than half that of hordenine; however, the incorporation of ¹⁴C into N-methyltyramine is 1.5 times that of hordenine. This indicates that N-methyltyramine is not formed by the demethylation of hordenine, but th...