Alkaloid Derivatives of Lysergic Acids

Cultivation of Claviceps paspali Alkaloid Derivatives of Lysergic Acids 

Ernst Boris Chain, Cesare Bonino, Antonio Tonolo, Rome, Italy July 19,1960 

In all these investigations, carried out over many years, the production of the alkaloids occurs only by saproph3dic surface culture after 20-40 days of incubation and besides the unitary production is so low as to be impractical. 

More recently, Spruson et al. Australian P. 34,313/58) have described a process for the biosynthetic production of ergot alkaloids by the cultivation of Claviceps purpurea Tul., under essentially anaerobic conditions and with a substantial reduction of cell respiration. Such conditions present a number of evident disadvantages. 

The organisms employed for the process of the present invention are new strains of Claviceps paspali Stevens and Hall. It had been found that the strains Claviceps paspali Stevens and Hall, which do not produce the lysergic acid derivatives alkaloids by submerged culture, may be virulented artificially, to give new strains of Claviceps paspali, which in turn allow said production. 

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The process of the invention is therefore one for the production of alkaloid derivatives of lysergic acid which comprises fermenting under aerobic conditions an aqueous nutrient medium containing a source of carbon, nitrogen and mineral salt with a new strain of Claviceps paspali Stevens and Hall as herein before defined. 

As regards the production of alkaloid derivatives of lysergic acid, the present invention is not limited to the use of the described strains, but comprises also the mutants thereof, which may be obtained, e.g., by means of either a selection or a mutation by the action of U.V. rays or Roentgen rays or any other mutagenous substance or, particularly, by artificial infection of either embryos or grasses cultivated in vitro or plants of grasses cultivated both in vivo or in vitro and the said mutants are to be included in the definition of a new strain of Claviceps paspali Stevens and Hall. 

Bromocriptine Bromocriptine, 2-bromoergocriptine (10.1.13), is a semisynthetic derivative of a natural ergot alkaloid, ergocriptin (a derivative of lysergic acid), which is synthesized by bromination of ergocriptin using M-bromosuccinimide [18,19]. 

Ergot alkaloids were the first adrenoblockers to be studied. Despite the fact that the majority of ergot alkaloids exhibit a-adrenoblocking activity, their pharmacology is often different. In terms of chemistry, ergotamine and ergonovine are derivatives of lysergic acid. 

The delicate structures as well as the interesting patterns of pharmacological activity of certain ergot alkaloids have received continuous attention among synthetic chemists. This is especially true of derivatives of lysergic acid, and this chapter will be devoted to the most remarkable developments in syntheses of this class of natural compounds. 

The structural and configurative relationships between the alkaloids of the clavine group on the one hand, and the derivatives of lysergic acid alkaloids (LXII, LXIII) on the other, are shown by the illustrated formula scheme (LIX to LXVI). 

The ergot alkaloids are derivatives of the four-ring structure of ergoline. These alkaloids can be divided into three groups derivatives of lysergic acid... 

The separation of the naturally occurring ergot alkaloids derived from lysergic acid in... 

Wurst et al.2 reported the separation of clavines and lysergic acid derivatives on a stationary phase containing alkylamine groups in combination with neutral organic solvents (Tables 9.6 and 9.7). For the clavines, the best separation - under isocratic conditions -was obtained with diethyl ether - ethanol (84 16) a gradient elution was, however, found to give better results. For the alkaloids derived from lysergic acid, diethyl ether - ethanol... 

Cerletti, A. Doepfner, W. Comparative Study on the Serotonin Antagonism of Amide Derivatives of Lysergic Acid and of Ergot Alkaloids J. Pharmacol Exp. Then (1958) 122 124-136... 

The fundamental chemistry is outlined in Figure 10-5. All the alkaloids can be considered as derivatives of (+)lysergic acid. The epimeric (+)isolysergic acid (epimerized on C-8) and its corresponding alkaloids produced during extraction are essentially inert. 

All these ergot alkaloids are amide derivatives of lysergic acid, but only the diethylamide LSD produces the profound hallucinatory effects for which it is so well-known. 

Probably the most important alkaloids are some of the potent habit-forming narcotic and hallucinogenic substances extracted from coca, opium, and peyote cactus plants. These include cocaine, morphine, heroin, and mescaline. LSD, an amide derivative of lysergic acid, first synthesized three decades ago, is among the most potent psychedelic drugs. Halo derivatives of mescaline are several times as potent as mescaline. 

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