Production of Lysergic Acid Derivatives

The process of the invention, therefore, for the production of lysergic acid derivatives comprises cultivating the strain of Claviceps paspali Stevens and Hall, NRRL 3027, in a nutrient medium and isolating lysergic acid derivatives from the said medium. 

The ready formation of conidia by the new strain confers other advantages besides ease of inoculation. Thus, single spores can be isolated by the usual techniques and genetically homogeneous material thus obtained. 

Moreover, it is easier to produce mutants from such spores by artificial methods, such as X-ray or ultra-violet irradiation or the use of certain chemicals, than from sterile mycelium. The conidia can be freeze-dried and thus stored indefinitely. Finally, should the strain begin to lose its vigor it can be restored by growth on Paspalum plants which may be readily infected with conidia. 

The sclerotica formed by the new strain of Claviceps paspali Stevens and Hall on Paspalum plants contain alkaloids, unlike those formed by other strains of this fungus. 

The alkaloid content of the sclerotica amounts to 0.04%, calculated on an average molecular weight of 300. The composition of the alkaloid mixture is as follows  

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Arcamone, F., C. Bonino, E. B. Chain, A. Ferretti, P, Pennella, A. To-nolo, and L. Veto Production of Lysergic Acid Derivatives by a Strain of Claviceps paspali Stevens and Hall in Submerged Culture. Nature 187, 238 (1960). 

The conidia produced in this way may he used to inoculate culture media used for the production of lysergic acid derivatives. For this purpose the submerged culture technique is preferably used. 

Kelleher, W. J., Kim, B.K., Schwarting, AE. Production of Lysergic Acid Derivatives in Submerged Culture. 5. Effect of Surfactants on Alkaloid Accumulation Llyodia (1969) 32 (3) 327-333... 

Mary, N.Y., Kelleher, W.J., Schwarting, A.E. Production of Lysergic Acid Derivatives in Submerged Culture. 3. Strain Selection on Defined Media Lloydia (1965) 28 (3) 218-229... 

Rutschmann, R. Kobel, H. Microbiological Production of Lysergic Acid Derivatives 1965 US 3,219,545... 

Arcamone, F. etal i960. Production of lysergic acid derivatives by a strdn of Cla-vicepspaspali ixsvetss and Hall in submerged culture Nature 187 238—239. 

Chain did not intend to repeat his experience with penicillin a lot of honor but no economic benefits. In fact, the production of penicillin by English laboratories was submitted to payment of royalties to the American laboratories who owned the patents, dated before the isolation of penicillin itself, on the producer microorganisms. Chain had a position in a public institution in Rome, the ISS, so he could not be either the owner of a patent on the production of lysergic acid derivatives (LAD) or sell it to anyone. In order to bypass the problem he agreed with the head of the ISS to create a foundation which was allowed to give financial support to the research performed in the ISS. A patent was issued... 

Arcamone, E, Bonino, C., Chain, E.B., Ferretti, A., Pennella, R, Tonolo, A. and Vero, L. (1960) Production of lysergic acid derivatives by a strain of Claviceps paspali in submerged culture. Nature (London), 187,238-239. 

Pacific , L.R., Kellehei W.J. and Schwarting, A.E. (1962) Production of lysergic acid derivatives in submerged culture. I. Fermentation studies. Lloydia, 25, 37-45. 

Rozman, D., Pertot, E., Komel., R. and Prosek, M. (1989) Production of lysergic acid derivatives with immobilized Claviceps paspali mycelium. Appl. Microbiol. Biotecbnol., 32, 5-10. 

Pertot, E., Cadez, J., Milici c, S. and Socic, H. (1984) The effect of citric acid concentration and pH on the submerged production of lysergic acid derivatives. Appl Microbiol. Biotechnol, 20, 29-32. 

Ricicova, A., Fliegei M., Sedmera, R, Vokoun, J., Rehacek, Z., Stuchlik, J. and Krumphanzl, V. (1982b) Process for the production of lysergic acid derivatives by submerged fermentation. C5 pat. 224 532 (In Czech). 

Socic, H., Gaberc-Porekar, V., Pertot, E., Puc, A. and Milicic, S. (1986) Developmental studies of Claviceps paspali seed cultures for the submerged production of lysergic acid derivatives./. Basic Microbiol., 26, 533-539. 

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