Patent GB-837423-A (GB)
Title: Improvements in or relating to the production of ergot alkaloids
IPC: C12P17/18
Filed: 1956-03-02
Abstract: Ergot alkaloids are obtained by saprophytic cultivation of Claviceps sp. on a nutrient substrate under aerobic conditions, first at a pH of 3.0-5.0 until a desired growth has been attained and then at a pH of 5.5-7.0, with adjustment of the conditions and/or the composition of the substrate so that respiration is reduced and alkaloid production is stimulated.  The substrate should contain assimilable sources of carbon and nitrogen, and also phosphate, magnesium, iron and trace elements which are usually present in tap water.  Various animal or vegetable extracts (e.g. malt, yeast) may be added as growth factors. Suitable compounds are listed for making up the substrate.  The adjustment of conditions and/or composition may comprise (1) successive or sudden reductions of redox potential from an initial value of 24 or more to 18 or less, by addition of a reducing agent such as ascorbic acid, sulphite, hydroquinone or animal organ extracts, or by exclusion of atmospheric oxygen; (2) reduction of the nitrogen to carbon ratio; (3) reduction of the phosphate to carbon ratio; (4) reduction of the sulphate to carbon ratio; or (5) addition of a respiratory toxin, e.g. cyanide, iodine acetate, arsenite, fluoride, azide or 2 : 4-dinitrophenol. These methods may be applied in combination.  Examples are given of these methods, with the isolation by normal methods of ergotoxine, ergotinine, ergotamine, ergotaminine, ergometrine, ergometrinine, ergosine, ergosinine and (unspecified) simpler clavinetype alkaloids. The process is stimulated by the presence of indole or a compound having the indole nucleus, e.g. tryptophan or indoleacetic acid.  The two stages of the process can be carried in the same or different culture media provided the specified conditions are satisfied. Specifications 755,555 and 757,696 are referred to.ALSO:Ergot alkaloids are obtained by saprophytic cultivation of Claviceps sp. on a nutrient substrate under aerobic conditions, first at a pH of 3.0-5.0 until a desired growth has been attained and then at a pH of 5.5-7.0, with adjustment of the conditions and/or the composition of the substrate so that respiration is reduced and alkaloid production is stimulated.  The substrate should contain assimilable sources of carbon and nitrogen, and also phosphate, magnesium, iron and trace elements which are usually present in tap water.  Specified carbon sources are arabinose, xylose, glucose, fructose, galactose, mannose, sucrose, dextrin, starch, mannite, fatty oils (e.g. olive), phosphoglyceric acid, succinic acid and oxalacetic acid; lactose is not suitable. Specified nitrogen sources are peptone, hydrolysed casein, yeast extract, glutamic acid, asparagine, glycine, leucine, alanine, guanidine, urea, ammonium salts and nitrates.  Other elements can be supplied as potassium phosphate, magnesium sulphate, magnesium chloride, ferrous sulphate, zinc sulphate, copper sulphate, manganese sulphate, boric acid and ammonium molybdate.  The process is aided by the presence of indole or a compound containing the indole nucleus, e.g. tryptophan or indoleacetic acid, or of growth factors added as animal or vegetable extracts, e.g. of yeast or malt. The adjustment of conditions and/or composition may comprise (1) successive or sudden reductions of redox potential from an initial value of 24 or more to 18 or less, by addition of a reducing agent such as ascorbic acid, sulphite, hydroquinone or animal organ extracts, or by exclusion of atmospheric oxygen; (2) reduction of the nitrogen to carbon ratio; (3) reduction of the phosphate to carbon ratio; (4) reduction of the sulphate to carbon ratio; or (5) addition of a respiratory toxin, e.g. cyanide, iodine acetate, arsenite, fluoride, azide or 2 : 4-dinitrophenol.  Examples are given of these methods, alone or in combination.  The two stages of the process can be carried out in the same or different culture media provided the specified conditions are satisfied.  Specifications 755,555 and 757,696 are referred to.