Clavine-Type Alkaloids

Clavine-type alkaloids have been isolated from various fungal strains, and, in particular, they have been found in the family Trichocomaceae (Fig. 4.4) (SS). Agroclavine (139) and elymoclavine (140) contain a double bond in the D-ring of the ergoline framework. Festuclavine (141) and pyroclavine (142) possess a saturated D-ring and differ in their stereochemistry at C-8. Their stereoisomers costaclavine (143) and epicostaclavine (144) have been isolated also from various fungi 88, 92). 

Recently Ge and co-workers reported the isolation of other prenylated fumigaclavines from A. fumigatus, namely, 9-deacetoxyfumigaclavine C (150) and 9-deacetylfumigaclavine C (151) (55, 93). 

The most important representative of the ergopeptine subclass is ergotamine (157), which is produced by C. purpurea as the main ergot alkaloid (Fig. 4.8) 88,106-108). 

Whereas ergotamine (157) and its semi-synthetic derivative dihydroergotamine (158) have a clinical purpose for the treatment of several diseases (SS, 109-112), ergovaline (159) is involved in livestock toxicoses caused by ingestion of endophyte-infected grasses (SS, 113,114). 

This section of the chapter will describe alkaloids identified in fungal strains that are biosynthetically related to ergot alkaloids. These compounds carry a modified ergoline scaffold like epoxyagroclavine-I (168) or even an obviously different skeleton like aurantioclavine (176) (Fig. 4.10) (88, 91,117). 

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Ramstad, E., Chan-Lin, W.-N., Shough, H.R., Goldner, K.J., Parikh, R.P. and Tayloi E.H. (1967) Norsetoclavine, a new clavine-type alkaloid from Pennisetum ergot. Lloydia, 30,441 4. 

Yamatodani, S., Kozu, Y., Yamada, S. and Abe, M. (1962) XLVIII. Microbial conversions of clavine type alkaloids, agroclavine, and elymoclavine. Takeda Kenkyusho Nempo (Ann. Repts. Takeda Res. Lab.), 21, 88-94 Chem. Abstr., (1963) 59, 3099c. 

Recently, with the aid of the new, efficient methods of detection, e.g., paper and thin-layer chromatography, clavine alkaloids have also been found to occur in ergot obtained from rye. Furthermore, in 1960, Hofmann and Tscherter surprisingly found the occurrence of alkaloids of the clavine type in higher plants, i.e., in genera of the family of twining plants (Convolvulaceae) (70, 71). 

The addition of mevalonic acid-l-C14 to a pyroclavine- and festuclavine-producing fungus strain yielded inactive alkaloids which, in agreement with the scheme, showed that the carboxyl group of the mevalonic acid is not incorporated. Lowering of the assimilation of mevalonic acid-2-C14 by the addition of dimethylallylpyrophosphate or isopentenylpyrophos-phate supported the assumption that mevalonic acid enters the alkaloid molecule via one of these activated isoprene radicals. This was confirmed by the incorporation of deuterated isopentenylpyrophosphate in alkaloids of the clavine type in saprophytic cultures of a Claviceps strain (128). 

Neurotoxic mycotoxins of the indole alkaloid type from many mold fungi of the genus Penicillium. e.g., P. roqueforti. P cyclopium, P. commune, P crustosum, P. chrysogenum, P. griseofulvum. The R. occur in blue cheese and cotton seeds and have also been found in beer. The main alkaloid is R. C. R. can lead to abortions in animal experiments. Today, toxin-free strains are used for the production of cheese. R. C and R. D are formed from tryptophan, histidine (diketopipera-zine part) and mevalonic acid. R. A and R.B are alkaloids of the clavine type (see ergot alkaloids). The LD50 for mice (i.p.) is 15 mg R.C/kg. 

Fig. 4.5 Biosynthesis of ergoline alkaloids II. Paspalic acid as the key intermediate between clavine type and lysergic amide type ergoline alkaloids (oxidation of elymodavine by elymodavine 17-monooxygenase and isomerization of the resulting paspalic acid to activated lysergic acid)...

Some of the clavine type of alkaloids e.g. elymoclavine, chanoclavine, and their analogues influence the monoamine turnover in the brain (Petkov and Konstantinova, 1986). Chanoclavine and its derivatives, as well as bromokryptine stimulating the dopamine D2R expression (Watanabe et ah, 1987), are important for selective pharmacologic intervention in the treatment of various psychosis, hyperprolactinemia and PRL-producing tumours (Wu et al., 1996). On the other hand, effects of ergot alkaloids on vasoconstriction, metabolic influences or smoth muscle cells contraction are mediated by a-adrenoceptors (Abrass et al, 1985 Arnason et al., 1988). 

On the basis of their structural differences, the ergot alkaloids may be divided into two main groups one group to include all lysergic acid derivatives of the acid amide type, and the other to include the so-called clavine alkaloids. Further structural groups may be recognized within these main groups, as is shown by Tables I and II. 

Following procedure as a practical example describes submerged cultivation of Claviceps fusiformis SD-58 for clavine alkaloid production. The strain can be obtained, e.g., from American Type Culture Collection (ATCC). 

A specific relationship between exogenous tryptophan and alkaloid level was found in P. roqueforti (Kozlovsky et ai, 1982 Reshetilova and Kozlovsky, 1985). This strain produces two types of alkaloids, clavines (festuclavine, isofumigaclavine A and isofumigaclavine B) (Figure 2) and diketopiperazines (roquefortine and 3,12-dihydroroquefortine) (Figure4) (Kozlovsky etal., 1979) that have both a common precursors—tryptophan and mevalonic acid. Exogenous tryptophan has different effect on these alkaloid types. Biosynthesis of diketopiperazines was enhanced by the precursor addition, whereas the production of clavines did not depend on the precursor and sometimes it was even inhibited by its addition (Reshetilova and Kozlovsky, 1985). 

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