Ergoline nucleus

Two major families of compounds that incorporate the tetracyclic ergoline nucleus may be identified the amine alkaloids and the peptide alkaloids (Table 16-6). Drugs of therapeutic and toxicologic importance are found in both groups. 

The biosynthetic pathway to the ergoline nucleus proceeds through 4-dimethylallyl tryptophan (4-DMAT), chanoclavine-I, agroclavine, and lysergic acid. Two cis, trans isomerizations occur one before chanocla-vine-I and the other before agroclavine, as shown by experiments with [2- C]-mevalonic acid and [Z-CH3]-4-DMAT (Fig. 36). The peptide unit is derived from a combination of three amino acids, one of which is always proline. Several genera in the plant family Convolvulaceae Rivea, Ipomoea, etc.) also produce ergot alkaloids. 

Ogunlana, E.O., Wilson, B.J., Tylei V.E. and Ramstad, E. (1970) Biosynthesis of ergot alkaloids. Enzymatic closure of ring D of the ergoline nucleus. /. Chem. Soc. Chem. Commun., 775-776. 

For the development of clavines as potential antitumor agents four main aims were of particular importance (1) Variations of the ergoline nucleus and structure-activity relationship studies in order to find compounds with increased cytostatic potency in vitro. (2) Development of active compounds with enhanced metabolic stability since ergolines usually are metabolized very quickly in vivo (pronounced first pass effect). (3) Dissociation between antineoplastic and mutagenic activities presumed the latter is not the mechanism of action for the first. (4) Decrease of their affinity for neurotransmitter receptors mentioned above on the assumption that the... 

As far as the biosynthesis is concerned it was soon established that the indole nucleus is derived from the amino acid tryptophan. It was much more difficult to determine the origin of the residual C skeleton but it has been found in recent years that it is furnished by mevalonate or iso-pentenyl pyrophosphate. Thus, in the ergoline alkaloids the indole nucleus is linked with a 5 C unit derived from terpenoid metabolism. 

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