Clavines as Antitumor Agents; 2^1,2,3. Natural 8-Hydroxymethyl-ergoline Type Clavines and their Derivatives

Abstract

The cytostatic potentials of 16 clavines were determined in the L5178y mouse lymphoma cell system: three of them are natural 8-hydroxymethylergoline type alkaloids (elymoclavine, lysergol, dihydrolysergol-I) and 13 are semisynthetic derivatives (O-acyl-; 1-alkyl-; 1-alkyl-O-acyl-; 1,O-dialkyl-; masked aldehydes). It is shown that in contrast to these alkaloids some of their derivatives are potent cytostatic agents: 1-propylelymoclavine (ED₅₀ cone.: 2.2 µM), 1-propylelymoclavine-O-butyrate (2.7 µM), 6-methyl-8β-(2′-oxo-cyclohexylidenemethyl)-ergoline-I (4.0 µM). O-Acyl derivatives without substitution at N-1 were almost inactive. The substitution of the hydrogen at N-1 of inactive clavines by an alkyl group with three carbon atoms led to very active compounds indicating that the nature of the substituent at N-1 is very important for cytostatic activity. Incorporation studies in the presence of 1-propylelymoclavine showed that this compound inhibits primarily DNA synthesis. Partial syntheses of new ergolines are described.