STRUCTURAL PARAMETERS OF ERGOT ALKALOIDS

Bohumil Kratochvíl¹, Jan Cejka¹, Michal Hušák¹, Svetlana Pakhomova¹, Jioí Had², Alexandr Jegorov³

¹Department of Solid State Chemistry, Prague Institute of Chemical Technology, Technická 5, CZ-166 28 Praha 6, Czech Republic, kratochb@vscht.cz
²Central Laboratories, Prague Institute of Chemical Technology, Technická 5, CZ-166 28 Praha 6, Czech Republic
³Galena Co., Research Unit, Branišovská 31, CZ-370 05 Ceské Budijovice, Czech Republic

Keywords: Ergot alkaloids, Crystal structure determination, Structural parameters, Conformation, Polymorphism, Phase analysis, Solvatation, Biologically active/inactive form

The systematic study of polymorphism, solvatation and structural differences of 33 biologically active and inactive ergot alkaloids was done (20 papers have been published, see review in [1]). All main types of natural and semisynthetic derivatives both of pharmaceutically used and new structures were included.

The structure and absolute chirality of new isolated alkaloids: ergogaline, ergoladinine and 8a-hydroxy-a-ergokryptine have been established. The presence of new unusual natural amino acid S,S-homoisoleucine in ergogaline has been confirmed. The discovery of sulphur containing alkaloid ergoladinine among the ergopeptines is of a major importance. Introduction of methionine into the tripeptide moiety of ergoladinine may indicate additional interactions with a receptor binding site.

Ergot alkaloids have considerable tendency to form solvates, for example terguride was crystallized as anhydrous form, monohydrate, twothird hydrate, dihydrate, methanol solvate and ethanol solvate. The transformation terguride methanol solvate-terguride monohydrate was studied. Solid polymorphism also occurs in ergot alkaloids very frequently. The structural comparison of nicergoline forms I and II was made and phase analysis of nicergoline binary mixture form I/form II was studied.

Pharmacological profiles of ergot alkaloids are complicated, minor chemical alternations surprisingly produce great changes in their biological activity. From comparison of conformational and other structural parameters of studied ergot alkaloids followed that the most important factors responsible for biological activity are: stereochemistry at all chiral centres, conformation of the ergoline or ergolene D-ring and flexibility of side chains. The absolute configuration of the proline G-ring must also be taken into consideration for ergopeptines.

Among eight possible isomers of terguride, the only (5R,8S,10R)-form is used as pharmaceutical formulation Mysalfon® (terguride hydrogen maleate monohydrate). Absolute structures of terguride forms (5R,8S,10R) and (5R,8S,10S) were compared.

The inversion of L-proline (G-ring in ergocristine) to D-proline (G-ring in ergocristam) as well as epimerization of natural ergopeptines at the C8 carbon (ergoladinine, -inine series) leads to inactive compounds. Inactive ergoladinine posseses configuration 8a(8S) while active ergopeptines have 8b(8R) chirality. For inactive alkaloids (ergoladinine and ergocristam) carbonyl oxygen O1 is oriented in the direction of C5 (D-ring) while active ergopeptines have the opposite orientation.

1. M.Hušák, B.Kratochvíl, P.Sedmera, V.Havlícek, H.Votavová, L.Cvak, P.Bulej, A.Jegorov, Collect. Czech. Chem. Commun. 63 (1998) 425-433.