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.