CONFORMATION OF CYCLOSPORIN IN DIFFERENT CRYSTAL FORMS. Michal Husk, Jan Ondrcek and Alexandr Jegorov, Department of Solid State Chemistry, Prague Institute of Chemical Technology, Technick 5, 166 28 Prague 6, Czech Republic, Galena Co., R & D., Branisovsk 31, 370 05 esk Budjovice, Czech Republic

Cyclosporin is a general name for the cyclic undecapeptides related to the structure of cyclosporin A: cyclo-[MeBmt-(-Abu-Sar-MeLeu-Val-MeLeu-Ala-D-Ala-MeLeu-MeLeu-MeVal], where MeBmt is (2S,3R,4R,6E)-3-hydroxy-4-methyl-2-methylamino-6-octenoic acid. Cyclosporin A has been successfully used as an immunosuppressant in the field of organ transplantation (Consupren⁽, Galena, Sandimmun⁽, Sandoz) and moreover some of its derivatives exhibit some potential for the treatment of multidrug resistance and even of AIDS. Despite the intensive investigations, the details of their mechanism of action still remains obscure. Since the solid state conformation of cyclosporin could be used as a starting point for molecular dynamic simulation, a study of two new cyclosporin crystal forms was undertaken.

Two new solid state modification of cyclosporin are reported. The first one is the structure of cyklosporin A arlasolve solvate ( a = 15.521(2), b=20.833(3), c=12.949(3) , = 100.21(1), P2₁, Z=2). The second one is the structure of cyclosporin H monohydrate (a = 12.338(1), b=18.964(1), c=11.111 , = 96.21(1), I2, Z=4) the degradation product of cyclosporin A having as [D-MeVal] instead of the original L-amino acid.

Conformation of the title compounds has been compared with 3 known solid state conformations of cyclosporin A, and 2 types of conformation of cyklosporin complexed either to cyclophilin or with cyclosporin complexed to the FAB fragment of an antibody.

The results lead to following conclusion: Cyclosporin has in solid state 4 different stable conformations, the first one occurs in cyclosporin A monohydrate, cyclosporin A dihydrate, and cyclosporin H, the second is common for thiocyclosporin and cyclosporin A arlasolv solvate, the third is typical for all complexes of cyclosporin with cyclophilin and the fourth one was found for the cyclosporin complex with the FAB fragment of an antibody.