ÉTUDES ON CONFORMATION OF CYCLOSPORIN A BACKBONE
Svetlana Pakhomova1, Alexandr Jegorov2, Michal Hušák1, Bohumil Kratochvíl1, Petr Bulej3 and Ladislav Cvak3
1Department of
Solid State Chemistry, Prague Institute of Chemical Technology,
Technická 5, 166 28 Prague 6, Czech Republic; e-mail: pachomos@vscht.cz
2Galena Co.,
Research Unit, Branišovská 31, 370 05 Eeské Budijovice, Czech
Republic 3Galena Co., R.& D., 747 70
Opava-Komárov, Czech Republic
Keywords: Cyclosporin A, Crystal structure determination, Conformation
Cyclosporin A is a cyclic undecapeptide of the structure 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. It is nowadays widely used as immunosuppressivum for organ transplantations and for treatment of autoimmune diseases (Galena a.s., Consupren®). X-ray crystal structural studies revealed that cyclosporin A crystallizes in three structural types: tetragonal P41, orthorhombic P212121 and monoclinic P21, all of which have nearly identical conformation of the cyclopeptide backbone [1]. The similar structure also applies for some related cyclosporins [2] which indicates that the conformation is highly conserved and apparently stabilized by hydrogen bond network. Hence, we decided to block one OH group by an acetyl group and subsequently to introduce one atom of bromine expecting that this rather harsh intervention into the structure should affect the conformation and packing of cyclosporin. In contrast to any expectation, neither the acetylation nor the subsequent bromination of cyclosporin A affects its conformation and packing in the solid state. Both compounds are isomorphous and crystallize in the orthorhombic space group P212121 with a = 12.936(2) A , b = 15.590(2) A, c = 36.280(3) A, for [O-acetyl-MeBmt1]-cyclosporin A, and a = 12.916(3) A, b =15.675(4) A, c =36.715(7) A, for [O-acetyl-(-w-bromo-MeBmt1]-cyclosporin A.