Structure-activity studies of novel colchicine analogs

Sammanfattning: Colchicine, a well-known alkaloid isolated from Colchicum autumnale, interferes with microtubule growth and, therefore affects mitosis and other microtubule dependent functions. We have been interested in the structural requirements of colchicine for tubulin recognition. In particular our interests have been focused on the active colchicine conformation with respect to the pivot bond joining the A- and C- rings. The configuration of the pivot bond is aS and the dihedral angle is close to 54° in colchicine and most of the active analogs. The main objective of the work presented in this thesis was to synthesize and study novel colchicine analogs with systematic variations in the torsional angle between the A- and C-rings. One way to modify the dihedral angle of the pivot bond is to change the number of atoms in the B-ring. A number of colchicine analogs have been synthesized and studied by NMR, circular dichroism, X-ray crystallography and by molecular mechanics calculations. The first colchicine derivative with an eight membered B-ring obtained via a Beckmann reaction, is described and only one of the stable atropisomeric enantiomers arrests microtubule assembly. The results demonstrate that highly twisted, conformationally rigid colchicinoids retain tubulin-binding ability provided that they possess the same helicity as colchicine.