DISTANCE GEOMETRY ANALYSIS OF THE N.M.R. EVIDENCE ON THE SOLUTION CONFORMATION OF BLEOMYCIN

Abstract

Bleomycin is a glycopeptide antibiotic with strong antineoplastic activity. Conformational constraints derived from NMR experiments, X-ray data and the known stereochemistry were used to investigate by the distance geometry method the range of allowed solution conformations for Cu(II):P-3A (a biosynthetic bleomycin precursor), Fe(II):bleomycin:CO, and Zn(II):bleomycin. The experimental data were self-consistent and lead to the following observations. Designation of the ligands and the dihedral angles available from vicinal coupling constants are not sufficient to define uniquely the geometry around the metal. When only 5 bleomycin ligands are invoked (e.g., Cu(II):P-3A or Fe(II):bleomycin:CO) there is considerable freedom in the allowed coordination scheme around the metal, but some regions of the molecule have well determined conformation. Introduction of a 6th bleomycin ligand, as in Zn(II):bleomycin, considerably constrains the conformational freedom of the groups coordinated to the Zn. The utility of the distance geometry approach for analysis of data and design of experiments is discussed.