Coordination Chemistry of Co(II)-Bleomycin:  Its Investigation through NMR and Molecular Dynamics^,

Abstract

Previous studies on the coordination chemistry of Co-bleomycin have suggested the secondary amine in beta-aminoalanine, the N5 and N1 nitrogens in the pyrimidine and imidazole rings, respectively, and the amide nitrogen in beta-hydroxyhistidine as equatorial ligands to the cobalt ion. The primary amine in beta-aminoalanine and the carbamoyl group of the mannose have been proposed alternatively as possible axial ligands. The first coordination sphere of Co(II) in Co(II)BLM has been investigated in the present study through the use of NMR and molecular dynamics calculations. The data collected from the NMR experiments are in agreement with the equatorial ligands previously proposed, and also support the participation of the primary amine as an axial ligand. The paramagnetic shifts of the gulose and mannose protons could suggest the latter as a second axial ligand. This possibility was investigated by way of molecular dynamics, with distance restraints derived from the relaxation times measured through NMR. The molecular dynamics results indicate that the most favorable structure is six-coordinate, with the primary amine and either the carbamoyl oxygen or a solvent molecule occupying the axial sites. The analysis of the structures previously derived for HOO-Co(III)-bleomycin and HOO-Co(III)-pepleomycin led us to propose the six-coordinate structure with only endogenous ligands, as the one held in solution by the Co(II) derivative of bleomycin.

Possible structural role of the disaccharide unit in Fe-bleomycin before and after oxygen activation

“…We have previously modelled the three-dimensional structures of Co(II) and Fe(II) bound BLM through NMR and molecular dynamics. 18,19 The results of this modelling work indicated that the most favourable structures for the aforementioned metalloBLMs is six coordinated, with the primary amine and either the carbamoyl group in the mannose (M) moiety or a solvent molecule occupying the axial sites. Our results bolster the arguments offered by Loeb et al 17 in their spectroscopic investigation of the metal ligation of the ferrous active site of BLM through magnetic CD (MCD).…”

“…[6][7][8][9][10] The overall structure of this agent can be thought of as containing four distinct regions ( Figure 1): the metalbinding domain, which is responsible for metal binding, 11,12 oxygen activation 8,11,13,14 and site-selective DNA cleavage; 12,15 the peptide linker; the DNA binding domain, containing a bithiazole moiety, which provides the majority of the DNA binding affinity, 7,16 and the disaccharide moiety, which may influence metal ion binding. 12,[17][18][19][20][21][22][23][24] With the aim of establishing structure-function correlations, much research has been devoted to the elucidation of the three-dimensional structures of some metallo-BLMs. 25 The results of these studies have led to the general agreement that the secondary amine of b-aminoalanine (A) segment, the pyrimidinylpropionamide (P) and imidazole rings, and the amide nitrogen in b-hydroxyhistidine (H) are the equatorial ligands to the metal centers in most of the metal-BLM adducts studied to date.…”

Preparation, Structure Determination and Cytotoxicity of the PdII·Bleomycin A2 Complex

“…In models I and II they were placed at opposite sides of the coordination plane, whereas in model III they both share the same side. Models I and II were based on the coordinates of the NMR structure of Co II ·bleomycin A2 (PDB code 1DEY), [41] while model III was based on the X-ray crystal structure of Cu II ·bleomycin A2 (PDB code 1JIF). [16] Scheme 2.…”

“…Other direct structural studies on metallo-bleomycins have been performed with manganese, [26Ϫ28] ruthenium, [29,30] vanadyl, [31,32] zinc, [33Ϫ36] cadmium, [37] nickel, [38,39] calcium and trivalent lanthanides, [40] as well as the paramagnetic Co II ·bleomycin complex. [41,42] In view of the fact that bleomycins are often administered in combination with cisplatin [cis-PtCl 2 (NH 3 ) 2 ] for the treatment of malignant tumors, [43] Garnier-Suillerot and Albertini have carried out an investigation on the interaction between the two compounds. [44] Apart from cisplatin, cis-PdCl 2 (NH 3 ) 2 , PdCl 2 (ethylenediamine) and PdCl 4…”

NMR and Molecular Modelling Studies on the Solution Structure of the InIII−Bleomycin A2 Complex

“…[18] On the other hand, some NMR studies have introduced a controversy regarding the coordination of the M carbamoyl group. [19,26,31,32] Recent conformational analysis of all the binding geometries of Co III ϪBLMs has been used to explore the configurations available in the proposed binding geometries. [34,35] A large number of radioactive metal ion complexes of BLM have been prepared and tested as tumour imaging agents.…”