New robust bleomycin analogues: Synthesis, spectroscopy, and crystal structures of the copper(II) complexes

Two new bleomycin analogues, 2-[((2-(Pimidazolyl)ethyl)amino)carbonyl methyl]pyridine = L-3 and 2-[((2-(4-imidazolyl)ethyl)amino)carbonyl]-6-[((2-amino-1,1,2-trimethylprapyl)amino)methyl]pyridine =L-4, were synthesized in order to create air-stable ligands of their Cu-I (and Fe-II) complexes. The protonation constants (log K-n) of the ligands at 25 degrees C and I = 0.1 M NaNO3 were 9.9, 6.9, and 5.2 for L-3 and 10.0, 6.7, and 3.9 for L-4. The complexation of the triprotonated L-3 and L-4. with Cu-II started at pH < 5 to yield 4-coordinate [Cu-II(H-1L) . H+](2+) complexes, 4 and 6, respectively, followed by formation of square-pyramidal [Cu-II(H-1L)](+) complexes, 5 and 7, with pK(a) values of 5.6 for 5 and 5.9 for 7. The complexation constants, log K-Cu(H-IL,)II were 8.9 for [Cu-II(H-1L3)](+), 5, and 8.6 for [Cu-II(H-1L4)](+), 7, respectively. The structures of [Cu-II(H-1L3)1CrO(4) (5 . ClO4) and [Cu-II(H-1L4)]BF4 (7 . BF4) were determined by X-ray crystallography. Crystal data for 5 . ClO4: monoclinic, space group P2(1)/n (No. 14), a = 13.978(6) Angstrom, b = 8.103(3) Angstrom,c = 18.037(5) Angstrom, beta = 98.61(3)degrees, V = 2019(1) Angstrom(3), Z = 4, R = 0.053, and R-w = 0.044 for 2996 [I > 3 sigma(I)] reflections. Crystal data for 7 BF4: monoclinic, space group P21/n (No. 14), a = 16.092 (4) Angstrom, b = 7.974(4) Angstrom, c = 16.819(2) Angstrom, beta = 99.64(1)degrees, V = 2127(1) Angstrom(3), Z = 4, R = 0.040, and R-w,= 0.025 for 1633 [I > 4 sigma(I)] reflections. The coordination geometry arormd the copper was a distorted square-pyramid in 5, while that of 7 was the intermediate between a trigonal-bipyramid and a square-pyramid. The distortion is influenced strongly by the number of the methyl group. The EPR spectral data for both copper(II) complexes were consistent with the retention of the solid-state structure in frozen DMF/MeOH (1:1) solution at 77 K. The visible absorption spectra of 10% DMF/aqueous solutions (pH 9.5) of 5 and 7 at I = 0.1 M NaNO3 showed absorption maxima at 646 nm with a shoulder at ca. 900 nm for 5 and at 658 and 888 ma for 7. The red-shift: of 7 by ca. 12 nm relative to 5 reflects the distortion toward the trigonal-bipyramidal geometry of 7 in solutions. Both complexes displayed irreversible redox behavior in DMF at I = 0.1 M tetra(n-butyl)ammonium tetrafluoroborate. The anodic and cathodic peak potentials obtained by cyclic voltammetry for 5 and 7 were -0.14 and -0.76 V for 5 and -0.17 and -0.80 for 7 vs Ag/AgCl. The cathodic potentials of copper(II) complexes were shifted toward the anodic direction by ca; 20-60mV compared to the nonsubstituted 5-coordinate, [Cu-II(H-1L1)](+) complex, 16 (-0.82 V vs Ag/AgCl). The Cu-I complexes (9 and 10) are air-oxidized to the corresponding (CI)-I-uI complexes, 5 and 7, respectively.