New Robust Bleomycin Analogues: Synthesis, Spectroscopy, and Crystal Structures of the Copper(II) Complexes

Two new bleomycin analogues, 2-[((2-(4-imidazolyl)ethyl)amino)carbonyl]-6-[((2-amino-2-methylpropyl)amino)methyl]pyridine = L(3)() and 2-[((2-(4-imidazolyl)ethyl)amino)carbonyl]-6-[((2-amino-1,1,2-trimethylpropyl)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 NaNO(3) 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(-)(1)L).H(+)](2+) complexes, 4 and 6, respectively, followed by formation of square-pyramidal [Cu(II)(H(-)(1)L)](+) complexes, 5 and 7, with pK(a) values of 5.6 for 5 and 5.9 for 7. The complexation constants, log K(Cu)()II(H)()-1(L), were 8.9 for [Cu(II)(H(-)(1)L(3))](+), 5, and 8.6 for [Cu(II)(H(-)(1)L(4))](+), 7, respectively. The structures of [Cu(II)(H(-)(1)L(3))]ClO(4) (5.ClO(4)) and [Cu(II)(H(-)(1)L(4))]BF(4) (7.BF(4)) were determined by X-ray crystallography. Crystal data for 5.ClO(4): monoclinic, space group P2(1)/n (No. 14), a = 13.978(6) Å, b = 8.103(3) Å, c = 18.037(5) Å, beta = 98.61(3) degrees, V = 2019(1) Å(3), Z = 4, R = 0.053, and R(w) = 0.044 for 2996 [I > 3sigma(I)] reflections. Crystal data for 7.BF(4): monoclinic, space group P2(1)/n (No. 14), a = 16.092 (4) Å, b = 7.974(4) Å, c = 16.819(2) Å, beta = 99.64(1) degrees, V = 2127(1) Å(3), Z = 4, R = 0.040, and R(w) = 0.025 for 1633 [I > 4sigma(I)] reflections. The coordination geometry around 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 NaNO(3) showed absorption maxima at 646 nm with a shoulder at ca. 900 nm for 5 and at 658 and 888 nm 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 solution. 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. 20-60 mV compared to the nonsubstituted 5-coordinate, [Cu(II)(H(-)(1)L(1))](+) complex, 16 (-0.82 V vs Ag/AgCl). The Cu(I) complexes (9and 10) are air-oxidized to the corresponding Cu(II) complexes, 5 and 7, respectively.