Synthesis and enantiopreferential DNA‐binding profile of late 3d transition metal R ‐ and S ‐enantiomeric complexes derived from N , N ‐bis‐(1‐benzyl‐2‐ethoxyethane): Validation of R ‐enantiomer of copper(II) complex as a human topoisomerase II inhibitor

To evaluate the biological preference of chiral drug candidates for molecular target DNA, new potential metal‐based chemotherapeutic agents 1 , 1a , 1b , 2 , 2a , 2b , 3 , 3a , 3b of late 3d transition metals Ni(II), Cu(II), and Zn(II), respectively, derived from ( R )‐ and ( S )‐2‐amino‐2‐phenylethanol with CH 2 CH 2 linker were synthesized and thoroughly characterized. Interaction studies of 1 , 1a , 1b , 2 , 2a , 2b , 3 , 3a , 3b with calf thymus DNA in Tris buffer were studied by electronic absorption titrations, luminescence titrations, cyclic voltammetry, and circular dichroism. The results reveal that the extent of DNA binding of R ‐enantiomer of copper 1a was highest in comparison to rest of the complexes via electrostatic interaction mode. The nuclease activity of 1a , 1b with supercoiled pBR322 DNA was further examined by gel electrophoresis, which reveals that complex 1a exhibits a remarkable DNA cleavage activity (concentration dependent) with pBR322DNA, and the cleavage activity of both enantiomers of complex 1 was significantly enhanced in the presence of activators. The activating efficiency follows the order Asc > H 2 O 2 > MPA for 1a , and reverse order was observed for 1b , because of the differences in enantioselectivity and conformation. Further, it was observed that cleavage reaction involves singlet oxygen species and superoxide radicals via oxidative cleavage mechanism. In addition , complex 1a exhibits significant inhibitory effects on the topoisomerase II (topo II) activity at a very low concentration ∼24 μM, which suggest that complex 1a is indeed catalytic inhibitor or (poison) of human topo II. Chirality 2011 © 2011 Wiley‐Liss, Inc.