title: 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.
abstract: To evaluate the biological preference of chiral drug candidates for molecular target DNA, new potential metal-based chemotherapeutic agents 1-3 (a and b) 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 1-3 (a and b) 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 1(a and b) 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.
authors.affiliation: Department of Chemistry, Aligarh Muslim University, Aligarh, Uttar Pradesh, India. farukh_arjmand@yahoo.co.in
authors.forename: Farukh
authors.initials: F
authors.lastname: Arjmand
authors.forename: Girish Chandra
authors.initials: GC
authors.lastname: Sharma
authors.forename: Mohd
authors.initials: M
authors.lastname: Muddassir
authors.forename: Sartaj
authors.initials: S
authors.lastname: Tabassum
mesh_terms: D000042:Absorption; D000818:Animals; D001593:Benzyl Compounds / Q000737:chemistry*; D002417:Cattle; D003300:Copper / Q000737:chemistry*; D004247:DNA / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004563:Electrochemistry; D006801:Humans; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D015203:Reproducibility of Results; D013057:Spectrum Analysis; D013237:Stereoisomerism; D013379:Substrate Specificity; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism
chemical_list: D001593:Benzyl Compounds; C561910:N,N-bis-(1-benzyl-2-ethoxyethane); D009942:Organometallic Compounds; D059005:Topoisomerase II Inhibitors; D003300:Copper; D004247:DNA; D004250:DNA Topoisomerases, Type II