title: Effects of N-alkyl and ammonium groups on the hydrolytic cleavage of DNA with a Cu(II)TACH (1,3,5-triaminocyclohexane) complex. Speciation, kinetic, and DNA-binding studies for reaction mechanism.
abstract: cis,cis-1,3,5-Triaminocyclohexane (c-TACH), its N-alkyl-derivatives (alkyl = methyl, ethyl), and trans,cis-1,3,5-triaminocyclohexane (t-TACH) were prepared, and speciation and DNA cleaving property of Cu(II) complexes of these ligands were investigated. All of the complexes efficiently promote the hydrolytic cleavage of supercoiled plasmid DNA under physiological conditions without further additives. The DNA cleavage rate (V(obs)) trend at pH values between 8 and 9 is N-Me(3) = N-Et(1) < t-TACH < c-TACH < N-Et(2) < N-Et(3). At pH 7, the trend is c-TACH < N-Et(3) = N-Et(2) < N-Et(1) < N-Me(3) << t-TACH. The cleavage rate constants at 35 degrees C, for the c-TACH complex are 3 x 10(-1) h(-1) at pH 8.1 and 2 x 10(-1) h(-1) at pH 7.0 ([DNA] = 7 microM, [Cu(II)-complex] = 105 microM). The hydrolytically active species at pH > 8 is CuL(H(2)O)(OH)(+) in which L coordinates to Cu(II) as a tridentate ligand for all complexes except for t-TACH. The hydrolytically active species at pH 7 is CuLH(H(2)O)(3)(3+) or CuLH(H(2)O)(4)(3+) in which LH coordinates as bidentate ligand. DNA-binding constants of c-TACH and t-TACH complexes are presented and the effects of N-alkyl and ammonium groups are discussed in light of the proposed reaction mechanism.
authors.affiliation: Department of Material and Biological Sciences, Ibaraki University, 2-1-1 Bunkyo, Mito 310-8512, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Satoko
authors.initials: S
authors.lastname: Tobita
authors.forename: Michiyoshi
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Takuya
authors.initials: T
authors.lastname: Imajyo
authors.forename: Makoto
authors.initials: M
authors.lastname: Chikira
authors.forename: Morio
authors.initials: M
authors.lastname: Yashiro
authors.forename: Yuki
authors.initials: Y
authors.lastname: Fujii
mesh_terms: D000478:Alkylation; D000818:Animals; D002417:Cattle; D003300:Copper / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D003514:Cyclohexylamines / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D004247:DNA / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D004278:DNA, Superhelical / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D006868:Hydrolysis; D066298:In Vitro Techniques; D007700:Kinetics; D009942:Organometallic Compounds / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D011199:Potentiometry; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship
chemical_list: C472375:(1,3,5-triaminocyclohexane)copper(II); D003514:Cyclohexylamines; D004278:DNA, Superhelical; D009942:Organometallic Compounds; D000644:Quaternary Ammonium Compounds; D003300:Copper; D004247:DNA