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.
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.
Kobayashi
Tohru
T
Department of Material and Biological Sciences, Ibaraki University, 2-1-1 Bunkyo, Mito 310-8512, Japan.
Tobita
Satoko
S
Kobayashi
Michiyoshi
M
Imajyo
Takuya
T
Chikira
Makoto
M
Yashiro
Morio
M
Fujii
Yuki
Y
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
C472375:(1,3,5-triaminocyclohexane)copper(II); D003514:Cyclohexylamines; D004278:DNA, Superhelical; D009942:Organometallic Compounds; D000644:Quaternary Ammonium Compounds; D003300:Copper; D004247:DNA