The Crucial Role of Divalent Metal Ions in the DNAActing Efficacy and Inhibition of the Transcription of Dimeric Chromomycin A3

摘要

Chromomycin A3 (Chro) is capable of forming a stable dimeric complex via chelation with Ni(II), Fe(II) and Co(II). Accordingto the circular dichroism study, the dimer conformations are significantly different among the Fe(II)-, Co(II)-, and Ni(II)-containing dimeric Chro complexes; however, the dimer conformations were preserved at high temperatures. Furthermore,we conducted a systematic study to determine the effects of these divalent metal ions on the DNA-acting efficacy of dimericChro, including its DNA-binding affinity, DNA stabilization capacity, DNA cleavage activity, and the inhibition of transcriptionboth in vitro and within cells. Kinetic analyses using surface plasmon resonance (SPR) showed that NiII(Chro)2 exhibited thehighest Ka with a value of 1.266107 M21, which is approximately 1.6- and 3.7-fold higher than the Ka values obtained forCoII(Chro)2 and FeII(Chro)2, respectively. The Tm and DG values for the DNA duplex increased after the addition of drugcomplexes in the following order: NiII(Chro)2.CoII(Chro)2.FeII(Chro)2. In the DNA integrity assays, the DNA cleavage rate ofCoII(Chro)2 (1.261023 s21) is higher than those of FeII(Chro)2 and NiII(Chro)2, which were calculated to be 161024 and3.161024 s21, respectively. Consistent with the SPR and UV melting results, NiII(Chro)2 possesses the highest inhibitoryeffect on in vitro transcription and c-myc transcription within cells compared to CoII(Chro)2 and FeII(Chro)2. By comparingthe cytotoxicity among CoII(Chro)2, FeII(Chro)2, and NiII(Chro)2 to several cancer cell lines, our studies concluded thatNiII(Chro)2 displayed more potential antitumor activities than CoII(Chro)2 and FeII(Chro)2 did due to its higher DNA-actingefficacy. Changes to the divalent metal ions in the dimeric Chro complexes have been correlated with improved anticancerprofiles. The availability of new metal derivatives of Chro may introduce new possibilities for exploiting the uniqueproperties of this class of compounds for therapeutic applications.