Abstract
Chromomycin A3 (Chro) is capable of forming a stable dimeric complex via chelation with Ni(II), Fe(II) and Co(II). According to 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 dimeric Chro, including its DNA-binding affinity, DNA stabilization capacity, DNA cleavage activity, and the inhibition of transcription both in vitro and within cells. Kinetic analyses using surface plasmon resonance (SPR) showed that NiII(Chro)2 exhibited the highest K a with a value of 1.26×107 M−1, which is approximately 1.6- and 3.7-fold higher than the K a values obtained for CoII(Chro)2 and FeII(Chro)2, respectively. The Tm and ΔG values for the DNA duplex increased after the addition of drug complexes in the following order: NiII(Chro)2>CoII(Chro)2>FeII(Chro)2. In the DNA integrity assays, the DNA cleavage rate of CoII(Chro)2 (1.2×10−3 s−1) is higher than those of FeII(Chro)2 and NiII(Chro)2, which were calculated to be 1×10−4 and 3.1×10−4 s−1, respectively. Consistent with the SPR and UV melting results, NiII(Chro)2 possesses the highest inhibitory effect on in vitro transcription and c-myc transcription within cells compared to CoII(Chro)2 and FeII(Chro)2. By comparing the cytotoxicity among CoII(Chro)2, FeII(Chro)2, and NiII(Chro)2 to several cancer cell lines, our studies concluded that NiII(Chro)2 displayed more potential antitumor activities than CoII(Chro)2 and FeII(Chro)2 did due to its higher DNA-acting efficacy. Changes to the divalent metal ions in the dimeric Chro complexes have been correlated with improved anticancer profiles. The availability of new metal derivatives of Chro may introduce new possibilities for exploiting the unique properties of this class of compounds for therapeutic applications.
Highlights
Chromomycin A3 (Chro), a glycosidic metalloantibiotic, is a member of the aureolic family of drugs isolated from Streptomyces griseus [1,2,3]
In the absence of DNA binding, the circular dchroism (CD) spectra of the Chro monomer exhibited an obvious positive peak at 275 nm, and the inversion of the peak in the 250–300 nm region was observed during the formation of FeII(Chro)2, CoII(Chro)2, and NiII(Chro)2 in the presence of metal ions, with a concomitant decrease in the positive and negative peak intensities at 413 nm and 400 nm in the visible region, respectively (Figure 2A)
The results presented here clearly indicate that a strong interaction exists between Chro and these three divalent metal ions because the electronic transition of the Chro chromophore was changed, as a result of the coordination of the divalent metal ions with the oxygen atoms of each chromophore ring of Chro
Summary
Chromomycin A3 (Chro), a glycosidic metalloantibiotic, is a member of the aureolic family of drugs isolated from Streptomyces griseus [1,2,3]. This drug contains di- and trisaccharide moieties connected to a b-ketophenol chromophore via O-glycosidic bonds arranged in a 2,6 relationship around the anthracene ring, with the disaccharide at the 2 position and the trisaccharide attached at the 6 position (Figure 1A) [4]. Bianchi et al demonstrated that Chro is a powerful inducer of erythroid differentiation of K562 cells by binding to the human cglobin promoter and altering the pattern of protein binding to this promoter [9]
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