Enantiomeric Amino Acid Schiff Base Copper(II) Complexes as a New Class of RNA-Targeted Metallo-Intercalators Single X-ray Crystal Structural Details, Comparative in Vitro DNA/RNA Binding Profile, Cleavage, and Cytotoxicity

Abstract : Chiral enantiomeric amino acid Schiff base copper(II) complexes 1 and 2 (a and b) were synthesized and characterized by various spectroscopic techniques (Fourier transform infrared, UV-vis, electron paramagnetic resonance, electrospray ionization-mass spectrometry, and circular dichroism) and single X-ray crystal diffraction analyses. To understand the selectivity and enantiomeric behavior of the complexes, binding interaction with ct-DNA and tRNA biomolecules was investigated by widely employed optical and hydrodynamic techniques. The binding experiments demonstrated that complexes 1 and 2 (a and b) interact strongly via the intercalative mode with preferential binding toward the tRNA biomolecule compared to ct-DNA. Furthermore, the order of binding propensity was 2a > 2b > la > lb, implicating greater binding affinity of L-enantiomeric complexes, and complex 2a showed the highest binding propensity possessing a rigid aromatic group in the amino acid framework. Scanning electron microscopy analyses of complexes 1a and 2a revealed the formation of different morphologies with ct-DNA/tRNA molecules depending on the nature and extent of condensation induced by the complexes. The cleavage activities of complexes 1a and 2a showed a preferential oxidative cleavage mechanism toward the pBR322 plasmid DNA mediated by reactive oxygen species radical scavengers involving singlet oxygen (O-1(2)) and superoxide anions (O-2(center dot)-). The tRNA cleavage mechanism of complexes 1a and 2a revealed time- and concentration-dependent activities of these Schiff base Cu(II) complexes. In vitro cytotoxic activities of complexes 1 and 2 (a and b) revealed that among all, complex 2a showed the highest cytotoxicity, being selectively targeted toward the human breast cancer cell line (MCF-7) with a GI(50) value of <1 mu M. The results suggest that the L-enantiomeric complexes are more avid binders toward the tRNA molecule and showed better cytotoxicity.
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Submitted on : Thursday, June 6, 2019 - 4:20:44 PM
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Siffeen Zehra, Thierry Roisnel, Farukh Arjmand. Enantiomeric Amino Acid Schiff Base Copper(II) Complexes as a New Class of RNA-Targeted Metallo-Intercalators Single X-ray Crystal Structural Details, Comparative in Vitro DNA/RNA Binding Profile, Cleavage, and Cytotoxicity. ACS Omega, ACS Publications, 2019, 4 (4), pp.7691-7705. ⟨10.1021/acsomega.9b00131⟩. ⟨hal-02149779⟩

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