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

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 > 1a > 1b,
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 (1O2) and superoxide anions (O2•–). 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 GI50 value of <1
μM. The results suggest that the l-enantiomeric complexes
are more avid binders toward the tRNA molecule and showed better cytotoxicity.