Synthesis and structure elucidation of tailored metal-based intercalative agents derived from anthraldehyde & L-valine that show selective inhibition against triple-negative resistant breast cancer cells

Abstract

A series of tailored metal-based drug candidates having the formulation [M(L)₂(bpy)] where ‘L’ represents the Schiff base ligand derived from a condensation reaction of anthraldehyde & L-valine, bpy = 2,2′-bipyridine and M = Co(II), Ni(II) & Zn(II) 1–3, respectively, were prepared and thoroughly characterized by spectroscopic techniques and single crystal X-ray diffraction (in case of 1 and 2) studies. The anticancer therapeutic potency of 1–3 was evaluated by performing interaction studies with therapeutic targets, ct-DNA/tRNA by complementary spectroscopic {absorption, fluorescence titrations and circular dichroism} methods, cleavage activity with pBR322 plasmid DNA, and cytotoxic activity against resistant {MDA-MB-231, HeLa, MIA-PA-CA-2, & Hep-G2} cancer cells. The corroborative results of these experiments revealed i) strong intercalative binding mode with ct-DNA in the order Co(II) > Ni(II) > Zn(II) as determined by their binding constant and intrinsic K_b and K_sv values in the order as follows; 2.28 × 10⁴ > 2.03 × 10⁴ > 1.55 × 10⁴ (M⁻¹) and 4.45 × 10⁴ > 3.84 × 10⁴ > 2.93 × 10⁴ (M⁻¹), respectively, ii) efficient cleavage activity at the concentration of 1 $\mu$M, and 3 $\mu$M mediated by oxidative pathway in 1 and hydrolytic pathway in 2 and 3, iii) remarkably good therapeutic potency against tested cancer cells with GI₅₀ < 8 $\mu$M, exhibiting preferential selectivity against triple-negative resistant breast cancer cell line MDA-MB-231.