Enhanced Cytotoxicity of Half-Sandwich Ruthenium(II) Complex Containing Nitro-Substituted...

A series of organometallic ruthenium(II) arene complexes of the type [(η⁶-p-cymene)-Ru(L)Cl] (1-5), where L represents N,O-bidentate ligands such as 2-(1-phenylimidazo[1,5-α]pyridin-3-yl)-phenol (L1) and methyl (L2), methoxy (L3), fluoro (L4), and nitro (L5) substituted 2-(1-phenylimidazo[1,5-α]pyridin-3-yl)-phenol have been synthesized and characterized systematically. The geometry of complex 5 was confirmed through single-crystal XRD, revealing a typical pseudo-octahedral piano-stool configuration. The solution study demonstrates that Ru-Cl hydrolysis is feasible in an aqueous medium, and all the complexes exhibit a hydrolysis mechanism similar to that of cisplatin at both 4 mM and 100 mM NaCl concentrations. In DFT study, interestingly, the nitro-substituted ruthenium(II)-p-cymene complex (I_NO2, 5) shows slightly improved interaction with guanine. In vitro investigations have shown that ruthenium(II) complexes (1-5) exhibit growth-inhibitory effects against various cancer cell lines, including those of the breast (MDA-MB-231), lung (A549, NCI-H460), ovary (PA-1), and colon (HCT-116), compared to the uncoordinated ligand and metal precursor. These complexes have minimal impact on noncancerous lung cells (L132). Among them, complex 5 demonstrates the most potent antiproliferative activity, particularly in hormone-independent triple-negative breast cancer (TNBC) cells (MDA-MB-231; IC₅₀ = 14.85 μM; SI = 36.74) and non-small cell lung cancer (NSCLC) cells (A549; IC₅₀ = 23.76 μM; SI = 22.96), both of which are among the most common and clinically challenging cancer types to treat. Complex 5 induces cell cycle arrest at the G1 phase, promotes cell death, and reduces the metastatic potential of both breast and lung cancer cells. Notably, complex 5 exhibits greater efficacy in TNBC cells than NSCLC cells. Mechanistic studies reveal that complex 5 selectively inhibits the AKT1/mTOR signaling pathway in both breast and lung cancer cells, without affecting normal cells. Collectively, these findings suggest that complex 5 could be a promising candidate for the treatment of breast and lung cancers through inhibition of the AKT1/mTOR pathway. At the same time, the possibility that the cytotoxicity of these complexes is also mediated through DNA binding or other mechanisms cannot be excluded. Further investigations are warranted to elucidate the selectivity of these complexes toward specific cancer types.