Synthesis, Structure and Cytotoxicity of N,N and N,O-Coordinated Ru II Complexes of 3-Aminobenzoate Schiff Bases against Triple-negative Breast Cancer.

Half-sandwich Ru ^II complexes, [(YZ)Ru ^II (η ⁶ -arene)(X)]+, (YZ=chelating bidentate ligand, X=halide), with N,N and N,O coordination (1-9) show significant antiproliferative activity against the metastatic triple-negative breast carcinoma (MDA-MB-231). 3-aminobenzoic acid or its methyl ester is used in all the ligands while varying the aldehyde for N,N and N,O coordination. In the N,N coordinated complex the coordinated halide(X) is varied for enhancing stability in solution (X=Cl, I). Rapid aquation and halide exchange of the pyridine analogues, 2 and 3, in solution are a major bane towards their antiproliferative activity. Presence of free -COOH group (1 and 4) make complexes hydrophilic and reduces toxicity. The imidazolyl 3-aminobenzoate based N,N coordinated 5 and 6 display better solution stability and efficient antiproliferative activity (IC ₅₀ ca. 2.3-2.5 μM) compared to the pyridine based 2 and 3 (IC ₅₀ >100 μM) or the N,O coordinated complexes (7-9) (IC ₅₀ ca. 7-10 μM). The iodido coordinated, 6, is resistant towards aquation and halide exchange. The N,O coordinated 7-9 underwent instantaneous aquation at pH 7.4 generating monoaquated complexes stable for at least 6 h. Complexes 5 and 6, bind to 9-ethylguanine (9-EtG) showing propensity to interact with DNA bases. The complexes may kill via apoptosis as displayed from the study of 8. The change in coordination mode and the aldehyde affected the solution stability, antiproliferative activity and mechanistic pathways. The N,N coordinated (5 and 6) exhibit arrest in the G2/M phase while the N,O coordinated 8 showed arrest in the G0/G1 phase.
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