Synthesis, Structure and Cytotoxicity of N,N and N,O‐Coordinated RuII Complexes of 3‐Aminobenzoate Schiff Bases against Triple‐negative Breast Cancer

Abstract

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 , 6 ) exhibit arrest in the G2/M phase while the N,O coordinated 8 , showed arrest in the G0/G1 phase.