Anticancer Activity and Autophagy Involvement of Self-Assembled Arene–Ruthenium Metallacycles

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A suite of six metallacycles ( 1 – 6 ) was generated via coordination-driven self-assembly using the three dicarboxylate-bridged arene–Ru precursors [Ru 2 (μ-η 4 -OO∩OO)(η 6 - p - i PrC 6 H 4 Me) 2 ][CF 3 SO 3 ] 2; (OO∩OO = oxalate ( A1 ), 2,5-dihydroxy-1,4-benzoquinonato (dobq) ( A2 ), 5,8-dihydroxy-1,4-naphthoquinonato (donq) ( A3 ); CF 3 SO 3 = triflate) with one of two dipyridyl ligands ( L1 and L2 ). The metallacycles were isolated in excellent yield (86–92%) as triflate salts and characterized by proton ( 1 H) and carbon-13 ( 13 C) nuclear magnetic resonance (NMR) and electrospray ionization–mass spectrometry (ESI-MS) to confirm their structural assignments. Single-crystal X-ray crystal analysis of 1 revealed that two L1 ligands bridged two A1 acceptors to form a rectangular architecture. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was conducted to evaluate the in vitro cytotoxicities relative to two chemotherapeutic agents: namely, cisplatin and doxorubicin. Metallacycles 3 and 6 potently inhibited the growth of HCT-15 human colon and AGS human gastric cancer cells. The hollow fiber (HF) assay was performed to investigate the in vivo antitumor activities of metallacycles 3 and 6 . Metallacycle 6 was more effective in inhibiting HCT-15 cells than metallacycle 3 in both in vitro and in vivo studies. Moreover, 3 and 6 induced autophagic activity in HCT-15 cells. These results suggested that the autophagic response elicited by metallacycles 3 and 6 could mediate the anticancer effects observed in human colorectal cancer cells.