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

Abstract

A suite of six metallacycles (16) was generated via coordination-driven self-assembly using the three dicarboxylate-bridged areneRu precursors [Ru-2(mu-eta(4)-OO boolean AND OO)(eta(6)-p-iPrC(6)H4Me)(2)][CF3SO3](2); (OO boolean AND OO = oxalate (A1), 2,5-dihydroxy-1,4-benzoquinonato (dobq) (A2), 5,8-dihydroxy-1,4-naphthoquinonato (donq) (A3); CF3SO3 = triflate) with one of two dipyridyl ligands (L1 and L2). The metallacycles were isolated in excellent yield (8692%) as triflate salts and characterized by proton (H-1) and carbon-13 (C-13) nuclear magnetic resonance (NMR) and electrospray ionizationmass 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.