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

A suite of six metallacycles (1–6) was generated via coordination-driven
self-assembly using the three
dicarboxylate-bridged arene–Ru precursors [Ru2(μ-η4-OO∩OO)­(η6-p-iPrC6H4Me)2]­[CF3SO3]2; (OO∩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 (86–92%)
as triflate salts and characterized by proton (1H) and
carbon-13 (13C) 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.