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New Organometallic Ruthenium(II) Compounds Synergistically Show Cytotoxic, Antimetastatic and Antiangiogenic Activities for the Treatment of Metastatic Cancer
Author(s) -
Wang Yuchen,
Jin Jiahui,
Shu Liwei,
Li Tongyu,
Lu Siming,
Subarkhan Mohamed Kasim Mohamed,
Chen Chao,
Wang Hangxiang
Publication year - 2020
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202002970
Subject(s) - ruthenium , chemistry , cytotoxicity , cisplatin , in vivo , cancer research , stereochemistry , chorioallantoic membrane , in vitro , cancer , metastasis , ligand (biochemistry) , biochemistry , receptor , medicine , biology , chemotherapy , microbiology and biotechnology , catalysis
In this study, we newly designed and synthesized a small library of ten structurally related C,N‐cyclometalated ruthenium(II) complexes containing various pyridine‐functionalized NHC ligand and chelating bipyridyl ligands (e.g., 2,2′‐bipyridine, 5,5′‐dimethyl‐2,2′‐bipyridine, and 1,10‐phenanthroline (phen)). The complexes were well characterized by NMR, electrospray ionization‐mass spectrometry, and single‐crystal X‐ray structure analyses. Among the new ruthenium(II) derivatives, we identified that the complex Ru8 bearing bulky moieties (i.e., phen and pentamethyl benzene) had the most potent cytotoxicity against all tested cancer cell lines, generating dose‐ and cell line‐dependent IC 50 values at the range of 3.3–15.0 μ m . More significantly, Ru8 not only efficiently inhibited the metastasis process against invasion and migration of tumor cells but also exhibited potent antivascular effects by suppressing HUVEC cells migration and tube formation in vitro and blocking vessel generation in vivo (chicken chorioallantoic membrane model). In a metastatic A2780 tumor xenograft‐bearing mouse model, administration of Ru8 outperformed antimetastatic agent NAMI‐A and clinically approved cisplatin in terms of antitumor efficacy and inhibition of metastases to other organs. Overall, these data provided compelling evidence that the new cyclometalated ruthenium complex Ru8 is an attractive agent because of synergistically suppressing bulky tumors and metastasized tumor nudes. Therefore, the complex Ru8 deserves further investigations.