title: Lipophilicity-antiproliferative activity relationship study leads to the preparation of a ruthenium(II) arene complex with considerable in vitro cytotoxicity against cancer cells and a lower in vivo toxicity in zebrafish embryos than clinically approved cis-platin.
abstract: Ru(II)-arene complexes are attracting increasing attention due to their considerable antitumoral activity. However, it is difficult to clearly establish a direct relationship between their structure and antiproliferative activity, as substantial structural changes might not only affect their anticancer activity but also tightly control their activation site(s) and/or their biological target(s). Herein, we describe the synthesis and characterization of four ruthenium(II) arene complexes bearing bidentate N,O-donor Schiff-base ligands ([Ru(η6-benzene)(N-O)Cl]) that display a significantly distinct antiproliferative activity against cancer cells, despite their close structural similarity. Furthermore, we suggest there is a link between their respective antiproliferative activity and their lipophilicity, as the latter affects their ability to accumulate into cancer cells. This lipophilicity-cytotoxicity relationship was exploited to design another structurally related ruthenium complex with a much higher antiproliferative activity (IC50> 25.0 μM) against three different human cancer cell lines. Whereas this complex shows a slightly lower activity than that of clinically approved cis-platin against the same human cancer cell lines, it displays a lower toxicity in zebrafish (Danio rerio) embryos at concentrations up to 20 μM.
authors.affiliation: INRS - Institut Armand-Frappier, Université du Québec, 531 boul. des Prairies, Laval, Quebec, H7V 1B7, Canada.
authors.forename: MohammadMehdi
authors.initials: M
authors.lastname: Haghdoost
authors.affiliation: INRS - Institut Armand-Frappier, Université du Québec, 531 boul. des Prairies, Laval, Quebec, H7V 1B7, Canada.
authors.forename: Golara
authors.initials: G
authors.lastname: Golbaghi
authors.affiliation: INRS - Institut Armand-Frappier, Université du Québec, 531 boul. des Prairies, Laval, Quebec, H7V 1B7, Canada.
authors.forename: Myriam
authors.initials: M
authors.lastname: Létourneau
authors.affiliation: INRS - Institut Armand-Frappier, Université du Québec, 531 boul. des Prairies, Laval, Quebec, H7V 1B7, Canada.
authors.forename: Shunmoogum A
authors.initials: SA
authors.lastname: Patten
authors.affiliation: INRS - Institut Armand-Frappier, Université du Québec, 531 boul. des Prairies, Laval, Quebec, H7V 1B7, Canada. Electronic address: annie.castonguay@iaf.inrs.ca.
authors.forename: Annie
authors.initials: A
authors.lastname: Castonguay
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D009589:Nitrogen Oxides; D009942:Organometallic Compounds / Q000737:chemistry* / Q000494:pharmacology; D012428:Ruthenium / Q000737:chemistry*; D013329:Structure-Activity Relationship; D015027:Zebrafish / Q000196:embryology
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D009589:Nitrogen Oxides; D009942:Organometallic Compounds; D012428:Ruthenium; D002945:Cisplatin
keywords: Antiproliferative activity; Cancer; In vivo toxicity; Lipophilicity; Ruthenium complexes; Zebrafish